Abstract

Inappropriate activation of intrarenal renin–angiotensin system (RAS) may contribute to the pathogenesis of cardio-renal syndrome (CRS). We aimed to examine the cross-sectional associations of urinary angiotensinogen (AGT) excretion, a biomarker of intrarenal RAS activity, with central (aortic) and renal hemodynamic parameters in middle-aged and older adults, including patients with chronic kidney disease. Aortic and renal hemodynamic parameters were measured using applanation tonometry and duplex ultrasonography in 282 participants. Urinary AGT, liver-type fatty acid-binding protein (L-FABP), and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured for each participant. Multiple linear regression analyses demonstrated that urinary AGT levels were associated with aortic blood pressures, pulsatile measures of renal blood flow, plasma NT-proBNP and urinary L-FABP levels after adjusting for potential covariates, including age, sex, body mass index, estimated glomerular filtration rate (GFR), and medication use. Additionally, when classified based on GFR stages and urinary AGT levels, plasma NT-proBNP and urinary L-FABP levels increased in participants with lower GFR and higher AGT groups. Our findings suggest that urinary AGT excretion is a shared determinant of central (aortic) and renal hemodynamics in middle-aged and older adults, providing clinical evidence for the potential role of intrarenal RAS activity in the development of CRS.

PURPOSE: Curcumin, a major component of turmeric, has anti-inflammatory and antioxidative properties, which are associated with protective effects against muscle damage. This study examined the effects of dietary curcumin on inflammation and muscle damage in female competitive soccer players. METHODS: A single-blinded, placebo-controlled, nonrandomized, crossover pilot study was conducted. Six competitive female soccer players (20.0 ± 2.0 yearsold) who participated in a 2-week preseason training program were assigned to two conditions: placebo and curcumin. The participants ingested a placebo or curcumin dosage (270 mg/day) during 2 weeks of preseason training, with 1 week of washout. Fasting blood samples were collected under resting conditions before (day 0) and after (day 15) the training period to examine changes in the concentration of interleukin 6 (IL-6), an inflammatory marker, and indices reflective of muscle damage. RESULTS: Curcumin decreased the concentration of IL-6 released (mean decrease, -30.2 ± 28.1%), whereas no decrease was observed in the placebo condition (13.4 ± 17.4%). Changes in plasma IL-6 concentrations were significantly greater in the curcumin condition than in the placebo condition (p < 0.05). However, curcumin supplementation had no significant effects on muscle damage indices. CONCLUSION: The present study shows that curcumin supplementation could attenuate inflammation, as indicated by IL-6 concentrations, in competitive female soccer players during the training period.

BACKGROUND: Recent clinical studies have indicated that poor trunk flexibility is associated with arterial stiffness in the aged. Arterial stiffness leads to elevated renal flow pulsatility, which accelerates age-related renal dysfunction and damages. However, data indicating the potential link between flexibility fitness and renal flow pulsatility are lacking. This study examined the cross-sectional association between trunk flexibility and renal flow pulsatility in middle-aged and older adults. METHODS: A total of 175 middle-aged and older adults (aged 63 ± 9 years) were included in this study. Sit-and-reach tests (SRT) were performed to assess their trunk flexibility. Using a Doppler ultrasound, renal pulsatility index (PI) and resistive index (RI) were measured as parameters of renal flow pulsatility. RESULTS: The study found that, in middle-aged and older adults, the SRT score was an independent determinant of renal PI (β = -0.134, P = 0.027) and RI (β = -0.135, P = 0.027). In the one-way analysis of covariance (ANCOVA), the renal PI and RI in the older group with a lower SRT score were found to be significantly higher than those in the middle-aged group. CONCLUSIONS: Trunk flexibility is an independent determinant of renal flow pulsatility in middle-aged and older adults.

Introduction

Aerobic exercise training has been shown to improve microstructural organization of the corpus callosum (CC); however, evidence of this topographic effect is limited.

Purpose

To compare the CC microstructural organization between endurance athletes and sedentary adults using a white-matter fiber tractography approach.

Materials and methods

Diffusion tensor imaging (DTI) and T₁-weighted structural data were collected from 15 male young endurance athletes and 16 age- and sex-matched sedentary adults. DTI data were analyzed with a global probabilistic tractography method based on neighborhood anatomical information. Fractional anisotropy (FA) and mean, radial (RD), and axial diffusivities were measured in the eight CC tracts: rostrum, genu, splenium, and body’s prefrontal, premotor, central, parietal, and temporal tracts. Cortical thickness of the CC tract endpoints and the CC tract length and volume were also measured. Physical activity level was assessed by metabolic equivalents (METs).

Results

The athlete group had an average VO₂max of 69.5 ± 3.1 ml/kg/min, which is above 90%ile according to the American College of Sports Medicine guideline. Compared with the sedentary group, the athlete group had higher FA in the CC body’s premotor and parietal tracts and the CC splenium. These tracts showed lower RD in the athlete compared with sedentary group. The voxelwise analysis confirmed that the athlete group had higher FA in the CC and other white matter regions than the sedentary group, including the corona radiata, internal capsule, and superior longitudinal fasciculus. Cortical thickness of the CC tract endpoints and the CC tract lengths and volumes were similar between the two groups. Physical activity levels were positively correlated with FA in the CC body’s parietal (r = 0.486, p = 0.006) and temporal (r = 0.425, p = 0.017) tracts and the CC splenium (r = 0.408, p = 0.023).

Conclusion

Young endurance athletes have higher microstructural organization of the CC tracts connected the sensorimotor and visual cortices than the age- and sex-matched sedentary adults.

BACKGROUND AND STUDY PURPOSE: Fibroblast growth factor-21 (FGF21) is a liver-derived hormone that lowers blood glucose. Although aerobic exercise training also lowers blood glucose, its effect on circulating FGF21levels remains obscure. This study aimed to examine the effect of aerobic exercise training on serum FGF21 levels in overweight and obese men. METHODS: A total of 14 overweight/obese men were included in the analyses. Participants attended supervised aerobic exercise training for 12 weeks (three times per week) and completed the standard oral glucose tolerance test pre- and post-exercise training. Plasma glucose, serum insulin, and serum FGF21 levels were measured at fasting and 60 and 120 min after glucose loading. RESULTS: The exercise training reduced plasma glucose and serum FGF21 levels during glucose loading (p < 0.05). The change in the area under the curve of plasma glucose was positively correlated with that in the area under the curve of serum FGF21 (rs = 0.569, p = 0.034). CONCLUSION: Lowering postprandial circulating FGF21 levels may be associated with the improved glucose tolerance induced by habitual aerobic exercise in overweight and obese men.

Excess activation of circulating xanthine oxidoreductase (XOR) may contribute to the pathogenesis of widespread remote organ injury, including kidney injury. The purpose of this study was to determine the acute impact of marathon running on plasma XOR activity and to examine whether plasma XOR activity is associated with marathon-induced elevations in biomarkers of acute kidney injury (AKI). Twenty-three young men (aged 20-25 years) who participated in the 38^th Tsukuba Marathon were included. Blood and urine samples were collected before, immediately, 2 h (only blood sample), and 24 h after a full marathon run. Plasma XOR activity was evaluated using a highly sensitive assay utilizing a combination of [¹³C₂,¹⁵N₂] xanthine and liquid chromatography-triple quadrupole mass spectrometry. The levels of several AKI biomarkers, such as serum creatinine and urinary liver-type fatty acid-binding protein (L-FABP) were measured in each participant. Marathon running caused a transient elevation in plasma XOR activity and levels of purine degradation products (hypoxanthine, xanthine, and uric acid) as well as serum creatinine, urinary albumin, and urinary L-FABP levels. Immediately after the marathon, individual relative changes in plasma XOR activity were independently correlated with corresponding changes in serum creatinine and urinary L-FABP levels. In addition, the magnitude of marathon-induced elevation in plasma XOR activity and levels of purine degradation products were higher in individuals who developed AKI. These findings collectively suggest that marathon running substantially influences the purine metabolism pathway including XOR activity. Moreover, activated circulating XOR can be partly associated with elevated biomarkers of AKI after marathon running.

PURPOSE: This study investigated the effects of lung volume and trigeminal nerve stimulation (TS) on diving responses in breath-hold divers (BHDs) and non-divers (NDs). METHODS: Eight BHDs and nine NDs performed four breath-hold trials at different lung volumes, with or without TS, and one trial of TS. Haemodynamic parameters and electrocardiograms were measured for each trial. RESULTS: During the TS trial, the total peripheral resistance increased more in BHDs. Breath-hold performed at total lung capacity showed a more pronounced decrease in stroke volume and cardiac output in BHDs. The decrease in heart rate and increase in total peripheral resistance were more pronounced in BHDs when breath-holding was performed with TS. CONCLUSION: The more pronounced diving response in BHDs was attributed to the greater increase in total peripheral resistance caused by TS. Furthermore, the lower stroke volume and cardiac output in BH performed at total lung capacity could also cause a more pronounced diving response in BHDs.

Height is inversely associated with an increase in arterial stiffness after habitual resistance exercise (RE). Considering that RE is performed during exercise prescriptions, the association between height and the acute effects of RE on arterial stiffness should be clarified. We investigated the effects of height on arterial stiffness following transient RE. Thirty-nine young Japanese men were studied under parallel experimental conditions [sham control (seated rest) and RE (5 sets of 10 repetitions at 75% of one-repetition maximum)], which were randomly ordered on two separate days. The subjects were divided into tertiles of height (each group, n = 13). The beta-stiffness index (index of arterial stiffness), assessed by carotid pulse pressure and distension, was measured in all subjects. A significant interaction between time, height, and RE was found for the beta-stiffness index (P = 0.01). RE significantly increased the beta-stiffness index in the lower-height group (P < 0.001), but not in the middle- and higher-height groups. Height was negatively associated with an increase in beta-stiffness index following RE, even after controlling the confounders, including exercise volume and changes in heart rate and carotid pulse pressure (P = 0.003). The mediation analysis demonstrated a mediating effect of carotid distension on the relationship between height and changes in the a-stiffness index. These results suggest that short height individuals have increased arterial stiffness following RE due to decreased mechanical distension, rather than through the widening of pulsatile pressure.

Height is inversely associated with an increase in arterial stiffness after habitual resistance exercise (RE). Considering that RE is performed during exercise prescriptions, the association between height and the acute effects of RE on arterial stiffness should be clarified. We investigated the effects of height on arterial stiffness following transient RE. Thirty-nine young Japanese men were studied under parallel experimental conditions [sham control (seated rest) and RE (5 sets of 10 repetitions at 75% of one-repetition maximum)], which were randomly ordered on two separate days. The subjects were divided into tertiles of height (each group, n = 13). The β-stiffness index (index of arterial stiffness), assessed by carotid pulse pressure and distension, was measured in all subjects. A significant interaction between time, height, and RE was found for the β-stiffness index (P = 0.01). RE significantly increased the β-stiffness index in the lower-height group (P < 0.001), but not in the middle- and higher-height groups. Height was negatively associated with an increase in β-stiffness index following RE, even after controlling the confounders, including exercise volume and changes in heart rate and carotid pulse pressure (P = 0.003). The mediation analysis demonstrated a mediating effect of carotid distension on the relationship between height and changes in the β-stiffness index. These results suggest that short height individuals have increased arterial stiffness following RE due to decreased mechanical distension, rather than through the widening of pulsatile pressure.

Sit-stand maneuvers (SSM) have increasingly been used for baroreflex sensitivity (BRS) measurement in physiological research, but it remains unknown as to how many SSM need to be performed to measure BRS and assess its relation with cardiovascular disease (CVD) risk. Therefore, this study aimed to determine 1) the effect of the number of SSM repetitions on BRS and 2) the association between BRS and CVD risk factors. Data were collected from 174 individuals during 5 minutes of spontaneous rest and 5 minutes of repeated SSM at 0.05 Hz (i.e., 15 cycles of 10-second sit and 10-second stand). During SSM, BRS was calculated from the incremental cycles of 3, 6, 9, 12, and 15 SSM using transfer function analysis of heart rate (HR) and systolic blood pressure (SBP). General CVD risk factors, carotid arterial stiffness, and cardiorespiratory fitness were measured. In result, HR and SBP increased during SSM (p&lt;0.05). The BRS remained at a similar level during the resting and SSM conditions, while the coherence function reached its peak after 3 cycles of SSM. BRS with ≥6 cycles of SSM was strongly correlated with age (r=-0.721 to -0.740), carotid distensibility (r=0.625 to 0.629), and cardiorespiratory fitness (r=0.333 to 0.351) (all p&lt;0.001). Multiple regression analysis demonstrated that BRS with ≥6 cycles of SSM explained &gt;60% of the variance in CVD risk factors. Therefore, our findings suggest that repeated SSM significantly strengthens the association between BRS and CVD risk factors. Particularly, BRS with ≥6 cycles of SSM is strongly associated with CVD risk.

Both eccentric (ECC) and concentric (CON) exercises improve energy expenditure and blood lipid profile. Although ECC exercise has a more beneficial effect on these factors than CON exercise, its benefits on vital organs are still unclear. This study investigated the mode-of-action-dependent effects on myocardial perfusion index. Seventeen healthy men (age: 26 ± 5 years) were randomly enrolled in CON (n = 9) and ECC (n = 8) groups. Transient exercise and regular training (three-day a week for 4-week) included bicep curl comprising 5-set of 10-repetition, each using 75% one-repetition maximum concentric loading. The ECC group performed one-repetition of ECC for 3-s and CON for 1-s, while the CON group performed one-repetition of CON for 3-s and ECC for 1-s. All participants were assessed for subendocardial viability ratio (SEVR, myocardial perfusion index) and aortic diastolic pressure decay. Before study, these were found to be same for both groups. Transient (ΔSEVR: 20.3 ± 13.3%, p = 0.01; Δdecay: -0.07 ± 0.02 s-1, p < .001) and regular (ΔSEVR: 18.5 ± 12.8%, p = .001; Δdecay: -0.06 ± 0.05 s-1, p = .004) ECC (but not CON) exercises significantly increased SEVR and decelerated decay. Increased SEVR with ECC exercise was associated with decelerated decay (transient ECC: r2 = 0.56, 95% confidence interval [CI] = -0.95 to -0.10, p = .03; regular ECC: r2 = 0.53, 95% CI = -0.95 to -0.05, p = .04). These findings suggest that ECC exercise improves myocardial perfusion and diastolic pressure contour is involved in physiological mechanisms.

INTRODUCTION: Aerobic exercise training has been shown to improve microstructural organization of the corpus callosum (CC); however, evidence of this topographic effect is limited. PURPOSE: To compare the CC microstructural organization between endurance athletes and sedentary adults using a white-matter fiber tractography approach. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) and T1-weighted structural data were collected from 15 male young endurance athletes and 16 age- and sex-matched sedentary adults. DTI data were analyzed with a global probabilistic tractography method based on neighborhood anatomical information. Fractional anisotropy (FA) and mean, radial (RD), and axial diffusivities were measured in the eight CC tracts: rostrum, genu, splenium, and body's prefrontal, premotor, central, parietal, and temporal tracts. Cortical thickness of the CC tract endpoints and the CC tract length and volume were also measured. Physical activity level was assessed by metabolic equivalents (METs). RESULTS: The athlete group had an average VO2max of 69.5 ± 3.1 ml/kg/min, which is above 90%ile according to the American College of Sports Medicine guideline. Compared with the sedentary group, the athlete group had higher FA in the CC body's premotor and parietal tracts and the CC splenium. These tracts showed lower RD in the athlete compared with sedentary group. The voxelwise analysis confirmed that the athlete group had higher FA in the CC and other white matter regions than the sedentary group, including the corona radiata, internal capsule, and superior longitudinal fasciculus. Cortical thickness of the CC tract endpoints and the CC tract lengths and volumes were similar between the two groups. Physical activity levels were positively correlated with FA in the CC body's parietal (r = 0.486, p = 0.006) and temporal (r = 0.425, p = 0.017) tracts and the CC splenium (r = 0.408, p = 0.023). CONCLUSION: Young endurance athletes have higher microstructural organization of the CC tracts connected the sensorimotor and visual cortices than the age- and sex-matched sedentary adults.

Exposure to continuous light at night, including night-shift work or a nocturnal lifestyle, is emerging as a novel deleterious factor for weight gain and obesity. Here, we examined whether a single bout of bright light (BL) exposure at night affects energy metabolism via changes in circadian rhythm and nocturnal melatonin production. Ten healthy young men were randomized to a two-way crossover experimental design protocol: control (< 50 lux) and BL (approximately 10000 lux) conditions, with at least seven days of interval. The participants were exposed to each condition for 3 h (21:00-24:00) before sleep (0 lux, 00:00-07:00) in a room-type metabolic chamber. On each experimental night (21:00-07:00), energy expenditure, respiratory quotient (RQ), and substrate oxidation were measured to determine the energy metabolism. BL exposure prior to bedtime altered biological rhythms, disrupted the nocturnal decline in body temperature, and suppressed the melatonin level before sleeping, resulting in an increase in sleep latency. Indirect calorimetry data revealed that BL exposure significantly decreased the fat oxidation and increased the RQ, an indicator of the carbohydrate-to-fat oxidation ratio, throughout the whole period (light exposure and sleep). We revealed that acute BL exposure prior to bedtime exacerbated circadian rhythms and substrate oxidations, suggesting that chronic BL exposure at night may lead to obesity risk due to disturbances in circadian rhythms and macronutrient metabolism.

PURPOSE: The aim of the study was to evaluate the relationship between changes in hemoglobin A1c (HbA1c) and exercise levels in type 2 diabetes mellitus (T2DM) patients when performing various types of exercise. METHODS: The inclusion criteria were randomized controlled trials involving adults with T2DM, intervention involving exercise alone, the overall duration of intervention ≥12 weeks, and reporting HbA1c. Weighted mean difference (WMD) was defined as the mean difference between the intervention group and the control group weighted by the inverse of the squared standard error for each study, and all WMDs were pooled as overall effects. A meta-regression analysis was performed to evaluate the relationship between the exercise level and the WMD in HbA1c. RESULTS: Forty-eight studies (2395 subjects) were analyzed. The pooled WMD in HbA1c decreased significantly (-0.5% [95% confidence intervals: -0.6 to -0.4]) but contained significant heterogeneity (Q = 103.8, P < 0.01; I2 = 36.6%). A meta-regression analysis showed that the intensity (metabolic equivalents [METs]), time (min/session), or frequency (sessions/week) of the exercise was not associated with the HbA1c. However, the overall duration of exercise (weeks) was significantly associated with the WMD in HbA1c (meta-regression coefficient: 0.01 [95% confidence intervals: 0.002-0.016]; R2 = 70.0%), and that result did not contain significant heterogeneity (P > 0.05; I2 = 14.7%). CONCLUSIONS: The exercise intervention decreases HbA1c in T2DM patients. In addition, exercise for an extended duration was associated with an increase in HbA1c, so the effects of exercise may be evident early on, but results suggested that exercise for a prolonged period alone may increase HbA1c.

Background/objectives: The current systematic review and meta-analysis evaluated the relationship between the form of exercise and changes in resting blood pressure (RBP) in older adults and the overall level of evidence. Methods: The inclusion criteria were studies involving intervention with only regular exercise limited to subjects ≥65 years old. The combined changes in RBP in each study were calculated and the relationship between the form of exercise and changes in the RBP were evaluated. The overall evidence was assessed using the GRADE approach. Results: Nineteen studies (1081 subjects) were analyzed. The combined changes in the RBP decreased as a result of aerobic exercise or resistance exercise. The intensity of resistance exercise (METs) was related to the change in the RBP of systolic (meta-regression coefficient, –2.5 [95% confidence interval, –4.7 to –0.4]
R2=35.4%). When excluding studies with high overall risk of bias, the overall duration of aerobic exercise (weeks) was related to the change in the RBP of systolic (meta-regression coefficient, –0.6 [95% confidence interval, –1.0 to –0.2]
R2=93.2%). In addition, there was a low level of evidence overall for a decrease in RBP as a result of aerobic exercise, but there was a moderate level of evidence for a decrease in RBP as a results of resistance exercise. Conclusion: A decrease in the RBP of systolic may be associated with active exercise in older adults. However, there may be insufficient evidence for the decrease in RBP as a result of aerobic exercise.

Increasing central blood pressure is an independent predictor of cardiovascular disease and is an acute effect of high-intensity resistance exercise. It has been shown that classical music suppresses increased peripheral pressure during exercise. We hypothesized that classical music would suppress increased central pressure induced by high-intensity resistance exercise. To confirm this hypothesis, we examined the effect of classical music on central pressure following high-intensity resistance exercise in 18 young men. A randomized, single-blinded, sham-controlled, crossover trial was conducted under parallel experimental conditions on four separate days. The order of experiments was randomized between sham control (seated rest), music (20-min classical music track compilation), resistance exercise (5 sets of 10 repetitions at 75% of 1 repetition maximum), and resistance exercise with music conditions. Aortic pressure was measured in all subjects. No significant interaction between time, music, and resistance exercise was observed for aortic systolic pressure and diastolic pressure. In contrast, aortic pulse pressure showed a significant interaction; that is, aortic pulse pressure significantly widened after resistance exercise, whereas music significantly attenuated this widening. No significant change was observed in aortic pulse pressure in sham control and music conditions. The present findings suggest that music attenuates resistance exercise-induced increase in central pressure.

Increasing central blood pressure is an independent predictor of cardiovascular disease and is an acute effect of high-intensity resistance exercise. It has been shown that classical music suppresses increased peripheral pressure during exercise. We hypothesized that classical music would suppress increased central pressure induced by high-intensity resistance exercise. To confirm this hypothesis, we examined the effect of classical music on central pressure following high-intensity resistance exercise in 18 young men. A randomized, single-blinded, sham-controlled, crossover trial was conducted under parallel experimental conditions on four separate days. The order of experiments was randomized between sham control (seated rest), music (20-min classical music track compilation), resistance exercise (5 sets of 10 repetitions at 75% of 1 repetition maximum), and resistance exercise with music conditions. Aortic pressure was measured in all subjects. No significant interaction between time, music, and resistance exercise was observed for aortic systolic pressure and diastolic pressure. In contrast, aortic pulse pressure showed a significant interaction; that is, aortic pulse pressure significantly widened after resistance exercise, whereas music significantly attenuated this widening. No significant change was observed in aortic pulse pressure in sham control and music conditions. The present findings suggest that music attenuates resistance exercise-induced increase in central pressure.

Background: Exercise training-induced adaptation of central Blood Pressure (BP) depends on exercise mode. Kendo, a traditional Japanese martial art, is a unique exercise mode because its training encompasses anaerobic and resistance training components. However, the effects of habitual kendo training on central BP have not been established.Objective: The aim of this study was to compare the central BP of high-level kendo athletes and age-matched controls without exercise habits.Methods: Thirty-six young university kendo athletes (the kendo athlete group) and 29 young sedentary individuals (the control group) participated in this cross-sectional study. Central hemodynamics were estimated from carotid arterial waveforms via a generalized transfer function. Stroke volume was computed from brachial arterial waveforms using the Modelflow method.Results: Central systolic BP and Central Pulse Pressure (cPP) were higher in the kendo athlete group than in the control group (both, p < 0.01). Central diastolic BP did not differ between the two groups. Stroke Volume Index (SVI; stroke volume adjusted for body surface area) and the maximum rate of aortic pressure rise during systole (dP/dT(max)), which reflects left ventricle contractility, were significantly higher in the kendo athlete group than in the control group (p < 0.05), and these parameters showed a significant positive correlation with cPP (SVI: r = 0.34, p < 0.01; dP/dT(max): r = 0.79, p < 0.01).Conclusion: These results suggest that habitual kendo training may increase central pulse pressure through increases in left ventricular systolic function.HIGHLIGHTSKendo is ideal for investigating of training adaptation since it induces the characteristics of anaerobic exercise training and resistance training; that is, kendo athletes had both high anaerobic capacity and high muscle strength compared with sedentary controls.In the present study, central blood pressure (central systolic blood pressure and central pulse pressure) was significantly higher in the kendo athlete group than in the control group.Stroke Volume Index (SVI; stroke volume adjusted for body surface area) and the maximum rate of aortic pressure rise during systole (dP/dT(max)) but not augmented pressure in the kendo athlete group were also significantly higher than those in the control group.In addition, SVI and dP/dT(max) showed a significant positive correlation with central pulse pressure.These results suggest that combined anaerobic exercise and muscular strength training may increase central blood pressure through increases in left ventricular systolic function. (C) 2021 The Authors. Publishing services by Atlantis Press International B.V.

Background Adropin is a peptide hormone that promotes nitric oxide (NO) production via activation of endothelial NO synthase (eNOS) in endothelial cells. Its circulating levels are reduced with aging and increased with aerobic exercise training (AT). Using a mouse model, we hypothesized that AT restores aging-associated reductions in arterial and circulating adropin and improves adropin-induced NO-dependent vasorelaxation. Further, we hypothesized these findings would be consistent with data obtained in elderly humans. Methods and Results In the animal study, 50-week-old SAMP1 male mice that underwent 12 weeks of voluntary wheel running, or kept sedentary, were studied. A separate cohort of 25-week-old SAMP1 male mice were used as a mature adult sedentary group. In the human study, 14 healthy elderly subjects completed an 8-week AT program consisting of 45 minutes of cycling 3 days/week. In mice, we show that advanced age is associated with a decline in arterial and circulating levels of adropin along with deterioration of endothelial function, arterial NO production, and adropin-induced vasodilation. All these defects were restored by AT. Moreover, AT-induced increases in arterial adropin were correlated with increases in arterial eNOS phosphorylation and NO production. Consistently with these findings in mice, AT in elderly subjects enhanced circulating adropin levels and these effects were correlated with increases in circulating nitrite/nitrate (NOx) and endothelial function. Conclusions Changes in arterial adropin that occur with age or AT relate to alterations in endothelial function and NO production, supporting the notion that adropin should be considered a therapeutic target for vascular aging. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000035520.

OBJECTIVE: Insufficient physical activity and excessive sedentary behavior can contribute to decreased skeletal muscle strength, which is strongly associated with increased mortality in patients with chronic kidney disease (CKD). However, the potential impact of replacing sedentary behavior with physical activity on skeletal muscle strength remains unclear in these patients. The purpose of this study was to examine the associations of physical activity, sedentary behavior, and skeletal muscle strength in patients with CKD using an isotemporal substitution model to estimate the associations on replacing time from one behavior to another while keeping the total time and other behaviors fixed. METHODS: A total of 108 patients with CKD (mean age = 65 [SD = 9] y; mean estimated glomerular filtration rate = 57 [SD = 22] mL/min/1.73m2) participated in this cross-sectional analysis study. The time spent in sedentary behavior, light-intensity physical activity, and moderate- to vigorous-intensity physical activity (MVPA) were assessed using a triaxial accelerometer. Handgrip strength, isometric knee extension strength, and 30-second chair stand test were used to measure skeletal muscle strength. RESULTS: In multivariate analyses (single-factor and partition models), the time spent in MVPA was beneficially associated with both isometric knee extension strength and 30-second chair stand test. Furthermore, the isotemporal substitution model found that replacing 10 minutes per day of sedentary behavior or light-intensity physical activity with equivalent MVPA time was beneficially associated with both isometric knee extension strength and 30-second chair stand test. CONCLUSIONS: Our cross-sectional findings indicate that MVPA time is beneficially associated with lower extremity muscle strength and that a slight increase in the MVPA time may contribute to maintaining skeletal muscle strength in patients with CKD. IMPACT: Increasing the time spent in MVPA (10 min/day) may be a feasible strategy in patients with CKD, who have a high prevalence of impaired physical function.

INTRODUCTION: High-intensity endurance training can elicit profound cardiac adaptations; however, the current evidence as to its impact on the proximal aorta is limited. The purpose of this study was to investigate the morphological and functional characteristics of the proximal aorta in endurance athletes. METHODS: Fifteen young male middle- and long-distance runners were compared with 19 age- and sex-matched sedentary control participants. CINE phase-contrast magnetic resonance imaging was used to measure blood flow velocities and cross-sectional areas of the ascending and proximal descending aorta. Aortic blood pressure was measured simultaneously during the phase-contrast magnetic resonance imaging scan using a generalized transfer function. Maximal oxygen uptake (V˙O2max) was measured in the athletes. Left ventricular morphology was assessed in a subgroup of participants (n = 16) with cardiac magnetic resonance imaging. RESULTS: The athlete group exhibited an average V˙O2max of 69.5 ± 3.1 mL·kg-1⋅min-1, which is above the 90th percentile of men with similar age according to the American College of Sports Medicine guideline. The athletes had significantly higher stroke volume and slower heart rate at rest and greater left ventricular end-diastolic volume and mass than the sedentary participants. Significantly larger cross-sectional areas and higher compliance of the ascending and proximal descending aorta were also found in the athletes, independently of body surface area. Moreover, higher compliance of the ascending aorta was associated with greater stroke volume (r = 0.382, P = 0.026) and slower heart rate (r = -0.442, P = 0.009) across all participants. CONCLUSIONS: The proximal aorta of young male endurance athletes undergoes morphological and functional adaptations that may be resulting from the significant hemodynamic alterations associated with their cardiac function.

Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, while MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.

Background: Both endothelial dysfunction and low circulating androgen levels predict cardiovascular disease in men. Endothelial function evaluation is commonly performed by measuring flow-mediated vasodilatation of the brachial artery. However, studies have suggested that compared with evaluation of large arteries, microvascular function evaluation of peripheral arteries is a better predictor of increased cardiovascular disease risks. Although circulating levels of androgens, such as testosterone and dehydroepiandrosterone sulfate (DHEA-S), positively correlate with cardiovascular function, the association between circulating androgen levels and microvascular function is unknown. In this study, we investigated whether serum androgen levels correlate with microvascular endothelial function in men.Methods: The study included 105 Japanese men (age 59 +/- 1 years) in whom we measured serum testosterone and DHEA-S levels. The reactive hyperemia index (RHI) determined by the Endo-PAT system (finger plethysmography) was used to evaluate microvascular endothelial function.Results: Serum testosterone levels were significantly correlated with the RHI (r = 0.32, P < 0.01). The association between serum testosterone levels and the RHI remained significant even after adjustment for confounders, including age and body mass index (beta = 0.31, P < 0.01). Notably, serum DHEA-S levels were not associated with the RHI (r = 0.01, n.s.).Conclusion: This study showed that serum testosterone levels were positively correlated with microvascular endothelial function in men. These results suggest that endogenous testosterone level is one of the determinants of microvascular endothelial function and may become a biomarker reflecting lifestyle modifications-induced improvement in cardiovascular function in men.

Background: Both endothelial dysfunction and low circulating androgen levels predict cardiovascular disease in men. Endothelial function evaluation is commonly performed by measuring flow-mediated vasodilatation of the brachial artery. However, studies have suggested that compared with evaluation of large arteries, microvascular function evaluation of peripheral arteries is a better predictor of increased cardiovascular disease risks. Although circulating levels of androgens, such as testosterone and dehydroepiandrosterone sulfate (DHEA-S), positively correlate with cardiovascular function, the association between circulating androgen levels and microvascular function is unknown. In this study, we investigated whether serum androgen levels correlate with microvascular endothelial function in men. Methods: The study included 105 Japanese men (age 59 ± 1 years) in whom we measured serum testosterone and DHEA-S levels. The reactive hyperemia index (RHI) determined by the Endo-PAT system (finger plethysmography) was used to evaluate microvascular endothelial function. Results: Serum testosterone levels were significantly correlated with the RHI (r = 0.32, P < 0.01). The association between serum testosterone levels and the RHI remained significant even after adjustment for confounders, including age and body mass index (β = 0.31, P < 0.01). Notably, serum DHEA-S levels were not associated with the RHI (r = 0.01, n.s.). Conclusion: This study showed that serum testosterone levels were positively correlated with microvascular endothelial function in men. These results suggest that endogenous testosterone level is one of the determinants of microvascular endothelial function and may become a biomarker reflecting lifestyle modifications-induced improvement in cardiovascular function in men.

Background and objective: Reduction in cerebral blood flow with aging leads to cognitive decline and brain atrophy. Cerebrovascular hemodynamics are associated with vascular function. However, little is known about endothelial function in relation to cerebral blood flow at rest. The present study aimed to examine the association between microvascular endothelial function and middle cerebral blood flow. Material and methods: This study involved 60 healthy middle-aged and elderly men. The microvascular endothelial function was measured via digital reactive hyperemia index using pulse amplitude tonometry, and the mean middle cerebral blood flow velocity and cerebrovascular conductance were measured using transcranial Doppler ultrasonography. Results and conclusions: Reactive hyperemia index was significantly correlated with the mean middle cerebral blood flow velocity and cerebrovascular conductance. Multiple regression analysis further indicated that the correlation was significant after adjustment of covariates, such as age, body mass index, smoking status, medication history, blood pressure, and arterial stiffness. Further, Reactive hyperemia index was found to be a significant independent determinant of the mean middle cerebral blood flow velocity and cerebrovascular conductance. The present study demonstrated that vascular endothelial function is associated with cerebral blood flow and is an independent potential confounding factor in healthy middle-aged and older men.

<p>Premenstrual syndrome (PMS) that occur during late luteal phase is a problem for many female athletes. Many studies reported that subjective condition is affected by PMS in female athletes. Moreover, female athletes with PMS have higher stress and/or anxiety levels during luteal phase compared with non-PMS athletes. However, the relationship between PMS and physical performance in female athletes are not clarified yet. The purpose of this study was to investigate the relationship between premenstrual syndrome (PMS) and jump performance in female track and field athletes. Sixteen participants who has natural basal body temperature pattern with the menstrual cycle (observed low-temperature and high-temperature phase), were participated in this study. PMS was assessed by ACOG's premenstrual syndrome questionnaire. As physical performance, counter movement jump (CMJ) and rebound jump (RJ) were evaluated in low-temperature phase and high-temperature phase. The result of this study, no significant differences were observed in body composition and physical performance between low-temperature phase and high-temperature phase. However, compared with participants who had non-symptom, participants who had a breast tenderness of PMS showed larger decreases in jump height of CMJ (p = 0.038) and RJ index (p = 0.015) in high-temperature phase. Therefore, PMS may have a negative effect on physical performance during high-temperature phase in female athletes.</p>

An increase in arterial stiffness with advance aging is a risk for cardiovascular disease. Cardiovascular dysfunction is associated with the imbalance of adrenal cortex hormones, especially with the cortisol/dehydroepiandrosterone sulfate (DHEAs) ratio. However, the impact of aerobic fitness on arterial stiffness and cortisol/DHEAs ratio is unclear. The aim of this study was to investigate the relationship between aerobic fitness, arterial stiffness, and cortisol/DHEAs ratio. A total of 198 middle-aged and older adults (aged 50-79 years old) participated in this study. The aerobic fitness evaluated by peak oxygen consumption (VO2peak), carotid-femoral pulse wave velocity (cfPWV) as an indicator of arterial stiffness, and serum cortisol and DHEAs and their ratio were measured. The subjects were divided into the lower (n = 100) and the higher (n = 98) aerobic fitness groups based on the median value of VO2peak. There were no significant differences in serum cortisol and DHEAs concentration alone between the lower and higher fitness groups. However, the cortisol/DEHAs ratio and cfPWV in the higher fitness group was smaller than in the lower fitness group (p < 0.05). The cortisol/DHEAs ratio was significantly correlated with cfPWV (r = 0.159, p < 0.05). These findings suggest that the cortisol/DHEAs ratio is associated with aerobic fitness and arterial stiffness in middle-aged and older adults.

The leading cause of aging-induced male-specific disorders such as physical, mental and/or sexual symptoms is testosterone deficiency. Although aerobic exercise is suggested to improves circulating testosterone levels, physical fitness, depressive symptoms, and sexual function, the effect of regular aerobic exercise on aging-induced disorders has not yet been clarified. Here we performed cross-sectional and interventional studies to identify the effect of aerobic exercise on aging-induced disorders assessed by the Aging Males' Symptoms questionnaire (AMS). In study 1, the relationship between aerobic exercise capacity (i.e. peak oxygen consumption) and AMS scores were cross-sectionally examined in 169 adult men. In study 2, the effect of a 12-week regular aerobic exercise on AMS scores was longitudinally investigated in 18 adult men. In study 1, the AMS-total, AMS-somatic, AMS-psychological, and AMS-sexual scores were significantly correlated to aerobic exercise capacity even after considering age and testosterone levels. In study 2, 12-week aerobic exercise training significantly improved AMS-sexual and tended to improve AMS-total scores. Additionally, an increase in vigorous physical activity was correlated to improve in the AMS-sexual score. These results suggest that regular aerobic exercise is an effective strategy to improve aging-induced disorders in men.

© 2020 Elsevier Inc. Objective: Circulating levels of fibroblast growth factor 21 (FGF21) increase with advancing age and may lead to the development of cardiometabolic diseases via impaired lipid and glucose metabolism. While physical activity can reduce these risks of cardiometabolic dysfunction, it remains obscure whether circulation FGF21 levels are influenced by physical activity. The purpose of this study was to investigate the relations between daily physical activities and circulating FGF21 levels in middle-aged and older adults. Methods: In this cross-sectional study with 110 middle-aged and 102 older adults, circulating (serum) FGF21 levels were evaluated by enzyme-linked immunosorbent assay, and the time spent in light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was assessed using a uniaxial accelerometer. Results: Serum FGF21 levels in the older group (158 pg/mL) were significantly higher than those in the middle-aged group (117 pg/mL). When we examined the joint association of age (middle-aged or older) and MVPA (lower or higher than the median) groups, serum FGF21 levels in the older and higher MVPA group (116 pg/mL) were significantly lower than those in the older and lower MVPA group (176 pg/mL). However, there was no difference in serum FGF21 levels between the lower and higher MVPA groups in the middle-aged group. In multivariable liner regression analysis, serum FGF21 levels were independently determined by MVPA time after adjusting for potential covariates in older adults (β = −0.209). Conclusions: These cross-sectional study findings indicate that the time spent in MVPA is an independent determinant of circulating FGF21 levels, and that an age-related increase in serum FGF21 levels may be attenuated by habitually performing MVPA. (250/250 words).

OBJECTIVE: Circulating levels of fibroblast growth factor 21 (FGF21) increase with advancing age and may lead to the development of cardiometabolic diseases via impaired lipid and glucose metabolism. While physical activity can reduce these risks of cardiometabolic dysfunction, it remains obscure whether circulation FGF21 levels are influenced by physical activity. The purpose of this study was to investigate the relations between daily physical activities and circulating FGF21 levels in middle-aged and older adults. METHODS: In this cross-sectional study with 110 middle-aged and 102 older adults, circulating (serum) FGF21 levels were evaluated by enzyme-linked immunosorbent assay, and the time spent in light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was assessed using a uniaxial accelerometer. RESULTS: Serum FGF21 levels in the older group (158 pg/mL) were significantly higher than those in the middle-aged group (117 pg/mL). When we examined the joint association of age (middle-aged or older) and MVPA (lower or higher than the median) groups, serum FGF21 levels in the older and higher MVPA group (116 pg/mL) were significantly lower than those in the older and lower MVPA group (176 pg/mL). However, there was no difference in serum FGF21 levels between the lower and higher MVPA groups in the middle-aged group. In multivariable liner regression analysis, serum FGF21 levels were independently determined by MVPA time after adjusting for potential covariates in older adults (β = -0.209). CONCLUSIONS: These cross-sectional study findings indicate that the time spent in MVPA is an independent determinant of circulating FGF21 levels, and that an age-related increase in serum FGF21 levels may be attenuated by habitually performing MVPA. (250/250 words).

The World Health Organization has recommended 5 g/day as dietary reference intakes for salt. In Japan, the averages for men and women were 11.0 g/day and 9.3 g/day, respectively. Recently, it was reported that amounts of sodium accumulation in skeletal muscles of older people were significantly higher than those in younger people. The purpose of this study was to investigate whether the risk of sarcopenia with decreased muscle mass and strength was related to the amount of salt intake. In addition, we investigated its involvement with renalase. Four groups based on age and salt intake ("younger low-salt," "younger high-salt," "older low-salt," and "older high-salt") were compared. Stratifying by age category, body fat percentage significantly increased in high-salt groups in both younger and older people. Handgrip strength/body weight and chair rise tests of the older high-salt group showed significant reduction compared to the older low-salt group. However, there was no significant difference in renalase concentrations in plasma. The results suggest that high-salt intake may lead to fat accumulation and muscle weakness associated with sarcopenia. Therefore, efforts to reduce salt intake may prevent sarcopenia.

BACKGROUND: Physical inactivity and sedentary behaviour (too much sitting) can contribute to renal dysfunction. However, the potential benefits of behavioural change (e.g. replacing sedentary behaviour with physical activity) on renal function are not well understood. We used isotemporal substitution to model potential impacts of behaviours on renal function by replacing time spent in one behaviour to another. METHODS: In 174 older Japanese adults (age, 50-83 years; females, 76%), the time spent in sedentary behaviour, light-intensity physical activity (LPA), and moderate- to vigorous-intensity physical activity (MVPA) were assessed using an uniaxial accelerometer. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) from serum creatinine and cystatin C levels. RESULTS: In univariate analyses, eGFR was significantly, albeit weakly, correlated with time spent in sedentary behaviour (rs = - 0.229), LPA (rs = 0.265), and MVPA (rs = 0.353). In the isotemporal substitution models, replacement of 30 min/day of sedentary behaviour with an equivalent LPA time was not significantly associated with eGFR (β = 2.26, p = 0.112); however, replacement with an equivalent time of MVPA was beneficially associated with eGFR (β = 5.49, p < 0.05). CONCLUSIONS: These cross-sectional findings suggest that sedentary behaviour (detrimentally) and physical activity (beneficially) may affect renal function and that replacing sedentary behaviour with MVPA may benefit renal health in older adults.

Exercise-induced redistribution of tissue blood flow decreases the renal blood flow in an exercise intensity-dependent manner. However, the acute effects of incremental short maximal exercise on renal tubular conditions remain unknown. The purpose of this study was to investigate the acute effects of incremental short maximal exercise on the urinary liver-type fatty acid-binding protein, which is a highly sensitive tubular biomarker that correlates excellently with peritubular capillary blood flow. A total of 116 adults (aged 24-83 years) without chronic kidney disease performed the incremental short maximal exercise using a cycling ergometer, wherein the exercise sequence consisted of commencing with a 2-min workout period at 20 W (as a warm-up period) and then followed by a 10-20 W increase every 1 minute until termination criteria were reached. Urinary samples were gathered before and immediately after the exercise to evaluate the concentrations of urinary creatinine, albumin, and liver-type fatty acid-binding protein. Urinary excretion levels of albumin and liver-type fatty acid-binding protein were significantly increased post-exercise (P P = .008, respectively). Furthermore,

Aging causes arterial stiffening which can be mitigated by increased physical activity. Although low circulating levels of salusin-α are associated with cardiovascular disease, whether salusin-α decreases with aging and whether the reduced arterial stiffening occurring with exercise training is associated with increased serum salusin-α is unknown. Herein we assessed carotid-femoral pulse wave velocity (cfPWV), systolic (SBP) and diastolic (DBP) blood pressures in a cross-sectional study that compared young (20-39-year-old, n=45) versus middle-aged and older (40-80-year-old, n=60) subjects. We also performed an interventional study in which 36 young and 40 middle-aged and older subjects underwent eight weeks of aerobic exercise training. In the cross-sectional study, serum salusin-α levels were lesser in middle-aged and older subjects compared to young individuals and negatively correlated with age, SBP, DBP, or cfPWV. In the interventional study, exercise training increased serum salusin-α in middle-aged and older subjects. Notably, negative correlations were noted between the exercise training-induced changes in serum salusin-α and cfPWV, SBP and DBP. Results indicate that advanced age associates with low circulating salusin-α, the levels of which can be augmented by exercise training. Importantly, increased serum salusin-α with exercise correlates with improvements in arterial stiffness and a reduction in blood pressure.

This study aims to evaluate the association between duration of overweight/obesity and arterial stiffness. In total, 103 men and women aged 45-68 years with a body mass index (BMI) of ≥25 kg/m2 were enrolled in this study. Duration of overweight/obesity was calculated for individuals with at least two consecutive BMI occurrences of ≥25 kg/m2 in the previous (5-year intervals from 20 years old) and present BMI information. Multiple regression analysis showed that carotid-femoral pulse wave velocity, an index of arterial stiffness, was independently associated with the duration of overweight/obesity, but not with current degree of overweight/obesity.

Intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of ectopic fat in muscles are associated with arterial stiffness in normal-weight individuals. Furthermore, aerobic exercise training-induced changes in IMCL or EMCL content are related to a decrease in arterial stiffness in elderly people. Though arterial stiffness is strongly related with obesity, but the effects of aerobic exercise training on IMCL or EMCL content, with a particular focus on arterial stiffness, in obese individuals remains unclear. Here, we investigated the effects of aerobic exercise training on IMCL or EMCL content and arterial stiffness in obese individuals. First, in a cross-sectional study, we examined the relationship between arterial stiffness and IMCL or EMCL content in 24 overweight and obese men. Secondly, we investigated the effects of aerobic exercise intervention on arterial stiffness and IMCL or EMCL content in 21 overweight and obese men. In the cross-sectional study, EMCL content was positively correlated with baPWV and β-stiffness index, whereas IMCL content was negatively correlated with baPWV. In the intervention study, there were no significant changes in baPWV, β-stiffness index, and IMCL and EMCL contents after aerobic exercise training. However, exercise-induced change in baPWV and β-stiffness index were positively correlated with changes in EMCL content. Moreover, the group of improvements in baPWV was only correlated significantly with reduced EMCL content. These results suggest that IMCL and EMCL contents may affect arterial stiffness in overweight and obese men.

<p>Objective: A 52-week, open-label, randomized, controlled, cross-over with a wash-out period of 20 weeks, preliminary trial was performed to examine the effects of beta-hydroxy-beta-methylbutyrate (HMB) supplementation with resistance training on skeletal muscle mass and muscular strength in postmenopausal women.</p><p>Methods: Fifty-seven postmenopausal women (mean age 60.2 ± 6.0 years) were randomly allocated to an immediate intervention group (IIG: n = 29) or delayed intervention group (DIG: n = 28). The IIG participated in our 12-week resistance training program along with HMB supplementation. No intervention was administered to the DIG during the initial 12-week period, and both groups were crossed over for the latter 12-week period. There was a 20-week wash-out between both periods. Effects of the intervention on primary (appendicular skeletal muscle mass: ASM) and secondary (maximum muscular strength: MMS) outcomes were examined for both baseline and post-intervention (12-week) periods.</p><p>Results: Compared with control condition, intervention condition showed no significant improvement in ASM (intervention condition +0.2 ± 0.8 kg, control conditi

© 2020 Jun Tanabe et al. Background. Type 2 diabetes (T2D) is a known risk factor for diabetic kidney disease (DKD) and sarcopenia in older patients. Because there may be an interaction between DKD and sarcopenia, the aim of the present study is to investigate the relationship between urinary levels of liver-type fatty acid-binding protein (L-FABP) and sarcopenia using a novel rat model of T2D. Methods. Male spontaneously diabetic Torii (SDT) fatty rats (n=5) at 16 weeks of age were used as an animal model of T2D. Age- and sex-matched Sprague-Dawley (SD) rats (n=7) were used as controls. Urine samples were obtained from the rats, and muscle strength was evaluated with the use of the forelimb grip test at 16, 20, and 24 weeks of age. Serum, kidney, soleus, and extensor digitorum longus (EDL) muscle samples were collected at 24 weeks of age. Urinary L-FABP levels were measured using dedicated enzyme-linked immunosorbent assays. Results. Increased urinary L-FABP levels, focal glomerular sclerosis, moderate interstitial inflammation and fibrosis, and accumulation of renal oxidative proteins were significantly observed in the SDT fatty rats, compared to the SD rats. Muscle weight, muscle strength, cross-sectional areas of both type I and type IIb muscle fibers, and increasing rate of muscle strength were significantly decreased in the SDT fatty rats compared to the SD rats at 24 weeks. Urinary L-FABP levels at 20 and 24 weeks were significantly negatively correlated with muscle strength. Urinary L-FABP levels at 16 weeks were significantly negatively correlated with the increasing rate of muscle strength. Conclusions. Urinary L-FABP reflects the degree of muscle strength and weight, as well as cross-sectional areas of muscle fibers. Although further clinical study is needed, urinary L-FABP may be useful to monitor the progression of sarcopenia and DKD in T2D patients.

肥満は生活習慣病の一つであり死亡リスクの増大に関与する.近年の先行研究で,血中アミノ酸濃度が様々な生活習慣病のスクリーニングに有効であることが報告された.本研究では,肥満男性における食習慣改善と有酸素性運動を併用した12週間の生活習慣改善介入が血中アミノ酸濃度に及ぼす影響を網羅的に検討することを目的とした.肥満男性32名(年齢,49±2歳;BMI,29.2±0.3kg/m2)が食習慣改善(1680kcal/日,全8回の集団指導と個別カウンセリング)と有酸素性運動(90分/回,3回/週,60-80%HRmax)を組み合わせた12週間の生活習慣改善介入を完遂した.介入前後で網羅的に39種の血中アミノ酸濃度を測定した.12週間の生活習慣改善介入後,体重は有意に低下した(-12.6kg).介入後,総摂取エネルギー量は有意に減少した一方で,最高酸素摂取量,身体活動量,歩数は有意に増加した.また介入後,6種のアミノ酸の血中濃度は有意に増加し,9種のアミノ酸の血中濃度は有意に低下した.本研究では,肥満男性における生活習慣改善は血中アミノ酸濃度を有意に変化させることが示唆された.(著者抄録)

Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liver-derived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. However, roles that FGF21 plays in pathophysiology of CKD remains elusive. Here we show in mice that FGF21 is required to survive CKD but responsible for blood pressure dysregulation. When introduced with CKD, Fgf21-/- mice died earlier than wild-type mice. Paradoxically, these Fgf21-/- CKD mice escaped several complications observed in wild-type mice, including augmentation of blood pressure elevating response and activation of the sympathetic nervous system during physical activity and increase in serum noradrenalin and corticosterone levels. Supplementation of FGF21 by administration of an FGF21-expressing adeno-associated virus vector recapitulated these complications in wild-type mice and restored the survival period in Fgf21-/- CKD mice. In CKD patients, high serum FGF21 levels are independently associated with decreased baroreceptor sensitivity. Thus, increased FGF21 in CKD can be viewed as a survival response at the sacrifice of blood pressure homeostasis.

Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liver-derived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. However, roles that FGF21 plays in pathophysiology of CKD remains elusive. Here we show in mice that FGF21 is required to survive CKD but responsible for blood pressure dysregulation. When introduced with CKD, Fgf21-/- mice died earlier than wild-type mice. Paradoxically, these Fgf21-/- CKD mice escaped several complications observed in wild-type mice, including augmentation of blood pressure elevating response and activation of the sympathetic nervous system during physical activity and increase in serum noradrenalin and corticosterone levels. Supplementation of FGF21 by administration of an FGF21-expressing adeno-associated virus vector recapitulated these complications in wild-type mice and restored the survival period in Fgf21-/- CKD mice. In CKD patients, high serum FGF21 levels are independently associated with decreased baroreceptor sensitivity. Thus, increased FGF21 in CKD can be viewed as a survival response at the sacrifice of blood pressure homeostasis.

No effective and easily implemented intervention strategies for reducing sedentary behavior have been established. This pilot trial (UMIN000024372) investigated whether vibrotactile feedback reduces sedentary behavior. Twenty-six adults aged 30-69 years who were sedentary ≥8 h/day were randomly assigned to control ( = 13) or vibration ( = 13) groups. Participants wore a monitor 9 h daily for seven-day periods at baseline (week zero), during the intervention (weeks one, three, five, and seven), and after the intervention (week eight). During the eight-week intervention, vibration-group participants were notified by a vibration through the monitor whenever continuous sedentary time reached ≥30 min; they also received weekly reports of their sedentary patterns. Control-group participants did not receive feedback. The primary outcome was change in total sedentary time. Changes in longer bouts of sedentary time (≥35 min) were also assessed. No significant difference was found in the change in total sedentary time (control: -17.5 min/9 h, vibration: -9.1 min/9 h; = 0.42). Although no significant differences were observed in sedentary time in longer bouts, vibration-group participa

Tubulointerstitial damage is a crucial therapeutic target in preventing chronic kidney disease (CKD) progression. Inappropriately activated renin-angiotensin-aldosterone system (RAAS) in the tubulointerstitial area is strongly associated with tubulointerstitial damage progression. Therefore, this study aimed to determine whether there is a beneficial effect of voluntary running exercise training on aldosterone-induced renal injury. Human L-type fatty acid-binding protein (L-FABP) chromosomal transgenic (L-FABP+/-) male mice were used to evaluate the effect of exercise by using urinary L-FABP, a tubular marker. The mice were assigned to either the exercise group that performed voluntary running exercise training using a running wheel or the control group. Subsequently, two groups were injected with aldosterone (0.125 μg kg-1 min-1) and administered 1% NaCl water, and two groups were administered aldosterone only in solvent 4 weeks after initiating the exercise. Aldosterone was injected for another 4 weeks, and NaCl water was administered from 5 weeks after starting the exercise until 8 weeks. Although both aldosterone and NaCl water significantly decreased the running distance, tubulointerstitial damage involving interstitial infiltration of macrophages and fibrosis and the elevation of urinary human L-FABP induced by aldosterone injection was prevented by voluntary running exercise training. Urinary human L-FABP levels were significantly correlated with the degree of tubulointerstitial damage. In conclusion, voluntary running exercise training delayed tubulointerstitial damage progression in the aldosterone-induced renal injury model and therefore may be a promising nonpharmacological strategy in CKD.

Intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of ectopic fat in muscles are associated with arterial stiffness in normal-weight individuals. Furthermore, aerobic exercise training-induced changes in IMCL or EMCL content are related to a decrease in arterial stiffness in elderly people. Though arterial stiffness is strongly related with obesity, but the effects of aerobic exercise training on IMCL or EMCL content, with a particular focus on arterial stiffness, in obese individuals remains unclear. Here, we investigated the effects of aerobic exercise training on IMCL or EMCL content and arterial stiffness in obese individuals. First, in a cross-sectional study, we examined the relationship between arterial stiffness and IMCL or EMCL content in 24 overweight and obese men. Secondly, we investigated the effects of aerobic exercise intervention on arterial stiffness and IMCL or EMCL content in 21 overweight and obese men. In the cross-sectional study, EMCL content was positively correlated with baPWV and β-stiffness index, whereas IMCL content was negatively correlated with baPWV. In the intervention study, there were no significant changes in baPWV, β-stiffness ind

<p>Curcumin is known to have potent anti-inflammatory effects. We have reported that acute curcumin ingestion attenuates eccentric exercise-induced muscle damage. This study aimed to examine the effect of curcumin ingestion timing (before or after exercise) on the changes in muscle damage markers after eccentric exercise. In this randomized, single-blind, parallel design study, 24 healthy young men performed 30 maximal isokinetic (120º/s) eccentric contractions of the elbow flexors using an isokinetic dynamometer. Subjects were randomly assigned to ingest 180 mg/d of oral curcumin either 7 d before (PRE) or 4 d after exercise (POST) or 180 mg/d of oral placebo 4 d after exercise (CON). The maximal voluntary contraction (MVC) torque of the elbow flexors, elbow joint range of motion (ROM), muscle soreness, and serum creatine kinase (CK) activity were measured before, immediately after, and 1-4 d after exercise. Changes in these variables were compared over time. In the POST group, ROM were higher at 3-4 d and muscle soreness was lower at 3 d after exercise compared with the CON group (p<0.05). However, in the PRE group, there were no significant differences compared with the

The circulatory level of pentraxin 3 (PTX3), an anti-inflammatory cardioprotective protein, has been shown to be lower in obese individuals than in those with normal weight. However, reports on the effects of different weight-loss methods on PTX3 are limited. The present study aimed to investigate the effect of weight loss on circulating PTX3 levels in overweight and obese men and to examine the combined effect of dietary modification and exercise training on PTX3 levels. Forty-eight overweight and obese men were assigned to 2 groups: dietary modification (group D) or exercise training and dietary modification (group DE). Groups D and DE were composed of 27 and 21 participants, respectively. We observed a significant independent relationship between changes in PTX3 and body mass index (BMI) in all participants (β = −0.617, p &lt; 0.01). Subsequently, we compared the effects of the 2 weight-loss methods on plasma PTX3 in groups D and DE. The magnitude of the increase in plasma PTX3 levels was similar in the 2 groups. Interestingly, we observed that PTX3 levels in group DE increased significantly more than those in group D in subjects who achieved normal weight, based on BMI, after interventions. Our study suggested that weight reduction after lifestyle modification significantly increased PTX3 levels in overweight and obese men, and the addition of habitual exercise to dietary modification enhanced the magnitude of the increase in PTX3 levels in obese individuals achieving normal weight after weight loss.

Reference is lacking in Table 1 and Fig. 2. <br>In addition, Reference 37 should be added in the list.

[PURPOSE] Sleep duration is known to affect physiological and circadian metabolites and human homeostasis. However, little is known about the relationship between sleep quality and metabolite and cognitive function during exercise. Therefore, the aim of the present study was to investigate the impact of sleep quality on metabolite level and cognitive function in female volleyball athletes.
[METHODS] Twelve female volleyball athletes participated in this study. Sleep efficiency was measured for 1 week using NemuriSCAN (Paramount Bed Co. Ltd., Japan) as an index of sleep quality. The subjects were divided into better (n = 6) and lesser (n = 6) sleep quality groups by the median value of sleep efficiency. Saliva samples were collected using a Salimetric oral swab cotton and salivary metabolites were analysed using capillary electrophoresis and time-of-flight mass spectrometry. The subjects performed Stroop tasks (simple and difficult tasks) at rest and during aerobic exercise in recumbent cycle ergometer at light and heavy intensity.
[RESULTS] Increased sleep efficiency was found in the better sleep quality group, whereas total sleep time was similar. There were differences in

High-intensity resistance exercise (RE) increases aortic stiffness and decreases the index of myocardial oxygen supply/demand balance (Buckberg index, BI); there is a correlation between the changes in these parameters. Central hemodynamics during diastole can explain the correlation. We aimed to investigate whether the aortic diastolic decay index mediates the association between changes in aortic stiffness and BI by high-intensity RE. We evaluated the effect of high-intensity RE on aortic stiffness, BI, aortic decay index, and their associations in 52 young men. Subjects were studied under parallel experimental conditions on two separate days. The order of experiments was randomized between RE (5 sets of 10 repetitions at 75% of 1-repetition maximum) and sham control (seated rest). Aortic pulse wave velocity (PWV; index of aortic stiffness), BI, and aortic decay index were measured in all subjects. Aortic decay index was quantified by fitting an exponential curve: P(t) = P0e-λt (where λ is decay index, P0 is end-systolic pressure and t is time from end-systole). Aortic PWV and decay index increased and BI decreased after RE. RE conditions showed that change in the aortic decay index was associated with changes in aortic PWV and changes in aortic PWV were related to changes in BI, although the PWV-BI relationship was not significant after accounting for decay index change. Mediation analysis revealed the mediating effect of the aortic decay index on the relationship between changes in aortic PWV and BI. The present findings suggest that high-intensity RE-induced aortic stiffening worsens myocardial viability by accelerating aortic diastolic exponential decay.NEW & NOTEWORTHY Aortic pulse wave velocity (PWV) and diastolic decay index increased and Buckberg index (BI) decreased after resistance exercise (RE). Mediation analysis revealed a mediating effect of aortic decay index on the relationship between changes in aortic PWV and BI. The present study provides evidence that high-intensity RE-induced aortic stiffening accelerates aortic decay and aortic decay can account for the relationship between aortic stiffening and a deteriorated surrogate marker of myocardial oxygen supply/demand balance induced by high-intensity RE.

線維芽細胞増殖因子21(FGF21)は肥満や糖尿病などの様々な慢性疾患の発症および進行と関連することが報告されている.しかし,血中FGF21濃度と有酸素性体力および中心血圧の関連性は十分に明らかになっていない.そこで本研究では,中高齢女性118名の血中FGF21濃度,有酸素性体力および中心血圧の関連性を横断的に検討することを目的とした.血中FGF21濃度が高い群における中心脈圧は,血中FGF21濃度が低い群に比べて有意に高値を示した(38.4±1.1 vs. 34.9±0.8mmHg;P<0.05).重回帰分析では,血中FGF21濃度が中心脈圧の独立した規定因子であること(β=0.169;P<0.05),さらに,その血中FGF21濃度は最高酸素摂取量(β=-0.235;P<0.01)によって一部規定されることが示された.本研究の結果により,中高齢女性の血中FGF21濃度は,中心脈圧と正の関係性を示し,最高酸素摂取量と負の関係性を示すことが明らかになった.これらの結果は,FGF21が中高齢女性の中心脈圧の上昇に関与することを示唆しており,加えて,有酸素性体力の向上が血中FGF21濃度を低く保つために有用である可能性を示している.(著者抄録)

PURPOSE: Eccentric exercise induces a decrease in vascular endothelial function. Curcumin, a major component of turmeric, has potent antioxidant and anti-inflammatory properties that are associated with vascular protective effects. The present study examined the effect of acute supplementation of curcumin on eccentric exercise-induced endothelial dysfunction in healthy young men. METHODS: Fourteen healthy sedentary young men (range, 21-29 years) were assigned to either the curcumin (n = 6) or placebo (n = 8) group. All subjects consumed either curcumin or placebo before exercise, and eccentric exercise of the elbow flexors was performed with their nondominant arm. Before and 60 min after exercise, brachial artery flow-mediated dilation (FMD), as an indicator of endothelial function, was measured in the non-exercised arm. RESULTS: Brachial artery FMD significantly decreased following eccentric exercise (p < 0.05) in the placebo group, but acute supplementation with curcumin before exercise nullified this change. The change in FMD before and after eccentric exercise between the placebo and curcumin groups was significantly different (p < 0.05). CONCLUSION: The present study found that acute curcumin supplementation could attenuate the decrease in endothelial function, as measured by FMD, following eccentric exercise in healthy young men.

PURPOSE: Weight loss can reduce obesity-induced arterial stiffening that is attributed to decreased inflammation. Angiopoietin-like protein 2 (ANGPTL2) is a pro-inflammatory adipokine that is upregulated in obesity and is important in the progression of atherosclerosis and cardiovascular disease. The purpose of this study is to investigate the effects of dietary modification on circulating ANGPTL2 levels and arterial stiffness in overweight and obese men. METHODS: Twenty-two overweight and obese men (with mean age of 56 ± 2 years and body mass index of 28.6 ± 2.6 kg/m2) completed a 12-week dietary modification program. We measured the arterial compliance and β-stiffness index (as the indices of arterial stiffness) and serum ANGPTL2 levels before and after the program. RESULTS: After the 12-week dietary modification, body mass and daily energy intake were significantly reduced. Arterial compliance was significantly increased and β-stiffness index was significantly decreased after the 12-week dietary modification program. Serum ANGPTL2 levels were significantly decreased. Also, the changes in arterial compliance were negatively correlated with the changes in serum ANGPTL2 levels, whereas the changes in β-stiffness index were positively correlated with the changes in serum ANGPTL2 levels. CONCLUSION: These results suggest that the decrease in circulating ANGPTL2 levels can be attributed to the dietary modification-induced reduction of arterial stiffness in overweight and obese men.

High-intensity resistance exercise has been shown to increase arterial stiffness and reduce vascular endothelial function. Taurine supplementation has a favorable effect on maintaining vascular function. We had previously reported that taurine supplementation attenuated increases in resistance exercise-induced arterial stiffness. In the present study, we further investigate the effects of taurine supplementation on vascular endothelial function at rest and after resistance exercise.Twenty-nine healthy men were recruited and randomly assigned to either the placebo supplement group (n = 14) or the taurine supplement group (n = 15) in a double-blinded manner. Subjects were required to ingest 6 g of either a placebo or the taurine supplement for 2 weeks prior to and 3 days following the exercise. Two weeks after the commencement of supplementation, the subjects were asked to perform 2 sets of 20 repetitive unilateral maximal-effort resistance exercise of the elbow flexors on a Biodex isokinetic dynamometer, with each contraction lasting 3 s, with 1 repetition performed every 9 s and 4 min rest in between sets. We evaluated the changes in brachial artery flow-mediated dilation (FMD) in the non-exercised arm as an index of vascular endothelial function. Relative and absolute FMDs were measured prior to supplementation, before exercise, and 24, 48, and 96 h after exercise.Two weeks of taurine supplementation significantly increased both relative and absolute FMDs. Baseline diameter significantly increased at 96 h following the exercise in both groups. However, there was no change in the peak diameter. Consequently, both relative and absolute FMDs were significantly reduced at 96 h after the exercise in both groups. Taurine supplementation does not affect resistance exercise-induced reduction in FMD.Two weeks of taurine supplementation (6 g/day) significantly increased vascular endothelial function at rest; however, taurine supplementation did not improve resistance exercise-induced reduction in FMD.

レジタンストレーニングの実践により動脈スティフネスは上昇することが明らかにされているが,その上昇は,有酸素性運動を併用することで抑制できる可能性が考えられている.そこで本研究では,高齢者におけるレジスタンストレーニングと有酸素性運動の併用が大動脈スティフネスに及ぼす影響をランダム化比較試験により明らかにすることを目的とした.対象者は65歳以上の高齢者56名とし,レジスタンストレーニング(RT)群と有酸素性運動(AE)+RT群に無作為に割り付けた.介入は,週2回12週間の監視下での運動トレーニングと栄養強化ミルクを提供した.なお,AE+RT群では,レジスタンストレーニング前に有酸素性運動を実践するよう導いた.動脈スティフネスは,頸動脈-大腿動脈間(大動脈)および大腿動脈-足首動脈間(下肢動脈)の脈波伝播速度を用いて評価した.介入前の全ての評価項目において両群間に有意な群間差はみられなかった.介入後において,有意な交互作用は認められなかったものの,RT群では,大動脈脈波伝播速度が有意な上昇を示したのに対して(1032±35 vs. 1072±33cm/sec,P<0.05),AE+RT群では,大動脈脈波伝播速度は有意な変化を示さなかった.一方で,下肢動脈脈波伝播速度は,両群ともに介入前後の有意な変化は認められなかった.本研究では,高齢者において,レジスタンストレーニングの実践により大動脈スティフネスは有意に上昇するが,レジスタンストレーニング前に有酸素性運動を実践することで大動脈スティフネスの上昇が有意に抑制される可能性が示された.これらの結果は,レジスタンストレーニング前に有酸素性運動を実践することが,レジスタンストレーニングの実践により生じる動脈への悪影響の一つを抑制する上で重要であることを示唆している.(著者抄録)

<p></p><p>Arterial stiffness in endurance athletes is low, whereas arterial stiffness in strength athletes is high. The adaptation of the arterial stiffness may be different depending on the training type. On the other hand, there are mixed-trained athletes that can't be classified as endurance- or strength- trained athletes. The aim of this study was to investigate the arterial stiffness among mixed-trained athletes. The total of 51 young male athletes (15 long-distance runners, 10 handball players and 26 kendo players) and 16 young healthy sedentary individuals (control group) participated in this study. Carotid-femoral pulse wave velocity (cfPWV), carotid-brachial PWV (cbPWV) and femoral-ankle PWV (faPWV), were measured as indices of central and peripheral (upper and lower limbs) arterial stiffness, respectively. cfPWV showed significantly lower in long-distance runners (high endurance capacity) and handball players (strength and high endurance capacities) compared with kendo players (strength and low endurance capacities) and control groups (P < 0.05 for both). cbPWV showed significantly lower in handball players and kendo players compared with the control group (<i>P</i

[Background] Age-related declines in cognitive function and cerebral perfusion increase the risk of dementia. Although nutrition and exercise may be effective in reducing cognitive decline, the effect of lactotripeptide (LTP) on cerebral oxygenation and hemodynamics remains unclear.
[Objectives] The aim of this study was to investigate the effects of LTP ingestion on cerebral oxygenation, cognitive function, and vascular function in middle-aged and older adults with or without an exercise intervention.
[Methods] We recruited 2 separate groups of participants, one with and one without an exercise intervention. Each group was then randomly assigned into a placebo group and an LTP group. The participants ingested a placebo or LTP every day. The exercise group performed aerobic exercises 4-6 d/wk. Before and after the 8-wk intervention, we measured oxygenated hemoglobin (oxy-Hb) concentration (oxy-Hb change) in the prefrontal cortex during the Stroop task (primary outcome), Stroop interference time, and carotid artery β-stiffness (both secondary outcomes).
[Results] Sixty-four participants completed the study. Changes in oxy-Hb signal in the prefrontal cortex were greater in the LTP g

Central systolic blood pressure (cSBP) decreases after a meal or glucose challenge, but this response is impaired in obesity-related disorders. We investigated whether aerobic exercise training improves cSBP regulation during an oral glucose tolerance test (OGTT) in overweight/obese men. Thirteen overweight/obese men and six normal-weight men (as an alternative comparison instead of a no-exercise group) completed a 12-week aerobic exercise training program. Before and after the program, cSBP (i.e., radial second systolic pressure) was measured using an applanation tonometry at fasting and both 60 min and 120 min after 75 g glucose loading. Before and during the program, physical activity (PA) time was recorded using a tri-axial accelerometer. Pre-training, cSBP was significantly decreased with glucose loading in normal-weight men, while cSBP did not change in overweight/obese men. Post-training, a significant decrease in cSBP was observed in both groups following glucose loading. In addition, the increase in vigorous PA time during the exercise program was significantly correlated to the increase in area above the curve for cSBP during OGTT (demonstrating an improvement in the cSBP response to glucose loading) after the exercise program. These findings may provide novel insights into the role of PA in reducing the cardiovascular risk in obesity.

The contractile and metabolic properties of adult skeletal muscle change in response to endurance exercise. The mechanisms of transcriptional regulation in exercise-induced skeletal muscle adaptation, including fiber-type switching and mitochondrial biogenesis, have been investigated intensively, whereas the role of microRNA (miRNA)-mediated posttranscriptional gene regulation is less well understood. We used tamoxifen-inducible Dicer1 knockout (iDicer KO) mice to reduce the global expression of miRNAs in adult skeletal muscle and subjected these mice to 2 wk of voluntary wheel running. Dicer mRNA expression was completely depleted in fast-twitch plantaris muscle after tamoxifen injection. However, several muscle-enriched miRNAs, including miR-1 and miR-133a, were reduced by only 30-50% in both the slow and fast muscles. The endurance exercise-induced changes that occurred for many parameters (i.e., fast-to-slow fiber-type switch and increases in succinate dehydrogenase, respiratory chain complex II. and citrate synthase activity) in wild type (WT) also occurred in the iDicer KO mice. Protein expression of myosin heavy chain Ha, peroxisome proliferator-activated receptor-gamma coactivator- 1 alpha, and cytochrome c complex IV was also increased in the iDicer KO mice by the voluntary running. Furthermore, there was no significant difference in oxygen consumption rate in the isolated mitochondria between the WT and iDicer KO mice. These data indicate that muscle-enriched miRNAs were detectable even after 4 wk of tamoxifen treatment and there was no apparent specific endurance-exercise-induced muscle phenotype in the iDicer KO mice.

Background: Age-related declines in cognitive function and cerebral perfusion increase the risk of dementia. Although nutrition and exercise may be effective in reducing cognitive decline, the effect of lactotripeptide (LTP) on cerebral oxygenation and hemodynamics remains unclear.Objectives: The aim of this study was to investigate the effects of LTP ingestion on cerebral oxygenation, cognitive function, and vascular function in middle-aged and older adults with or without an exercise intervention.Methods: We recruited 2 separate groups of participants, one with and one without an exercise intervention. Each group was then randomly assigned into a placebo group and an LTP group. The participants ingested a placebo or LTP every day. The exercise group performed aerobic exercises 4-6 d/wk. Before and after the 8-wk intervention, we measured oxygenated hemoglobin (oxy-Hb) concentration (oxy-Hb change) in the prefrontal cortex during the Stroop task (primary outcome), Stroop interference time, and carotid artery beta-stiffness (both secondary outcomes).Results: Sixty-four participants completed the study. Changes in oxy-Hb signal in the prefrontal cortex were greater in the LTP group than in the placebo group under both the exercise and nonexercise conditions (P < 0.05). In addition, the magnitude of improvement in the oxy-Hb change in the left prefrontal cortex was correlated with Stroop interference (r = -0.39, P < 0.05) and carotid beta-stiffness (r=-0.41, P < 0.05).Conclusions: An 8-wk intake of LTP increased cerebral oxygenation in the prefrontal cortex region in middle-aged and older adults, with and without exercise. The intervention-induced improvements in brain neural activation were associated with cognitive and vascular function. This trial was registered at www.umin.ac.jp as UMIN000022313.

<p>The aim of this study was to investigate the effects of bright-light exposure immediately prior to sleep on the human urine metabolome. Eight young and healthy men were exposed to dim light (control condition) or bright-light (10000 lux) 3 hours before sleep (Bright-light condition: BL). Objective sleep quality was recorded by polysomnography, and subjective sleep quality was evaluated by the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA). Urine samples were collected after waking up under both the BL and control conditions. Polysomnographic analysis showed that sleep latency was significantly increased in BL compared to the control condition. OSA-MA score of refreshing was significantly lower in BL. Moreover, body temperature was significantly higher at times around sleep onset in BL (23:30, 0:00, and 0:30). Together, these results suggest that exposure to bright-light prior to sleep can alter sleep and circadian rhythms. According to analysis of the urine metabolome, the level of Allothreonine was significantly higher and the levels of N-acetylleucine, ornithine, 5-hydroxylysine, carnosine, and 4-amino-3-hydroxybutyric acid were significantly lower in BL (P < 0.05).

We examined the effect of curcumin (CUR) ingestion before or after exercise on changes in muscle damage and inflammatory responses after exercise. We conducted two parallel experiments with different CUR ingestion timings using a double-blind crossover. In Exp. 1, ten healthy men ingested 180 mg d of CUR or placebo (PLA) 7 days before exercise. In Exp. 2, ten other healthy men ingested 180 mg d of CUR or PLA 7 days after exercise. They performed 30 maximal isokinetic (120°s ) eccentric contractions of the elbow flexors using an isokinetic dynamometer, and this was repeated with the other arm ≥4 weeks later. Maximal voluntary contraction (MVC) torque of the elbow flexors, elbow joint range of motion (ROM), muscle soreness, and serum creatine kinase (CK) activity were measured before, immediately after, and 1-7 days after exercise. Plasma interleukin-8 (IL-8) was measured before, immediately after, 12 hours after, and 1-7 days after exercise. The changes were compared over time. In Exp. 1, no significant differences were found between CUR and PLA subjects for each parameter. However, increases in IL-8 were significantly reduced 12 hours after exercise when CUR was inges

Age-related decreases in cognitive function, cerebral perfusion, and vascular function increase the risk of dementia. However, the effects of central artery stiffness on cerebral oxygenation hemodynamics during executive function tasks and executive function remain unclear. The aim of this cross-sectional study was to investigate the relationships among central artery stiffness, cerebral oxygenation hemodynamics during executive function tasks, and executive function in middle-aged and older adults. Sixty-two middle-aged and older adults (age range: 51-79 years) were recruited for this study. For each participant, we measured the carotid artery β-stiffness, oxygenated hemoglobin (oxy-Hb) signal change in the prefrontal cortex during the Stroop task, and Stroop interference time. Correlation analyses revealed that the carotid artery β-stiffness was significantly correlated with the Stroop interference time (r = 0.43, P < 0.001) and with the oxy-Hb signal change in the left (r = -0.38, P = 0.002), but not the right, prefrontal cortex. In addition, the Stroop interference time was significantly correlated with the oxy-Hb signal change in the left (r = -0.42, P = 0.001), but not the right, prefrontal cortex. The participants were divided into the low and high arterial stiffness groups according to the median value. We found that the Stroop interference time was significantly shorter (P = 0.006) and the oxy-Hb signal change in the left prefrontal cortex was significantly larger in the low arterial stiffness group than in the high arterial stiffness group (P = 0.011). In the low, but not the high, arterial stiffness group, the oxy-Hb signal change of the left prefrontal cortex during executive function tasks was significantly larger than the oxy-Hb signal change of the right prefrontal cortex (P = 0.014). These results suggest that increases in central artery stiffness are associated with decreases in oxygenation hemodynamics in the left prefrontal cortex during executive function tasks and reductions in executive function.

Arterial compliance (AC) is an index of the elasticity of large arteries. Endothelial dysfunction has been reported to result in reduced arterial compliance, which represents increased arterial stiffness. A reduction in AC is elicited by high-intensity resistance training, however the mechanisms are obscure. Because a single bout of resistance exercise causes a transient increase in circulating plasma endothelin-1 in humans, some vasoconstrictors may play a role in the mechanisms. The present study aimed to investigate whether resistance training-induced decrease in AC is associated with changes in circulating vasoconstrictors levels in young men. Young sedentary men were assigned to control (n=5) or training (n=9) groups. The training group performed four-week high-intensity resistance training (weight training exercise; three sessions/week). We measured AC and plasma levels of endothelin-1, angiotensin II, and norepinephrine before and after intervention. Resistance training significantly decreased AC, whereas the changes in plasma levels of neither endothelin-1, nor angiotensin II, nor norepinephrine were significantly different between the control and the training groups. Moreo

The aim of this meta-analysis was to evaluate the effects of regular aerobic exercise on blood pressure in East Asians. The inclusion criteria of the randomized controlled trials were healthy East Asian adults, exercise group performing regular aerobic exercise and control group not exercising, and a description of the mean systolic blood pressure or diastolic blood pressure at rest. This study included 31 study groups and 1994 subjects. Pooled changes in blood pressure showed significant reductions (systolic blood pressure: −4.7 mmHg
diastolic blood pressure: −3.2 mmHg). In subgroup analyses, the change in systolic blood pressure for randomized controlled trials meeting the America Heart Association and American College of Sports Medicine guidelines for physical activity to maintain health was significantly larger than in randomized controlled trials not meeting the guidelines. In addition, meta-regression indicated that the change in systolic blood pressure was significantly related to “exercise time × exercise frequency.” The ideal volume of exercise is that for a long time at a high frequency, such as the volume recommended in the America Heart Association and American College of Sports Medicine guidelines: moderate intensity and &gt
150 min per week. List of abbreviations: BP: blood pressure
BMI: body mass index
SBP: systolic blood pressure
DBP: diastolic blood pressure
RCT: randomized controlled trial
AHA: America Heart Association
ACSM: America College of Sports Medicine
SD: standard deviation
HDL-C: high-density lipoprotein cholesterol
LDL-C: low-density lipoprotein cholesterol
TC: total cholesterol
TG: triglycerides
PEDro: Physiotherapy Evidence Database
CI: confidence intervals
%HRmax: percentage of maximal heart rate.

High-intensity resistance training decreases central arterial compliance (CAC). Subendocardial viability ratio (SEVR) is a useful tool that reflects the balance between coronary perfusion and left ventricular afterload. Animal studies have demonstrated that decreased CAC is associated with SEVR deterioration. Therefore, resistance training-induced decrease in CAC may be associated with changes in SEVR. The objective of the present study was to investigate the association between SEVR and CAC using both cross-sectional and longitudinal (i.e., resistance training) study designs. To achieve this, we first conducted a cross-sectional study to investigate the association between SEVR and CAC in 89 young men. Thereafter, a longitudinal study was performed to examine the effects of resistance training on SEVR and CAC in young men. A total of 28 young men were divided into 2 groups: control (n = 13) and training (n = 15). In the training group, subjects underwent supervised resistance training for 4 weeks (5 sets of 10 repetitions at 75% of 1-repetition maximum, 3 times/week). CAC and SEVR were then measured in all subjects. In the cross-sectional study, SEVR was significantly positively correlated with CAC, whereas resistance training significantly decreased both SEVR and CAC. Moreover, training-induced changes in CAC were significantly correlated with changes in SEVR. Thus, these results suggest that resistance training-induced decrease in CAC is associated with decreased SEVR in young men.

BACKGROUND: To identify one of the physiological underlying mechanisms of the predictive effects of urinary liver-type fatty acid-binding protein (L-FABP) for the onset of cardiovascular disease (CVD), we investigated the relationship between urinary L-FABP levels and subendocardial viability ratio (SEVR), a marker of myocardial perfusion, in middle- and older-aged adults. METHODS: This was a cross-sectional study of 249 middle- and older-aged adults (aged 46-83 years). We measured urinary L-FABP levels and central hemodynamic parameters, including SEVR, calculated by pulse wave analysis using an applanation tonometry. RESULTS: In the participants stratified in accordance with the tertiles of urinary L-FABP levels, SEVR decreased in a stepwise fashion with increasing tertiles (p < 0.001). Furthermore, this association remains significant after the consideration of various confounders. On the contrary, urinary albumin levels were not independently related with SEVR. CONCLUSION: Our results demonstrated that urinary L-FABP levels were independently associated with the SEVR of the middle- and older-aged adults. This result suggests that the increase in urinary L-FABP levels even within the normal range might be related to the decrease in myocardial perfusion (SEVR).

Based on research suggesting that nanomaterial containing nanodiamond- and nanoplatinum-coated fibres (DPV576-C) may reduce the stress response, garments to enhance athletes' recovery from training-induced stress have been manufactured. This study examined the effects of wearing recovery garments on the physical and psychological stress of Japanese male baseball players. Thirty-eight players aged 18-21 (19.6 ± 0.2 years) who participated in a two-week intensified training programme were randomly assigned to two groups: 19 wore recovery (DPV576-C) garments (RG group) and 19 wore non-recovery garments (placebo group). Both groups wore the garments overnight. Mood states, using the Profile of Mood States questionnaire, and salivary cortisol levels were measured before (day 0) and after (day 14) the training period. Saliva samples were collected from 07:00-07:30 am. Both groups' fatigue scores significantly increased after the training period (RG: 8.4 ± 0.8-10.1 ± 0.8 score; placebo: 9.8 ± 1.0-11.7 ± 1.0 score). The total mood disturbance (TMD) score increased significantly in the placebo group (21.0 ± 2.3-27.2 ± 3.0 score) but not in the RG group (17

Increased arterial stiffness has emerged as a strong predictor of future cardiovascular events and all-cause mortality. The aim of this study was to elucidate influences of endothelin (ET)-related genetic polymorphisms and regular physical activity on age-related arterial stiffening through a 10-yr longitudinal study. A decadal change in brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, was evaluated retrospectively among 92 volunteers (63 ± 14 yr, 51 men). The targeted single-nucleotide polymorphisms were ET-A receptor SNP rs5333 (ET-A) and ET-B receptor SNP rs5351 (ET-B). Subjects with either ET-A TC or CC genotypes exhibited significantly greater increases in baPWV (+ 15.3 ± 11.7 and +16.6 ± 15.7%/dec, respectively) than ET-A TT genotype holders (+9.2 ± 9.0%/dec), whereas subjects with the ET-B GG genotype showed a significantly greater increase in baPWV (+17.7 ± 14.1%/dec) than other ET-B genotype holders (AA: +9.5 ± 10.0%/dec
AG: + 11.2 ± 9.6%/dec). The combination of these ET-related genetic risks was associated with a 2.4 times greater decadal increase in baPWV compared with no genetic risk (+ 8.1 ± 8.4 vs. 19.5 ± 16.0%/dec). In contrast, individuals engaging in &gt
15 METs·h/wk of aerobic exercise showed substantially smaller increases in baPWV (+5.0 ± 9.7%/dec) compared with their physically inactive peers (approximately +13%/dec). These differences remained significant after adjusting for confounding factors, including baseline baPWV and ET-related genotype risk. Our current longitudinal study found that ET-related gene polymorphisms contribute to diverse age-related changes in arterial stiffness, and that regular sufficient aerobic exercise attenuates the age-related arterial stiffening independently of ET-related gene polymorphisms.

Aorta effectively buffers cardiac pulsatile fluctuation generated from the left ventricular (LV) which could be a mechanical force to high blood flow and low-resistance end-organs such as the brain. A dynamic orthostatic challenge may evoke substantial cardiac pulsatile fluctuation via the transient increases in venous return and stroke volume (SV). Particularly, this response may be greater in endurance-trained athletes (ET) who exhibit LV eccentric remodeling. The aim of this study was to determine the contribution of aortic compliance to the response of cerebral blood flow fluctuation to dynamic orthostatic challenge in ET and age-matched sedentary (SED) young healthy men. ET (n = 10) and SED (n = 10) underwent lower body negative pressure (LBNP) (-30 mmHg for 4 min) stimulation and release the pressure that initiates a rapid regain of limited venous return and consequent increase in SV. The recovery responses of central and middle cerebral arterial (MCA) hemodynamics from the release of LBNP (~15 s) were evaluated. SV (via Modeflow method) and pulsatile and systolic MCA (via transcranial Doppler) normalized by mean MCA velocity (MCAv) significantly increased after the cessation of LBNP in both groups. ET exhibited the higher ratio of SV to aortic pulse pressure (SV/AoPP), an index of aortic compliance, at the baseline compared with SED (P &lt
0.01). Following the LBNP release, SV was significantly increased in SED by 14 ± 7% (mean ± SD) and more in ET by 30 ± 15%
nevertheless, normalized pulsatile, systolic, and diastolic MCAv remained constant in both groups. These results might be attributed to the concomitant with the increase in aortic compliance assessed by SV/AoPP. Importantly, the increase in SV/AoPP following the LBNP release was greater in ET than in SED (P &lt
0.01), and significantly correlated with the baseline SV/AoPP (r = 0.636, P &lt
0.01). These results suggest that the aortic compliance in the endurance athletes is able to accommodate the additional SV and buffer the potential increase in pulsatility at end-organs such as the brain.

The purpose of this study was to examine the effect of habitual exercise on urinary liver-type fatty acid-binding protein (L-FABP), which can reflect the degree of various stresses on renal proximal tubule related to the progression of renal disease, in middle-aged and older adults. Cross-sectional and interventional approaches were used to comprehensively achieve this purpose. In the cross-sectional study, we investigated the relationship between physical activity levels and urinary L-FABP levels in 130 middle-aged and older adults. In the interventional study, subjects (n=31) were divided into two groups: exercise (n=19) and control group (n=12), whereby we examined the effects of 12-week aerobic exercise training on urinary L-FABP levels. The cross-sectional study showed that the urinary L-FABP levels were significantly lower in the higher physical activity group than in the lower physical activity group (P&lt
.05). In the interventional study, 12-week aerobic exercise training significantly decreased urinary L-FABP levels (P&lt
.01). Furthermore, the relative changes in urinary L-FABP levels were significantly correlated with the relative changes in physical activity levels and mean arterial pressure after intervention (r=−.374 and r=.530, respectively). Our results revealed that the urinary L-FABP levels were lower in the higher physical activity individuals, and aerobic exercise training decreased urinary L-FABP levels. These results suggest that habitual exercise appears to be associated with a decrease in the degree of several stresses on renal proximal tubule and to be beneficial for kidney health in middle-aged and older adults.

The objective of this study was to examine the effect of sleep on the acquisition of motor skills in young badminton players. Thirteen badminton players, aged 6–9 years (8.0 ± 0.3 years
mean ± SE), practiced the shuttle bouncing drill, and a skill none of the players had prior experience with. After practice sessions, shuttle bouncing performance was immediately tested and then retested 1 week later. We evaluated sleep parameters for 7 consecutive days using actigraphy. Using the median value of sleep efficiency, subjects were divided into two groups: good sleepers and poor sleepers. Good sleepers had shorter sleep latency (p &lt
0.05), longer wake after sleep onset (p &lt
0.001), longer total sleep time (p &lt
0.005), and higher sleep efficiency (p &lt
0.001) than the poor sleepers. Interestingly, improvement in shuttle bouncing performance was significantly greater in the good sleeper group than that in the poor sleeper group (p &lt
0.05). In addition, we found that changes in the shuttle bouncing performance positively correlated with sleep efficiency (β = 0.765, p &lt
0.01) and total sleep time (β = 0.588, p &lt
0.05) after adjusting for their badminton career. These data suggest that sleep may affect the acquisition of motor skills in young players.

血管内皮機能は血圧の恒常性維持に重要な因子である。近年、血管内皮細胞におけるマイクロRNAが血管内皮機能を調節することが明らかにされている。しかしながら、血圧の恒常性維持におけるマイクロRNAの役割は不明である。そこで我々は、血管内皮細胞特異的Dicer欠損マウスを用いて、安静時および8週間の食塩水摂取後に血圧を測定することで、血圧調節における血管内皮細胞のマイクロRNAの役割を検討した。血管内皮細胞特異的Dicerホモ欠損マウスは胎生致死であったため、ヘテロ欠損マウス(Het)を用いて血行動態の解析を行った。Hetマウスの肺におけるDicer mRNA発現は、WTマウスと比較して有意に減少した。しかしながら、8週間の食塩水摂取の前後において、心拍数、収縮期血圧および拡張期血圧のいずれにも顕著な差は認められなかった。本研究において、血管内皮細胞特異的Dicer欠損マウスが胎生致死であることから、血管内皮細胞のDicerおよびマイクロRNAはマウス胚発生に必須であることが示された。加えて、血管内皮細胞特異的Dicerヘテロ欠損マウスでは、血行動態に顕著な表現型は観察されなかった。(著者抄録)

<title>Abstract</title>Testosterone is a male sex hormone and low circulating testosterone levels are associated with various health disorders in men. Obesity results in reduced circulating testosterone levels in men. Previously, we demonstrated that lifestyle modifications (combination of aerobic exercise and dietary modification) increase circulating testosterone levels in overweight/obese men. However, the effect of regular aerobic exercise on serum testosterone levels remains unclear. The purpose of this study was to investigate the effect of a 12-week aerobic exercise intervention on circulating testosterone levels in normal-weight and overweight/obese men. Sixteen normal-weight men and twenty-eight overweight/obese men completed a 12-week aerobic exercise intervention. Before and after the intervention, we measured serum total testosterone, free testosterone, and bioavailable testosterone levels, and categorized the physical activity levels (light, moderate, or vigorous) in all participants. At baseline, serum total testosterone, free testosterone, and bioavailable testosterone levels were significantly lower in overweight/obese men than in normal-weight men (all p&lt;0.01). After the 12-week aerobic exercise intervention, serum total testosterone, free testosterone, and bioavailable testosterone levels significantly increased in overweight/obese men (p&lt;0.01). In addition, stepwise multivariable linear regression analysis revealed the increase in vigorous physical activity was independently associated with increased serum total testosterone levels (β=0.47, p=0.011). We demonstrated that a 12-week aerobic exercise intervention increased serum total testosterone, free testosterone, and bioavailable testosterone levels in overweight/obese men. We suggest that an increase in vigorous physical activity increased circulating testosterone levels in overweight/obese men.

The aim of present study was to investigate the association plasma xanthine oxidoreductase activity, which has gained attention as a novel preventive target of cardiovascular disease, and various physiological parameters and was to determine the effects of habitual exercise on plasma xanthine oxidoreductase activity in middle-Aged and older women. In the cross-sectional study, we investigated the association between plasma xanthine oxidoreductase activity and various physiological parameters in 94 middle-Aged and older women. In the interventional study, subjects (n = 22) were divided into two groups: exercise (n = 12) or the control group (n = 10), whereby we examined the effect of 12-week aerobic exercise training on plasma xanthine oxidoreduc- tase activity in middle-Aged and older women. The cross-sectional study demonstrated that plasma xanthine oxidoreductase activity was significantly associated with various physiological parameters, including visceral fat and daily step counts. In the interventional study, the plasma xanthine oxidoreductase activity significantly decreased after the 12-week aerobic exercise training, its changes were inversely associated with the changes in daily step counts. Our results revealed that the plasma xanthine oxidoreductase activity was associated with visceral fat accumulation and lack of exercise, and it was decreased by the aerobic exercise training.

The age-related decrease in cerebral blood flow velocity increases the risk of cerebrovascular disease. Milk protein-derived bioactive peptides, e.g., lactotripeptide (LTP), have been shown to inhibit angiotensin converting enzyme activities and increase vasodilator production. We hypothesized that LTP ingestion increases cerebral blood flow velocity in middle-aged and older adults. In a randomized, placebo-controlled, double-blind design, 15 healthy middle-aged and older adults were assigned to either a LTP group or a placebo group. The subjects ingested LTP or placebo orally for 8 weeks. Before and after intervention, middle cerebral blood flow velocity was measured using transcranial Doppler ultrasonography. The baseline middle cerebral blood flow velocity and most other key dependent variables did not differ between the groups. LTP ingestion significantly increased middle cerebral blood flow velocity, but there was no such improvement in the placebo groups. We concluded that 8 weeks of LTP ingestion increased middle cerebral blood flow velocity in middle-aged and older adults.

The brain's low resistance ensures a robust blood flow throughout systole and diastole and is susceptible to flow pulsatility. Increased cerebral pulsatility contributes to the progression of cerebrovascular disease. Although aerobic exercise affects vascular function, little is known about the effect of exercise on the cerebral pulsatility index in older adults. The aim of this study was to investigate the effect of exercise training on the post-exercise cerebral pulsatility response in older adults. Ten healthy older adults participated in a 12-week exercise training intervention. Before and after the intervention, we measured the pulsatility index of the middle cerebral artery by means of transcranial Doppler method at baseline and following a cycling exercise bout performed at an intensity corresponding to the ventilatory threshold. Before exercise training, there was no significant change in the cerebral pulsatility response to an acute bout of cycling exercise. However, after the intervention, cerebral pulsatility decreased significantly following 30 min of an acute cycling exercise (P < 0.05). This study demonstrated that cerebral pulsatility index did not change following an acute bout of cycling exercise at an intensity corresponding to ventilatory threshold, but that, after 12 weeks of exercise training, cerebral pulsatility index was reduced at 30 min after a single bout of cycling exercise. These results suggest that long-term aerobic exercise training may enhance the post-exercise reduction in pulsatility index in older adults.

Cerebral hemodynamics plays an important role in cognitive performance, and as such, age-related cognitive dysfunction and cerebral hypoperfusion increase the risk of dementia. However, age-related changes in cerebral oxygenation and cognitive function remain unclear. The aim of this study was to investigate age-related declines in cerebral oxygenation and executive function cross-sectionally. Ninety-eight healthy Japanese adults (age range: 23-79 years; 40 males, 58 females) participated in the present study using local advertisements. The participants were divided into 4 age groups: young (20-39 years; M15/F7), 50s (50-59 years; M10/F12), 60s (60-69 years; M9/F31), and 70s (70-79 years; M6/F8). We measured oxygenated hemoglobin (oxy-Hb) signal change in the prefrontal cortex during the Stroop task, and calculated Stroop interference time in cross-sectional design. This test is widely used to measure the ability to properly control attention and behavior in executing tasks, and to evaluate executive functions mainly associated with the prefrontal cortex. Oxy-Hb signal changes in the left prefrontal cortex in the 60s and 70s groups were significantly lower than those in the young group (both P < 0.05). Additionally, Stroop interference time was significantly longer in the 60s and 70s groups than in the young group (both P < 0.05). Furthermore, differences in oxy-Hb signal change between the left and right prefrontal cortex were evident only in the young group. These results suggest that the age-related decrease in executive function is associated with decrease in the cerebral oxygenation hemodynamics in the left prefrontal cortex.

The capillary network is distributed throughout the body. and its reconstruction is induced under various pathophysiological conditions. MicroRNAs are small noncoding RNAs that regulate gene expression via posttranscriptional mechanisms and are involved in many biological functions, including angiogenesis. Previous studies have shown that each microRNA of miR-23 clusters, composed of the miR-23a cluster (miR-23a-27a-24-2) and miR-23b cluster (miR-23b-27b-24-1), regulates angiogenesis in vitro. However, the role of miR-23 clusters. located within a single transcription unit, in angiogenesis in vivo has not been elucidated. In the present study. we generated vascular endothelial cell (EC)-specific miR-23 cluster double-knockout (DKO) mice and demonstrated sprouting angiogenesis under various conditions, including voluntary running exercise. hindlimb ischemia, skin wound healing, and EC sprouting from aorta explants. Here, we demonstrated that EC-specific miR-23 DKO mice are viable and fertile, with no gross abnormalities observed in pups or adults. The capillary number was normally increased in the muscles of these DKO mice in response to 2 wk of voluntary running and hindlimb ischemia. Furthermore, we did not observe any abnormalities in skin wound closure or EC sprouting from aortic ring explains in EC-specific miR-23 cluster DKO mice. Our results suggest that endothelial miR-23 clusters are dispensable for embryonic development and postnatal angiogenesis in vivo.NEW & NOTEWORTHY We generated vascular endothelial cell (EC)-specific miR-23a/b cluster double-knockout mice and determined sprouting angiogenesis under various conditions, including voluntary running exercise. hindlimb ischemia, skin wound healing, and EC sprouting from aorta explants. We demonstrated that the double-knockout mice were viable and fertile, with no gross abnormalities in exercise- and ischemia-induced angiogenesis and skin wound closure or EC sprouting from aortic ring explants.

The aim of the current study was to perform a systematic review and meta-analysis to evaluate the relationship between step count and changes in blood pressure (BP). Studies involving healthy adults and an intervention in the form of brisk walking with a pedometer were included. Net changes in BP and step count in each trial were calculated and pooled. In addition, the pooled net changes of two categories (trials that achieved walking 10,000 steps a day and those that did not) were compared. A meta-regression analysis was performed to examine the relationship between net changes in BP and step count. Fourteen trials were analyzed. Pooled net changes in BP improved significantly (systolic BP, -3.1 mm Hg; diastolic BP, -1.6 mm Hg). When the trials were categorized depending on whether they achieved walking 10,000 steps a day, the pooled net change in systolic BP and diastolic BP did not differ significantly between both groups of subjects. The meta-regression analyses indicated that net change in systolic BP was significantly associated with an increased step count (e.g., systolic BP is expected to decrease approximately 4 mm Hg if increased step count by 2000 steps a day). However, net change in systolic BP was not associated with the step count in an intervention group following the intervention. At present, there is presumably no evidence that walking 10,000 steps a day lowers the BP to any marked degree. In order to reduce systolic BP by walking with a pedometer, one should be mindful of increasing one's step count.

Background: Postprandial regulation of central systolic blood pressure (cSBP) is impaired by obesity-related disorders. The present study aimed to examine the effect of hypocaloric diet intervention on cSBP when performing oral glucose tolerance test (OGTT) in overweight/obese men and explore its mechanism.
Methods: Fifteen overweight/obese men (mean +/- SD; age, 52 +/- 10 years; BMI, 29.1 +/- 2.3 kg/m(2)) completed a 12-week dietary modification program (group lectures and individual counseling conducted 8 times in 12 weeks, 1680 kcal/day). Before and after the program, body mass, daily intakes of total energy and major macronutrients, serum lipid profiles, and homeo-stasis model assessment for insulin resistance (HOMA-IR) were measured, and plasma glucose, serum insulin, and cSBP (i.e., radial second systolic pressure) were assessed when fasting and at 60 min and 120 min after 75 g oral glucose loading.
Results: The 12-week program led to successful weight loss (-10.1 kg or -12.1%) with significant reductions in the daily intakes of total energy and major macronutrients. Consequently, low-density lipoprotein cholesterol, triglycerides, HOMA-IR (2.1 +/- 1.3 to 0.8 +/- 0.3, p &lt; 0.01), and glucose and insulin during OGTT were substantially decreased after 12 weeks. The diet program had also resulted in significantly reduced 2-h averaged cSBP during OGTT ( 111 +/- 11 to 103 +/- 10 mmHg, p &lt; 0.01). There was a significant correlation between the changes from baseline in both HOMA-IR and 2-h averaged cSBP (r(s) = 0.69, p &lt; 0.01).
Conclusions: The current results suggest that the dietary modification-induced improvement in insulin resistance has contributed to a significant reduction in cSBP during OGTT in over-weight/obese men. (C) 2017 Association for Research into Arterial Structure and Physiology. Published by Elsevier B.V. All rights reserved.

Fortified milk and resistance training (RT) increase muscle mass, muscle strength, and physical performance in older adults, but it remains unclear whether RT combined with aerobic training (AT) would have stronger effects on these outcomes. The purpose of this study was to examine the effects of aerobic and resistance training (ART) combined with fortified milk consumption on muscle mass, muscle strength, and physical performance in older adults.
Open-labeled randomized controlled trial. Setting: University of Tsukuba.
Fifty-six older adults aged 65-79.
Participants were randomly allocated into resistance training (RT + fortified milk, n = 28) and aerobic and resistance training (ART + fortified milk, n = 28) groups. All participants attended supervised exercise programs twice a week at University of Tsukuba and ingested fortified milk every day for 12 weeks. Skeletal muscle index ([SMI]: appendicular lean mass/ height(2)) was assessed using dual-energy X-ray absorptiometry as a muscle mass measure. One-repetition maximum strength was measured using four kinds of resistance training machines (chest press, leg extension, leg curl, and leg press) as muscle strength measures. Sit-to-stand and arm curl tests were also assessed as physical performance measures.
The primary measurements were muscle mass and strength. The secondary outcomes were physical performance, blood samples, habitual diet, habitual physical activity, and medication use.
Although the muscle strength and physical performance measures significantly improved in both groups, SMI significantly improved in only the RT group. There was no significant difference in the change in SMI and muscle strength measures between the two groups. However, the change in sit-to-stand and arm curl measures in the ART group were significantly higher than those in the RT group.
These results suggest that AT before RT combined with fortified milk consumption has similar effects on skeletal muscle mass and strength compared with RT alone, but it may be a more useful strategy to improve physical performance in older adults. Although the mechanism of our intervention is uncertain, our program would be an effective prevention for sarcopenia in older adults.

The underlying mechanism linking the decline in exercise capacity with renal dysfunction remains unclear. Urinary liver-type fatty acid-binding protein (L-FABP) levels reflect the degree of peritubular capillary blood flow, an important factor for renal dysfunction with aging. The aim of this study was to examine the relationship between exercise capacity and urinary L-FABP levels.
This was a cross-sectional study of 187 middle-aged and older individuals (aged 50-83 years) without chronic kidney disease (CKD). We assessed urinary L-FABP levels, peak oxygen consumption (), and grip strength.
Urinary L-FABP levels inversely correlated with both (r (s) = -0.349) and grip strength (r (s) = -0.485). When the participants were divided into four groups according to the median values of aerobic fitness and muscular strength ( and grip strength), urinary L-FABP levels were the highest in participants with lower levels of aerobic fitness and muscular strength (2.95 +/- 1.43 mu g/g creatinine) and the lowest in the participants with higher levels of aerobic fitness and muscular strength (1.33 +/- 0.76 mu g/g creatinine). The difference between the two groups was significant (P &lt; 0.001).
Our results demonstrate that both and grip strength were inversely associated with urinary L-FABP levels in middle-aged and older individuals without CKD. This suggests that a decline in exercise capacity is associated with a reduction in peritubular capillary blood flow, providing a novel insight into the underlying mechanism linking the decline in exercise capacity to the development of renal dysfunction.

Chlorella is a unicellular green alga that contains high levels of proteins, vitamins and minerals. The present study investigated the effects of a 4-week Chlorella-derived multicomponent supplementation on maximal oxygen uptake and circulating vitamin B-2 levels in healthy men. Thirty-four participants were randomly divided into two groups: placebo or Chlorella. Prior to the intervention, we observed that the intake of several minerals and soluble vitamins did not satisfy the nutrient requirements of either group by assessing the frequency of daily food intake. There was a significant negative relationship between the pre-intervention maximal oxygen uptake and serum vitamin B-2 concentrations in all subjects (r = -0.372). Maximal oxygen uptake significantly increased after Chlorella supplementation (before vs after, 42.1 +/- 1.5 vs 44.9 +/- 1.6 ml/kg/min), while serum vitamin B-2 concentrations did not (14.6 +/- 0.9 vs 14.0 +/- 0.9 mu g/L). In conclusion, Chlorella-derived multicomponent supplementation increases maximal oxygen uptake in individuals with an insufficient micro nutrient status, although there was no association between the increase in aerobic capacity and serum levels of vitamin B-2.

Brachial-ankle pulse wave velocity (baPWV) has become a popular modality of arterial stiffness measurement. However, its projected arterial segment does not include the proximal aorta which plays important roles for attenuating cardiac pulsation and reducing afterload. We hypothesised that aerobic capacity would be more strongly associated with PWV including the proximal aorta than that omitting the proximal aorta. To test our hypothesis, we compared the association between aerobic capacity and arterial stiffness parameters omitting vs. including the proximal aorta (i.e. baPWV vs. heart-ankle PWV [haPWV]) in 82 apparently healthy men (18-64 years). Estimated VO2max significantly correlated with baPWV (r = -0.394, P &lt; .001), and more strongly with haPWV (r = -0.546, P &lt; .001). The forward stepwise multi-regression analysis revealed that haPWV (beta = -0.335), as well as age, heart rate, and body mass index (beta = -0.280 to -0.297), was a significant independent determinant explaining variance of estimated VO2max. These results suggest that aerobic capacity is influenced more strongly by the proximal aortic stiffness than distal aortic stiffness.

High cerebral pressure and flow fluctuations could be a risk for future cerebrovascular disease. This study aims to determine whether acute systemic vasoconstriction affects the dynamic pulsatile hemodynamic transmission from the aorta to the brain. We applied a stepwise lower body negative pressure (LBNP) (-10, -20, and -30 mmHg) in 15 young men to induce systemic vasoconstriction. To elucidate the dynamic relationship between the changes in aortic pressure (AoP; estimated from the radial arterial pressure waveforms) and the cerebral blood flow velocity (CBFV) at the middle cerebral artery (via a transcranial Doppler), frequency-domain analysis characterized the beat-to-beat slow oscillation (0.02-0.30 Hz) and the intra-beat rapid change (0.78-9.69 Hz). The systemic vascular resistance gradually and significantly increased throughout the LBNP protocol. In the low-frequency range (LF: 0.07-0.20 Hz) of a slow oscillation, the normalized transfer function gain of the steady-state component (between mean AoP and mean CBFV) remained unchanged, whereas that of the pulsatile component (between pulsatile AoP and pulsatile CBFV) was significantly augmented during -20 and -30 mmHg of LBNP (+28.8% and +32.4% vs. baseline). Furthermore, the relative change in the normalized transfer function gain of the pulsatile component at the LF range correlated with the corresponding change in systemic vascular resistance (r = 0.41, P = 0.005). Regarding the intra-beat analysis, the normalized transfer function gain from AoP to CBFV was not significantly affected by the LBNP stimulation (P = 0.77). Our findings suggest that systemic vasoconstriction deteriorates the dampening effect on the pulsatile hemodynamics toward the brain, particularly in slow oscillations (e.g., 0.07-0.20 Hz).
NEW & NOTEWORTHY We characterized the pulsatile hemodynamic transmission from the heart to the brain by frequency-domain analysis. The low-frequency transmission was augmented with a mild LBNP stimulation partly due to the elevated systemic vascular resistance. A systemic vasoconstriction deteriorates the dampening effect on slow oscillations of pulsatile hemodynamics toward the brain.

A strategy for the preservation of intrarenal vasculature conditions remains obscure in middle-aged and older individuals without the renal disease. In the present study, we sought to identify whether the maintenance of muscular strength is an effective method of preserving the intrarenal vasculature condition of middle-aged and older individuals. Therefore, we applied a cross-sectional approach for investigating the relationship between muscular strength and the condition of the intrarenal vasculature. In 169 middle-aged and older individuals without renal disease, handgrip strength (HGS) and the renal resistive index (RRI) were measured as the parameters of muscular strength and intrarenal vascular resistance, respectively. The RRI was elevated with aging (r(s) = 0.499, P &lt; 0.001) and was inversely correlated with HGS (r(s) = 0.370, P &lt; 0.001). The relationship between RRI and HGS remained significant after the consideration of confounders, including age and various central hemodynamic parameters. Furthermore, when the individuals were divided into four groups according to age (middle-aged or older) and the median HGS values, the RRI exhibited the highest values in the older group with lower HGS values (P &lt; 0.001). Our findings indicate that muscular strength as assessed by HGS is independently associated with the RRI (i.e. intrarenal vascular resistance) in middle-aged and older individuals. This finding suggests that the muscular strength may be one of the key factors to preserve the intrarenal vasculature condition. (C) 2017 Elsevier Inc. All rights reserved.

Exercise has numerous health-promoting effects in humans(1); however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly(2-4). This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP)(5-7) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1)(8). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation(9) and peroxisome proliferative activated receptor gamma coactivator (Ppargc)-1 alpha (also known as PGC-1 alpha; encoded by Ppargc1a)(10) expression in skeletal muscle. Supplementation with the anti-oxidant N-acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle-effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP-LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

The symptoms of anemia, decreases in the levels of circulating red blood cells (RBC), hemoglobin (Hb) and hematocrit (Ht) lead to decrease endurance performance, and the risk of anemia increases in female endurance athletes. Although Hb is composed of a large amount of amino acids, the relationships between circulating levels of amino acids and RBC, Hb and Ht in female endurance athletes have not been clarified yet. Thus, the purpose of the present study was to investigate the relationship between circulating levels of amino acids and RBC, Hb and Ht in female endurance athletes. Twenty-four female endurance athletes (19.8 ± 0.2 years) participated in this study. We measured circulating levels of RBC, Hb and Ht from blood. Also, we measured circulating levels of amino acids from plasma by use of comprehensive analysis. The levels of circulating RBC, Hb and Ht in all subjects were within the normal range. We found that circulating taurine levels were significantly correlated with RBC (r = 0.48, p &lt
0.05), Hb (r = 0.44, p &lt
0.05) and Ht (r = 0.42, p &lt
0.05) in female endurance athletes. In the present study, we demonstrated that circulating taurine levels were significantly associated with RBC, Hb and Ht in female endurance athletes. These results suggest that circulating taurine levels may be a predictor of anemia and treatment strategy for anemia.

Decreased distensibility of carotid artery is independently associated with the incidence of cardiovascular and cerebrovascular events. Arterial distensibility is determined by vascular tone. Since shear stress is an important driving force of vasodilatory substances production form endothelial cells, we hypothesized that local basal (i.e., resting) arterial blood flow velocity is associated with regional arterial distensibility. To test this hypothesis, we determined the influence of local blood flow velocity on carotid arterial distensibility in cross-sectional study design. In a total of 73 apparent healthy men (18-64 years), carotid arterial properties, including measures of carotid arterial distensibility and BFV at rest, were evaluated via B-mode and Doppler ultrasound imaging and applanation tonometry system. Carotid arterial peak BFV and the absolute and normalized pulsatile BFV significantly correlated with age (r = -0.453 to -0.600, p &lt; 0.0001), whereas mean and minimum BFV were not influenced by age. Distensibility coefficient of carotid artery correlated with peak BFV (r = 0.305, p &lt; 0.01) and more strongly with pulsatile (i.e., systolic minus end-diastolic) BFV (r = 0.406, p &lt; 0.0001) and the normalized pulsatile BFV by time-averaged velocity (r = 0.591, p &lt; 0.0001). Multi-regression analysis revealed that age (beta = -0.57, p &lt; 0.0001) was the primary independent determinant for distensibility coefficient. In addition with this, carotid lumen diameter (beta = -0.202, p &lt; 0.01) and the normalized pulsatile BFV (beta = 0.237, p &lt; 0.05) were significant independent determinants of distensibility coefficient. Qualitatively similar results (although inverse in direction) were obtained by use of beta-stiffness index. These results suggest that greater gradient of blood flow velocity during a cardiac cycle are favorably associated with distensibility of carotid artery.

Hemodynamic shear stress is the frictional force of blood on the arterial wall. The shear pattern in the conduit artery affects the endothelium and may participate in the development and progression of atherosclerosis. We investigated the role of the shear pattern in age- and aerobic exercise-induced changes in conduit artery wall thickness via cross-sectional and interventional studies. In a cross-sectional study, we found that brachial shear rate patterns and brachial artery intima-media thickness (IMT) correlated with age. Additionally, brachial artery shear rate patterns were associated with brachial artery IMT in 102 middle-aged and older individuals. In an interventional study, 39 middle-aged and older subjects were divided into 2 groups: control and exercise. The exercise group completed 12 weeks of aerobic exercise training. Aerobic exercise training significantly increased the antegrade shear rate and decreased the retrograde shear rate and brachial artery IMT. Moreover, changes in the brachial artery antegrade shear rate and the retrograde shear rate correlated with the change in brachial artery IMT. The results of the present study indicate that changes in brachial artery shear rate patterns may contribute to age- and aerobic exercise training-induced changes in brachial artery wall thickness. (C) 2017 S. Karger AG, Basel

Regular exercise improves aging-induced deterioration of arterial stiffness, and is associated with elevated production of pentraxin 3 (PTX3) and anti-inflammatory as well as anti-atherosclerotic effects. However, the time-dependent effect of exercise training on arterial stiffness and PTX3 production remains unclear. The purpose of this study was to investigate the time course of the association between the effects of training on the circulating PTX3 level and arterial stiffness in middle-aged and older adults. Thirty-two healthy Japanese subjects (66.2 +/- 1.3 year) were randomly divided into two groups: training (exercise intervention) and sedentary controls. Subjects in the training group completed 8 weeks of aerobic exercise training (60-70% peak oxygen uptake (VO2peak) for 45 min, 3 days per week); during the training period, we evaluated plasma PTX3 concentration and carotid-femoral pulse wave velocity (cfPWV) every 2 wk. cfPWV gradually declined over the 8-week training period, and was significantly reduced after 6 and 8 week of exercise intervention (P &lt; 0.05). Plasma PTX3 level was significantly increased after 4 weeks of the intervention (P &lt; 0.05). In addition, the exercise training-induced reduction in cfPWV was negatively correlated with the percent change in plasma PTX3 level after 6 week (r = -0.54, P &lt; 0.05) and 8 weeks (r = -0.51, P &lt; 0.05) of the intervention, but not correlated at 4 weeks. Plasma PTX3 level was elevated at the early stage of the exercise training intervention, and was subsequently associated with training-induced alteration of arterial stiffness in middle-aged and older adults.

Choi, Y, Akazawa, N, Zempo-Miyaki, A, Ra, S-G, Shiraki, H, Ajisaka, R, and Maeda, S. Acute effect of high-intensity eccentric exercise on vascular endothelial function in young men. J Strength Cond Res 30(8): 2279-2285, 2016-Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and arterial stiffness after high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 ± 1 year) performed maximal eccentric elbow flexor exercise using their nondominant arm. Before and 45 minutes after eccentric exercise, carotid arterial compliance and brachial artery FMD and L-FMC in the nonexercised arm were measured. Carotid arterial compliance was significantly decreased, and β-stiffness index significantly increased after eccentric exercise. Brachial FMD was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial L-FMC before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in FMD (r = 0.779; p 0.05), and a negative correlation was detected between change in β-stiffness index and change in FMD (r = -0.891; p < 0.01) with eccentric exercise. In this study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction.

Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and arterial stiffness after high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 +/- 1 year) performed maximal eccentric elbow flexor exercise using their nondominant arm. Before and 45 minutes after eccentric exercise, carotid arterial compliance and brachial artery FMD and L-FMC in the nonexercised arm were measured. Carotid arterial compliance was significantly decreased, and b-stiffness index significantly increased after eccentric exercise. Brachial FMD was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial L-FMC before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in FMD (r = 0.779; p &lt;= 0.05), and a negative correlation was detected between change in b-stiffness index and change in FMD (r = 0.891; p &lt;= 0.01) with eccentric exercise. In this study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction.

Decreases in saliva secretion compromise food mastication and swallowing, reduce mucosal immune function, and increase the risk for oral diseases like dental caries. Chlorella is a green alga that contains a variety of nutrients including amino acids, vitamins, and minerals. In our previous study, Chlorella-derived multi component supplementation did not affect salivary flow rates in healthy young individuals, but Chlorella-derived supplementation attenuated a decrease in saliva secretion that was observed during a kendo training camp. Hence, we hypothesized that Chlorella-derived supplementation increases saliva secretion in individuals with lower rates of saliva flow. Sixty-four subjects took Chlorella-derived tablets for four weeks. Before and after supplementation, saliva samples were collected by chewing cotton. In the complete study group, there was no difference in saliva production before and after supplementation (1.91 +/- 0.11 ml/min before vs 2.01 +/- 0.12 ml/min after). Analysis of subgroups based on saliva production before supplementation found an increase in saliva secretion in the lower saliva flow group (1.18 +/- 0.06 vs 1.38 +/- 0.08 ml/min), but no change in the higher saliva flow group (2.63 +/- 0.11 vs 2.64 +/- 0.15 ml/min). These results suggest that Chlorella-derived multicomponent supplementation increases saliva production in individuals with lower levels of saliva secretion.

There is a delayed increase in arterial stiffness after eccentric exercise that is possibly mediated by the concurrent delayed increase in circulating oxidative stress. Taurine has anti-oxidant action, and taurine supplementation may be able to attenuate the increase in oxidative stress after exercise. The purpose of the present study was to investigate whether taurine supplementation attenuates the delayed increase in arterial stiffness after eccentric exercise. In the present double-blind, randomized, and placebo-controlled trial, we divided 29 young, healthy men into 2 groups. Subjects received either 2.0 g of placebo (n = 14) or taurine (n = 15) 3 times per day for 14 days prior to the exercise, on the day of exercise, and the following 3 days. The exercise consisted of 2 sets of 20 maximal-effort eccentric repetitions with the nondominant arm only. On the morning of exercise and for 4 days thereafter, we measured serum malondialdehyde (MDA) and carotid-femoral pulse wave velocity (cfPWV) as indices of oxidative stress and arterial stiffness, respectively. On the third and fourth days after exercise, both MDA and cfPWV significantly increased in the placebo group. However, these elevations were significantly attenuated in the taurine group. The increase in MDA was associated with an increase in cfPWV from before exercise to 4 days after exercise (r = 0.597, p &lt; 0.05) in the placebo group, but not in the taurine group. Our results suggest that delayed increase in arterial stiffness after eccentric exercise was probably affected by the exercise-induced oxidative stress and was attenuated by the taurine supplementation.

Obesity has reached epidemic proportions worldwide. Obesity results in reduced serum testosterone levels, which causes many disorders in men. Lifestyle modifications (increased physical activity and calorie restriction) can increase serum testosterone levels. However, it is unknown whether increased physical activity or calorie restriction during lifestyle modifications has a greater effects on serum testosterone levels. Forty-one overweight and obese men completed a 12-week lifestyle modification program (aerobic exercise training and calorie restriction). We measured serum testosterone levels, the number of steps, and the total energy intake. We divided participants into two groups based on the median change In the number of steps (high or low physical activities) or that in calorie restriction (high or low calorie restrictions). After the program, serum testosterone levels were significantly increased. Serum testosterone levels in the high physical activity group were significantly higher than those in the low activity group. This effect was not observed between the groups based on calorie restriction levels. We found a significant positive correlation between the changes in serum testosterone levels and the number of steps. Our results suggested that an increase in physical activity greatly affected the increased serum testosterone levels in overweight and obese men during lifestyle modification.

高齢女性の筋力、筋量、骨塩密度を増加することが知られている全身振動(WBV)を伴う抵抗運動が、動脈壁の硬化に及ぼす効果について検討した。運動やスポーツを行っていない閉経後の健康な非喫煙女性12名(年齢66±1歳)を対象とした。被験者は20分の仰臥位安静後に、WBVの有り無しで静止スクワット運動を20分実施し、15分仰臥位安静した。運動前と運動後15分に心拍数75beats/分における増大指数(AI@75)を計測して、動脈壁硬化の指標とした。WBV運動と非WBV運動は別の日に順不同で行った。AI@75はWBVを伴わない静止スクワット運動後15分で有意に増加した。一方、WBVを伴う静止スクワット運動の前後ではAI@75の変化は認められなかった。WBVを伴う静止スクワット運動は、高齢女性の動脈壁硬化の増加を防止できることが示唆された。

Chlorella is a unicellular green alga, which contains a variety of nutrients including amino acids, dietary fibers, n-3 unsaturated fatty acid, vitamins, and minerals. We previously demonstrated that Chlorella-derived multicomponent supplementation decreases arterial stiffness in young men. However, mechanisms underlying the reduction in arterial stiffness by Chlorella-derived supplementation and the effect in middle-aged and older individuals have remained unexplored. This study tested our hypothesis that Chlorella-derived supplementation improves arterial stiffness via an increase in nitric oxide (NO, a endothelium-derived relaxing factor) production in middle-aged and older individuals. Thirty-two subjects between 45 and 75 years of age assigned to placebo and Chlorella groups in a double-blinded manner and took respective tablets for 4 weeks. Before and after the supplementations, brachial-ankle pulse wave velocity (baPWV, an index of arterial stiffness) and plasma nitrite/nitrate (NOx, end product of NO) concentration were measured. There was no difference in baPWV between before and after the placebo intake, but baPWV decreased after the Chlorella supplementation. Changes in baPWV with the Chlorella supplementation were correlated with those in plasma NOx concentration. We concluded that Chlorella-derived multicomponent supplementation decreases arterial stiffness in middle-aged and older individuals. It may be associated with increase in NO production by vascular endothelium.

Central arterial blood pressure (BP) is more predictive of future cardiovascular events than is brachial BP because it reflects the BP load imposed on the left ventricle with greater accuracy. However, little is known about the effects of exercise training on central hemodynamic response to acute exercise. The purpose of the present study was to determine the influence of an aerobic exercise regimen on the response of aortic BP after a single aerobic exercise in postmenopausal women. Nine healthy postmenopausal women (age: 61 + 2 years) participated in a 12-week aerobic exercise training regimen. Before and after the training, each subjects performed a single bout of cycling at ventilatory thresholds for 30 min. We evaluated the post exercise aortic BP response, which was estimated via the general transfer function from applanation tonometry. After the initial pre-training aerobic exercise session, aortic BP did not change significantly: however, aortic pulse pressure and augmentation pressure were significantly attenuated after the single aerobic exercise session following the 12 week training regimen. The present study demonstrated that a regular aerobic exercise training regimen induced the post-exercise reduction of aortic pulse pressure and augmentation pressure. Regular aerobic exercise training may enhance post-exercise reduction in aortic BP.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in vascular endothelial function. Vascular endothelial function is a potent regulator of arterial stiffness, an independent risk factor for cardiovascular disease. However, it is unknown whether LOX-1 is associated with arterial stiffness. Plasma concentrations of soluble LOX-1 (sLOX-1) and brachial-ankle pulse wave velocity (baPWV, an index of arterial stiffness) were measured in 143 individuals between 51 and 83 years of age. Plasma sLOX-1 concentration was correlated with baPWV (r = 0.288, p = 0.0005). In stepwise regression analysis, plasma sLOX-1 concentration was associated with baPWV, after adjusting for age; body mass index; blood pressure; heart rate; blood levels of cholesterol, triglycerides, glucose, hemoglobin A1c, and insulin; sex; and use of antihypertensives, lipid-lowering agents, and other medications (R-2 = 0.575, p&lt;0.0001). Multiple logistic regression demonstrated that plasma sLOX-1 concentration was independently associated with elevated baPWV (&gt;= 14.0 m/s; odds ratio, 1.01; 95% confidence interval, 1.00-1.03; p = 0.03). These results suggest that LOX-1 is associated with arterial stiffness.

Polyphenolic curcumin is known to have potent anti-inflammatory effects; thus the present study investigated the hypothesis that curcumin ingestion would attenuate muscle damage after eccentric exercise.
Fourteen untrained young men (24 +/- A 1 years) performed 50 maximal isokinetic (120A degrees/s) eccentric contractions of the elbow flexors of one arm on an isokinetic dynamometer and the same exercise with the other arm 4 weeks later. They took 150 mg of curcumin (theracurmin) or placebo (starch) orally before and 12 h after each eccentric exercise bout in a randomised, crossover design. Maximal voluntary contraction (MVC) torque of the elbow flexors, range of motion of the elbow joint, upper-arm circumference, muscle soreness, serum creatine kinase (CK) activity, and plasma interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) concentration were measured before, immediately after, and 24, 48, 72 and 96 h after each eccentric exercise. Changes in these variables over time were compared between curcumin and placebo conditions by two-way repeated measures ANOVA.
MVC torque decreased smaller and recovered faster (e.g., 4 days post-exercise: -31 +/- A 13 % vs. -15 +/- A 15 %), and peak serum CK activity was smaller (peak: 7684 +/- A 8959 IU/L vs. 3398 +/- A 3562 IU/L) for curcumin than placebo condition (P &lt; 0.05). However, no significant differences between conditions were evident for other variables, and no significant changes in IL-6 and TNF-alpha were evident after exercise.
It is concluded that theracurmin ingestion attenuates some aspects of muscle damage such as MVC loss and CK activity increase.

Lack of elasticity in the central artery causes an increase in left ventricular (LV) afterload. Although regular moderate-intensity endurance exercise improves cardiovascular function, including arterial destiffening, little is known about the effect of short-term vigorous exercise on cardiovascular function (i.e., the interaction between cardiac and arterial functions). We measured arterial stiffness [via pulse wave velocity from the heart to ankle (haPWV)] and LV contractility (via systolic interval time) before and after a 1-week training camp in a total of 33 regularly highly-trained collegiate endurance runners. They participated in three training sessions per day which mainly consisted of long-distance running and sprint training. The averaged running distance was a parts per thousand 44 % longer during the camp than the regular training program. After the camp, heart rate at rest and haPWV were significantly increased, whereas blood pressure remained unchanged. Although a ratio of pre-ejection period and LV ejection time (PEP/LVET, an index of blunted LV contractility) was unaltered, presumably due to the large variability of individual response, there was a significant correlation between changes in haPWV and PEP/LVET (r = 0.54, P &lt; 0.01). These results suggest that, in regularly highly-trained endurance athletes, arterial stiffness increases after a training camp characterized by greater training volume (vs. regular training), and that the individual response in arterial stiffness correlates with the corresponding changes in myocardial contractility.

Normally, central elastic arteries (e.g., aorta and common carotid artery) effectively buffer cardiac pulsation-induced flow/pressure fluctuations. With advancing age, arterial stiffening deteriorates this function and produces the greater cerebral hemodynamic pulsatility that impacts vulnerable brain tissue. It is well known that the buffering function of the central artery is improved by regular aerobic exercise, but the influence of endurance training on the pulsatile component of cerebral hemodynamics remains poorly understood. To characterize the functional role of the central artery at the heart-brain hemodynamic connection comprehensively, we assessed relations among the endurance training-induced changes in the left ventricle (LV), carotid arterial compliance, and cerebral hemodynamics. Thirteen collegiate tennis players (20 +/- 1 yr) underwent a 16-wk endurance training intervention designed for improving cardiovascular function. Expectedly, maximal oxygen uptake ((V) over dotO(2peak)), LV ejection velocity (via Doppler ultrasound), and the maximal rate of pressure increase of estimated aortic pressure waveform (via general transfer function) improved after the training intervention, whereas middle cerebral arterial (MCA) hemodynamics (via transcranial Doppler), such as mean and pulsatile flow velocities, remained unchanged. Carotid arterial compliance (via ultrasound and applanation tonometry) increased after the training intervention, and a larger increase in carotid arterial compliance was significantly associated with the greater attenuations of pulsatile MCA velocity (r = -0.621) normalized by mean MCA velocity. These results suggest that the training-induced improvement of carotid artery Windkessel function might offset the expected increase in the pulsatile component of cerebral perfusion induced by the enhanced LV systolic function.

Central arterial pulse pressure (PP), a strong predictor of cardiovascular disease, mainly consists of an incident wave generated by left ventricular ejection and a late-arriving reflected wave emanating from the lower body. We have tested the hypothesis that a reduction in leg vascular tone by heat treatment of the lower leg attenuates the central arterial PP. Pressure and wave properties of the peripheral and central arteries were measured in eight young men before and after heat treatment of the lower leg (temperature approx. 43 A degrees C) for 30 and 60 min, respectively. Following the lower leg heat trial, leg (femoral-ankle) pulse wave velocity (PWV) was significantly decreased, but aortic (carotid-femoral) PWV and parameters of wave reflection and carotid arterial PP did not change significantly. No significant changes were observed in these parameters in the control trial. These results suggest that the reduction in leg vascular tone induced by heat treatment of the lower leg may not affect wave reflection and central arterial PP in young men.

Obesity has reached global epidemic proportions and is associated with multiple comorbidities, including cardiovascular disease. A novel predictor of cardiovascular disease is elevated central systolic blood pressure. In fact, lifestyle modifications have been shown to decrease the central systolic blood pressure in overweight and obese men. The mechanism underlying these changes has yet to be fully elucidated. Interestingly, testosterone has been found to have cardioprotective effects. Moreover, serum testosterone levels are lower in obese men than in normal weight men. However, it is still unclear whether testosterone participates in the decrease of central blood pressure in overweight and obese men following lifestyle modifications. So, the purpose of the present study was to investigate the effect of testosterone on central systolic blood pressure in overweight and obese men before and after the 12-week lifestyle modification program. Forty-four overweight and obese men completed a 12-week lifestyle modification program (aerobic exercise training and dietary modifications). For all participants, central systolic blood pressure and serum testosterone levels were measured before and after the program. After the program, central systolic blood pressure was significantly decreased while serum total testosterone levels were significantly increased in overweight and obese men. Moreover, we also found a significant negative relationship between the change in serum testosterone levels and that in central systolic blood pressure. The present study suggests that increased serum testosterone levels likely contribute to a decrease in central blood pressure in overweight and obese men.

Obesity and increased arterial stiffness are independent risk factors for cardiovascular disease. Arterial stiffness is increased in obese individuals than in age-matched nonobese individuals. We demonstrated that dietary modification and exercise training are effective in reducing arterial stiffness in obese persons. However, the differences in the effect on arterial stiffness between dietary modification and exercise training are unknown. The purpose of the current study was to compare the effect of dietary modification and aerobic exercise training on arterial stiffness and endothelial function in overweight and obese persons. Forty-five overweight and obese men (48 +/- 1 year) completed either a dietary modification (well-balanced nutrient, 1680 kcal/day) or an exercise-training program (walking, 40-60 min/day, 3 days/week) for 12 weeks. Before and after the intervention, all participants underwent anthropometric measurements. Arterial stiffness was measured based on carotid arterial compliance, brachial-ankle pulse wave velocity (baPWV), and endothelial function was determined by circulating level of endothelin-1 (ET-1) and nitric oxide metabolite (nitrites/nitrate as metabolite: NOx). Body mass and waist circumference significantly decreased after both intervention programs. Weight loss was greater after dietary modification than after exercise training (-10.1 +/- 0.6 kg vs. -3.6 +/- 0.5 kg, p &lt; .01). Although arterial stiffness and the plasma levels of ET-1 and NOx were improved after dietary modification or exercise training, there were no differences in those improvements between the 2 types of interventions. Exercise training improves arterial function in obese men without as much weight loss as after dietary modification.

© 2015, The American Geriatrics Society. Background The United States and Japan have similar standards of living, healthcare systems, and industrializations but exhibit markedly divergent life expectancies both at birth and at later ages (50 or 65 years old). Arterial stiffness has been widely regarded as a barometer of biological or physiological aging and could provide insight into the inter-country differences. Objectives To determine whether the increases in arterial stiffness across the adult age range are greater in U.S. than Japanese adults. Design Cross-sectional analyses. Setting Laboratory-based study. Participants Healthy, nonsmoking Japanese (n = 400) and U.S. (n = 400) adults without cardiovascular and other chronic diseases. Measurements Indices of arterial stiffness, including carotid-femoral (cfPWV) and brachial-ankle pulse wave velocity (baPWV) were measured, along with a variety of ancillary measures. The recruitment method, measurement technique, and protocol were standardized and identical between U.S. and Japanese facilities. Results cfPWV and baPWV increased progressively with advancing age in all subgroups (stratified according to sex and country). The rates of age-related increases in arterial stiffness were not different between U.S. and Japanese men, but age-associated increases in cfPWV were significantly greater in U.S. than Japanese women, widening the intercountry differences at older age ranges. Conclusion Japanese women had smaller increases in central arterial stiffness with advancing age than U.S. women.

Circulating Klotho is expected to have vascular protective effects, including the enhancement of nitric oxide (NO) production by endothelial cells. Aerobic exercise training increases circulating Klotho levels and improves endothelial function, which decreases with aging. However, it is unclear whether aerobic exercise training-induced improvement in endothelial function is related to elevation of circulating Klotho levels. In the present study, we investigated the effect of aerobic exercise training on the correlation between plasma Klotho levels and endothelial function in postmenopausal women. First, we studied the correlation between plasma Klotho levels and flow-mediated vasodilation (FMD) as an index of endothelial function. FMD correlated positively with plasma Klotho levels, but the baseline diameter did not correlate with plasma Klotho levels. Second, we examined the effects of aerobic exercise training on plasma Klotho levels and FMD. After aerobic exercise training, plasma Klotho levels and FMD increased significantly. Furthermore, there was a positive correlation between the changes in plasma Klotho levels and those in FMD. These results suggested that an increase in ci

Aims: A growing body of evidence shows the cardiovascular benefits of fish oil ingredients, including eicosapentaenoic acid (EPA), in humans and experimental animals. However, the effects of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy and the involved signaling cascade are largely unknown. A previous study has demonstrated that peroxisomal proliferator-activated receptor (PPAR)-alpha ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Although EPA is a ligand of PPAR-alpha, to date. no study has examined a relationship between EPA and PPAR-alpha in cardiomyocyte hypertrophy. Here, we investigated whether EPA can block ET-1-induced cardiomyocyte hypertrophy and the possible underlying mechanisms.
Main methods: At day 4 of culture, neonatal rat cardiomyocytes were divided into four groups: control, control cells treated with EPA (10 mu M), ET-1 (0.1 nM) administered only and EPA-pre-treated ET-1 administered groups. Also; the cardiomyocytes were treated with PPAR-alpha siRNA in order to elucidate the mechanisms that may underlie suppression of hypertrophy via the EPA-PPAR system.
Key findings: Following ET-1 treatment, 2.12- and 1.92-fold increases in surface area and total protein synthesis rate in cardiomyocytes, respectively, were observed and these changes were greatly blocked by EPA pretreatment. Further, the expression of PPAR-alpha increased in EPA-treated groups. PPAR-PPRE binding activity was suppressed in ET-1 administered cardiomyocyte and this suppression was improved by EPA treatment. Lastly. pre-treatment of cardiomyocytes with PPAR-alpha siRNA prior to EPA treatment attenuated the suppressing effects of EPA on cardiomyocyte hypertrophy.
Significance: In conclusion, the present study shows that EPA attenuates ET-1 induced cardiomyocyte hypertrophy by up regulating levels of PPAR-alpha pathway. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Strenuous and consecutive exercise leads to fatigue symptoms in athletes. Metabolomics is a comprehensive method to assess metabolites that involves the measurements of the overall metabolic signature of biological samples. Using metabolomic analysis, we investigated the identification of salivary fatigue markers in soccer players after 3 consecutive days of a game program. One hundred twenty-two male soccer players participated in 3 consecutive days of a game program. To detect fatigued athletes, we measured indices of traditional fatigue symptoms, i.e., heart rate, body mass and mood, before and after the program. We detected 37 fatigued players throughout the program. Before and after the program, the saliva in these players was analyzed using capillary electrophoresis and time-of-flight mass spectrometry (CE-TOFMS) and a multivariate statistical technique, principal component analysis, was used to process the data. CE-TOFMS was used to identify 144 metabolites in the saliva of fatigued players. A significant metabolomic difference was observed before and after 3 consecutive days of a soccer game program. Interestingly, metabolites were all increased after the program (P &lt; 0.001). The identified metabolites, including 3-methylhistidine, glucose 1- and 6-phosphate, taurine, and some amino acids, were involved in skeletal muscle catabolism, glucose metabolism, lipid metabolism, amino acid metabolism, and energy metabolism. Our work demonstrated some salivary metabolites were significantly increased in the fatigued players after consecutive days of short soccer matches. We propose that the detected salivary metabolites may be new fatigue markers in athletes.

Strenuous and consecutive exercise leads to fatigue symptoms in athletes. Metabolomics is a comprehensive method to assess metabolites that involves the measurements of the overall metabolic signature of biological samples. Using metabolomic analysis, we investigated the identification of salivary fatigue markers in soccer players after 3 consecutive days of a game program. One hundred twenty-two male soccer players participated in 3 consecutive days of a game program. To detect fatigued athletes, we measured indices of traditional fatigue symptoms, i.e., heart rate, body mass and mood, before and after the program. We detected 37 fatigued players throughout the program. Before and after the program, the saliva in these players was analyzed using capillary electrophoresis and time-of-flight mass spectrometry (CE-TOFMS) and a multivariate statistical technique, principal component analysis, was used to process the data. CE-TOFMS was used to identify 144 metabolites in the saliva of fatigued players. A significant metabolomic difference was observed before and after 3 consecutive days of a soccer game program. Interestingly, metabolites were all increased after the program (P &lt; 0.001). The identified metabolites, including 3-methylhistidine, glucose 1- and 6-phosphate, taurine, and some amino acids, were involved in skeletal muscle catabolism, glucose metabolism, lipid metabolism, amino acid metabolism, and energy metabolism. Our work demonstrated some salivary metabolites were significantly increased in the fatigued players after consecutive days of short soccer matches. We propose that the detected salivary metabolites may be new fatigue markers in athletes.

The aim of the present study was to determine whether dehydroepiandrosterone (DHEA) administration affects bone mass and local sex hormone levels in the cancellous region of young female rats. Eleven female rats (6 weeks old) were randomly divided into 2 groups: control rats (CON, n = 5) and rats treated with DHEA (DHEA, n = 6). DHEA dissolved in sesame oil was administered to the DHEA group intraperitoneally at 20 mg DHEA/kg body weight, and the CON group was treated with vehicle only (sesame oil, 0.5 ml). The rats were treated with DHEA or vehicle for 3 consecutive days, followed by 1 day of no treatment. The experimental period was 8 weeks. According to dual-energy X-ray absorptiometry and high-resolution microcomputed tomography data, the DHEA group exhibited increased trabecular bone mineral density (BMD), bone volume, and tibial thickness compared to the findings in the CON group, whereas no effect was observed on cortical BMD or morphometry. The concentrations of free testosterone and estradiol in the cancellous region of the tibia did not differ between the 2 groups, but the DHT concentration was significantly higher in the DHEA group than in the CON group. These findings suggest that an increase in local DHT levels may stimulate an increase in trabecular bone mass during growth phases in female rats.

Aims: The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels.
Main methods: Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1 mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1 mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump.
Key findings: The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment.
Significance: Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats. (C) 2014 Elsevier Inc. All rights reserved.

Aims: Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase, an enzyme responsible for the generation of NO. Plasma concentrations of ADMA increase in the elderly and in postmenopausal women. In fact, an elevated ADMA level is a risk factor of cardiovascular disease. Aerobic exercise has a beneficial effect on cardiovascular disease. However, the relationship between ADMA and aerobic fitness is unknown. The aim of this study was to determine whether plasma ADMA concentrations correlate with aerobic fitness levels in postmenopausal women.
Main methods: Thirty healthy postmenopausal women aged 50-76 years participated in this study. We measured plasma concentrations of ADMA and oxygen consumption at the ventilatory threshold (VO2VT) as an index of aerobic fitness. Subjects were divided into the low aerobic fitness (Low fitness) and high aerobic fitness (High fitness) groups, and the dividing line was set at the median VO2VT value.
Key findings: VO2VT was significantly higher in the High fitness group than in the Low fitness group (P &lt; 0.01). The plasma ADMA concentrations in the High fitness group were significantly lower than those in the Low fitness group (P &lt; 0.05). There was a negative correlation between plasma ADMA concentrations and VO2VT (r = -0.532, P &lt; 0.01).
Significance: We found that plasma ADMA concentrations were associated with aerobic fitness in postmenopausal women. The results of this study suggest that habitual aerobic exercise may decrease plasma ADMA concentrations. (C) 2014 Elsevier Inc. All rights reserved.

Aims: Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase, an enzyme responsible for the generation of NO. Plasma concentrations of ADMA increase in the elderly and in postmenopausal women. In fact, an elevated ADMA level is a risk factor of cardiovascular disease. Aerobic exercise has a beneficial effect on cardiovascular disease. However, the relationship between ADMA and aerobic fitness is unknown. The aim of this study was to determine whether plasma ADMA concentrations correlate with aerobic fitness levels in postmenopausal women.
Main methods: Thirty healthy postmenopausal women aged 50-76 years participated in this study. We measured plasma concentrations of ADMA and oxygen consumption at the ventilatory threshold (VO2VT) as an index of aerobic fitness. Subjects were divided into the low aerobic fitness (Low fitness) and high aerobic fitness (High fitness) groups, and the dividing line was set at the median VO2VT value.
Key findings: VO2VT was significantly higher in the High fitness group than in the Low fitness group (P &lt; 0.01). The plasma ADMA concentrations in the High fitness group were significantly lower than those in the Low fitness group (P &lt; 0.05). There was a negative correlation between plasma ADMA concentrations and VO2VT (r = -0.532, P &lt; 0.01).
Significance: We found that plasma ADMA concentrations were associated with aerobic fitness in postmenopausal women. The results of this study suggest that habitual aerobic exercise may decrease plasma ADMA concentrations. (C) 2014 Elsevier Inc. All rights reserved.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, increase with advancing age and menopausal status. ADMA plays a role in endothelial dysfunction and increasing arterial stiffness. Regular aerobic exercise has a positive effect on arterial function (i.e., arterial compliance). This study investigated the effects of aerobic exercise training on plasma ADMA concentrations and arterial compliance in postmenopausal women.
Thirty postmenopausal women were divided into 2 groups: an exercise group (n 20) and a control group (n 10). Subjects in the exercise group completed 12 weeks of aerobic exercise training (65%80% of maximal heart rate, 4060min/day, 36 days/week). Before and after each intervention, plasma ADMA concentrations and carotid arterial compliance were measured in all participants.
The baseline plasma ADMA concentrations, carotid arterial compliance, and most other key dependent variables did not differ between the 2 groups. In the exercise group, carotid arterial compliance significantly increased after exercise intervention (P &lt; 0.01), and plasma ADMA concentrations significantly decreased (P &lt; 0.05). In addition, changes in carotid arterial compliance after the exercise intervention were inversely correlated with changes in plasma ADMA concentrations (r 0.367; P &lt; 0.05).
We demonstrated that aerobic exercise training significantly decreased plasma ADMA concentrations with increase in carotid arterial compliance in postmenopausal women. These results suggest that reduction in ADMA may play an important role in the aerobic exercise traininginduced increase in arterial compliance.

Inflammation has been shown to promote obesity-induced insulin resistance. Although pentraxin (PTX) 3 is known as an anti-inflammatory factor, the effect of PTX3 on insulin sensitivity has not yet been elucidated. The aim of this study is to investigate a part of the role of PTX3 on insulin sensitivity. The authors studied the PTX3 and glucose transport protein expression levels in epididymal adipose tissue and soleus muscles of male diabetic-obese [Tsumura Suzuki obese-diabetic (TSOD)] and lean control mice. The levels of PTX3 in both skeletal muscle and adipose tissue were significantly lower in TSOD mice than in controls, and there was a significant positive correlation between them. They observed a significant positive correlation between PTX3 and glucose transport protein 4 levels in skeletal muscle. This study suggests that PTX3 may play a part of role as promoting insulin sensitivity of skeletal muscle in TSOD mice.

The Klotho gene is a suppressor of the aging phenomena, and the secretion as well as the circulation of Klotho proteins decrease with aging. Although habitual exercise has antiaging effects (e. g., a decrease in arterial stiffness), the relationship between Klotho and habitual exercise remains unclear. In the present study, we investigated the effect of habitual exercise on Klotho, with a particular focus on arterial stiffness. First, we examined the correlation between plasma Klotho concentration and arterial stiffness (carotid artery compliance and beta-stiffness index) or aerobic exercise capacity [oxygen uptake at ventilatory threshold (VT)] in 69 healthy, postmenopausal women (50-76 years old) by conducting a cross-sectional study. Second, we tested the effects of aerobic exercise training on plasma Klotho concentrations and arterial stiffness. A total of 19 healthy, postmenopausal women (50-76 years old) were divided into two groups: control group and exercise group. The exercise group completed 12 wk of moderate aerobic exercise training. In the cross-sectional study, plasma Klotho concentrations positively correlated with carotid artery compliance and VT and negatively correlated with the beta-stiffness index. In the interventional study, aerobic exercise training increased plasma Klotho concentrations and carotid artery compliance and decreased the beta-stiffness index. Moreover, the changes in plasma Klotho concentration and arterial stiffness were found to be correlated. These results suggest a possible role for secreted Klotho in the exercise-induced modulation of arterial stiffness.

Increased arterial stiffness is an independent risk factor for cardiovascular diseases, and it is well known that aging and obesity promote arterial stiffening. However, several previous reports have indicated that certain lifestyle modifications can decrease arterial stiffness in older and/or obese individuals. Arterial stiffness is determined by dietary pattern, nutritional balance, exercise habits, and other lifestyle factors. Given that arterial stiffness contributes to cardiovascular disease, a major cause of mortality, life expectancy could be determined by one's lifestyle patterns. In the nutritional field, improving the balance between energy intake and expenditure, or satisfying the basal metabolic demands play important roles in decreasing arterial stiffness. From the exercise science field, we know that arterial stiffness can be alleviated by changing exercise habits (pattern, intensity, duration, and frequency). In this review, we introduce recent reports relating to lifestyle habits and arterial stiffness, and review how improving one's lifestyle can help prevent cardiovascular disease. We believe that this information provides an opportunity to commit to a healthier life.

Obesity and increasing of arterial stiffness are known as independent risk factors for cardiovascular disease. Previously, we demonstrated that dietary modification or aerobic exercise training can decrease arterial stiffness in obese individuals. However, it has not been compared the effect of dietary modification and/or aerobic exercise training on arterial stiffness in obese men. We compared the effect of three patterns of lifestyle modification (i.e., dietary modification, aerobic exercise training or combined them) on arterial stiffness in obese men. Fifty-three obese men completed the 12-week lifestyle modification program, dietary modification (D), aerobic exercise training (E) or combined D and E (DE). Before and after the program, all participants were measured central, peripheral, and systemic arterial stiffness (measured by carotid-femoral pulse wave velocity [cfPWV], femoral-ankle PWV [faPWV] and brachial-ankle PWV [baPWV]). We demonstrated that the degree of decrease in BMI was the greatest after DE, and that was greater after D than E. The level of decrease in baPWV after DE was the greatest among three interventions. On the other hand, the level of decrease in baPWV in D group was similar to E group. These results suggested that systemic arterial stiffness may be decreased by different mechanisms between D and E groups. We demonstrated that dietary modification decreased central and systemic arterial stiffness, and aerobic exercise training decreased central, systemic, and peripheral arterial stiffness in obese individuals. We also showed an additional effect of decreasing systemic arterial stiffness by combining dietary modification and aerobic exercise training in obese individuals.

Circulating Klotho is expected to have vascular protective effects, including the enhancement of nitric oxide (NO) production by endothelial cells. Aerobic exercise training increases circulating Klotho levels and improves endothelial function, which decreases with aging. However, it is unclear whether aerobic exercise training-induced improvement in endothelial function is related to elevation of circulating Klotho levels. In the present study, we investigated the effect of aerobic exercise training on the correlation between plasma Klotho levels and endothelial function in postmenopausal women. First, we studied the correlation between plasma Klotho levels and flow-mediated vasodilation (FMD) as an index of endothelial function. FMD correlated positively with plasma Klotho levels, but the baseline diameter did not correlate with plasma Klotho levels. Second, we examined the effects of aerobic exercise training on plasma Klotho levels and FMD. After aerobic exercise training, plasma Klotho levels and FMD increased significantly. Furthermore, there was a positive correlation between the changes in plasma Klotho levels and those in FMD. These results suggested that an increase in ci

Strenuous and consecutive exercise results in fatigue symptoms accompanied decrease in salivary secretory immunoglobulin A (sIgA) in athletes. On the other hand, it has been reported that plasma taurine concentration was increased after the high intensity exercise. However, change in salivary taurine concentration after strenuous and consecutive exercise is unknown. The purpose of this study was to investigate the relationship between fatigue symptoms and changes in salivary taurine concentration in collegiate male soccer players. Thirty seven collegiate male soccer players participated in three consecutive days of match program. To detect of fatigued players, we measured awakening heart rate and body weight. As the results of these two measurements, we divided subjects to two groups (non-fatigue group, n=15
fatigue group, n=22). We also measured salivary sIgA and taurine concentrations before and after program. Before the program, there were no significant differences in any parameters between two groups. Salivary flow rate and sIgA secretion rate were significantly decreased after the program in the fatigue group. Furthermore, salivary taurine concentration was significantly increased after the program in the fatigue group. In the non-fatigue group, there were no significant differences in any parameters during program. Our results indicated that salivary taurine concentration increased after consecutive high-intense exercise in the collegiate male soccer players.

Proximal large elastic arteries (ascending aorta and carotid artery) have an important role in buffering the pulsatile pressure generated from the left ventricle, which forwards continuous peripheral blood flow and protects the brain microcirculation from end-organ damage. Although compliance of distal conduit arteries (extremities' arteries) is attenuated by the nitric oxide synthase (NOS) inhibition, it is yet unknown whether compliance of proximal elastic arteries changes by the systemic NOS inhibition. To address this question, we measured central artery compliance in 17 young adults (26±1 years) who underwent intravenous infusions of N G -monomethyl-L-arginine (L-NMMA) or saline (placebo) on separate days. Following the systemic NOS inhibition, the mean arterial pressure (MAP), total peripheral resistance and aortic augmentation index were significantly increased. However, carotid artery compliance was not affected significantly (from 0.10±0.01 to 0.11±0.01 mm 2 per mmHg) and the β-stiffness index (an index of arterial compliance adjusted for the distending pressure) tended to decrease (from 6.63±0.35 to 6.06±0.42 a.u., P=0.07). These parameters were not altered with saline infusion. Changes in the β-stiffness index tended to correlate negatively with the corresponding changes in MAP (r=-0.31, P=0.07). These results suggest that carotid artery compliance remains unchanged during the systemic NOS inhibition in spite of systemic vasoconstriction. © 2014 Macmillan Publishers Limited.

OBJECTIVE: It has recently been recognized that increased central blood pressure is a predictor of cardiovascular disease. Central blood pressure is higher in obese individuals than in nonobese individuals. However, the effect of lifestyle modification on central systolic blood pressure in obese individuals is unclear. The aim of this study was to determine whether lifestyle modification decreases central blood pressure in overweight and obese men. METHODS: Thirty-nine overweight and obese men (age, 49±2 years; BMI, 30±1 kg/m) were recruited into our study. We measured central systolic blood pressure and brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, before and after a 12-week lifestyle modification that included aerobic exercise and dietary modification. RESULTS: After the 12-week program, body mass, BMI, and waist circumstance decreased significantly. Central systolic blood pressure and baPWV were significantly decreased after the lifestyle modification in overweight and obese men. Furthermore, there was a significant correlation between the lifestyle modification-induced change in central systolic blood pressure and that in baPWV. CONCLUSION: This study showed for the first time that lifestyle modification-induced weight loss decreases central systolic blood pressure in overweight and obese men. The decrease in central systolic blood pressure was associated with the reduction in arterial stiffness. These results suggest that lifestyle modification-induced reduction in arterial stiffness may contribute toward the decreased central systolic blood pressure in overweight and obese men.

Background: Previous studies have evaluated the effectiveness of branched-chain amino acid (BCAA) supplementation for preventing delayed onset muscle soreness (DOMS) and muscle damage induced by eccentric exercise, their findings have been inconclusive. Since taurine has anti-inflammatory and anti-oxidative effects, the present study investigated the combined effect of BCAA and taurine on DOMS and muscle damage.Methods: Thirty-six untrained male subjects (22.5 ± 3.8 years) were assigned to four groups (placebo + placebo [placebo], BCAA + placebo, placebo + taurine, and BCAA + taurine [combined]) and given a combination of 3.2 g BCAA (or placebo) and 2.0 g taurine (or placebo), three times a day, for two weeks prior to and three days after eccentric elbow flexor exercises. DOMS and muscle damage in the biceps brachii were subjectively and objectively evaluated using the visual analogue scale (VAS), upper arm circumference (CIR), and blood parameters (creatine kinase, lactate dehydrogenase [LDH], aldolase, and 8-hydroxydeoxyguanosine [8-OHdG]).Results: In the combined group, VAS and 8-OHdG two days after exercise, CIR two and three days after exercise and LDH from one to three days after exercise were significantly lower than the placebo group. The area under the curve from before exercise to four days later for CIR, LDH, and aldolase was also significantly lower in the combined group than in the placebo group.Conclusion: A combination of 3.2 g BCAA and 2.0 g taurine, three times a day, for two weeks prior to and three days after exercise may be a useful nutritional strategy for attenuating exercise-induced DOMS and muscle damage. © 2013 Ra et al.
licensee BioMed Central Ltd.

BACKGROUND: Increased arterial stiffness is an independent risk factor for cardiovascular disease. Arterial stiffness is higher in obese individuals than in nonobese individuals. Lifestyle modifications (i.e. exercise and dietary modification) decrease arterial stiffness in obese individuals. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, an enzyme responsible for the generation of nitric oxide. AIM: The aim of this study was to examine whether lifestyle modifications affect circulating levels of ADMA in overweight and obese men and, if they do, whether ADMA is involved in the mechanism underlying the decrease in arterial stiffness with lifestyle modification. METHODS: Seventeen overweight and obese men (BMI: 29.8±0.8 kg/m(2)) completed a 12-week lifestyle modification program, which included aerobic exercise and dietary modification. Before and after the intervention, we evaluated brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, and plasma ADMA concentration in all participants. RESULTS: After the 12-week lifestyle modification program, BMI and baPWV decreased significantly and the plasma ADMA concentration decreased markedly in overweight and obese men. There was a significant positive correlation between percent change in baPWV and plasma ADMA concentration. CONCLUSION: Lifestyle modifications reduce arterial stiffness and plasma ADMA concentration in overweight and obese individuals. A decrease in arterial stiffness was associated with a corresponding reduction in plasma ADMA concentrations. These results suggest that reductions in ADMA may be an important mechanism underlying the beneficial effect of lifestyle modification on arterial stiffness.

BACKGROUNDObesity and increased arterial stiffness are independent risk factors for cardiovascular disease. The degree of arterial stiffness in obese individuals is greater than that in normal-weight subjects. Pentraxin 3 (PTX3) is mainly produced by vascular tissues and exerts a cardioprotective effect. However, the relationship between PTX3 and arterial stiffness in obese individuals has not yet been clarified. In this study, we examined the relationships between obesity, arterial stiffness, and PTX3 levels in 282 subjects.METHODSAll participants were classified as normal weight, overweight, or obese on the basis of their body mass index. We measured the brachial-ankle pulse wave velocity (baPWV
an index of arterial stiffness) and plasma PTX3 concentrations in all subjects. Additionally, the carotid-femoral PWV (cfPWV) was measured in 173 subjects.RESULTSWe found that baPWV and cfPWV in overweight and obese subjects were significantly higher than those in normal-weight subjects. Plasma PTX3 concentrations in normal-weight subjects were significantly higher than those in overweight and obese subjects. Moreover, PTX3 had a significant negative correlation with baPWV. However, stepwise multivariable linear regression analysis did not indicate any associations between these parameters.CONCLUSIONSArterial stiffness is increased in overweight and obese individuals. The increase in arterial stiffness may, at least in part, be associated with an obesity-related reduction in plasma PTX3 concentrations. © American Journal of Hypertension, Ltd 2013. All rights reserved.

Taurine (TAU) has a lot of the biological, physiological, and pharmocological functions including anti-inflammatory and anti-oxidative stress. Although previous studies have appreciated the effectiveness of branched-chain amino acids (BCAA) on the delayed-onset muscle soreness (DOMS), consistent finding has not still convinced. The aim of this study was to examine the additional effect of TAU with BCAA on the DOMS and muscle damages after eccentric exercise. Thirty-six untrained male volunteers were equally divided into four groups, and ingested a combination with 2.0 g TAU (or placebo) and 3.2 g BCAA (or placebo), thrice a day, 2 weeks prior to and 4 days after elbow flexion eccentric exercise. Following the period after eccentric exercise, the physiological and blood biochemical markers for DOMS and muscle damage showed improvement in the combination of TAU and BCAA supplementation rather than in the single or placebo supplementations. In conclusion, additional supplement of TAU with BCAA would be a useful way to attenuate DOMS and muscle damages induced by high-intensity exercise.

Chronic inflammation that occurs with aging is one of the risk factors for cardiovascular disease. Regular exercise may prevent cardiovascular morbidity by decreasing chronic systematic inflammation. Additionally, excess inflammation can be reduced by the anti-inflammatory protein pentraxin 3 (PTX3). Thus, both habitual exercise and PTX3 have an anti-inflammatory effect. However, it is unclear whether regular exercise leads to increased plasma PTX3 concentration. In the present study, we investigated the effects of regular aerobic exercise on plasma PTX3 concentration in middle-aged and elderly women. Twenty-two postmenopausal women (60 +/- 6 years) were randomly divided evenly into 2 groups (i.e., exercise intervention and control). Subjects in the exercise group completed 2 months of regular aerobic exercise training (walking and cycling, 30-45 min, 3-5 days.week(-1)). Before and after the intervention, we evaluated plasma PTX3 concentration, peak oxygen uptake, blood chemistry, and arterial distensibility (carotid arterial compliance and beta-stiffness) in all participants. There were no significant differences in baseline parameters between the 2 groups. Plasma PTX3 concentration was significantly increased in the exercise group after the intervention (p &lt; 0.05). High-density lipoprotein cholesterol, peak oxygen uptake, and arterial compliance were also significantly increased (p &lt; 0.05), while beta-stiffness was markedly decreased (p &lt; 0.01) after the intervention. On the other hand, there was no change in the parameters tested in the control group. This study demonstrates that regular aerobic exercise increases plasma PTX3 concentration with improvement of high-density lipoprotein cholesterol, peak oxygen uptake, and arterial distensibility in postmenopausal women.

BACKGROUND
Lifestyle modification (i.e., regular physical activity and diet) is effective in preventing the age-related increase in cardiovascular disease risks. Potential therapeutic effects of curcumin (diferuloylmethane) have been confirmed on various diseases, including cancer and Alzheimer's disease, but the effects of curcumin have not been tested on central arterial hemodynamics. The aim of this pilot study was to test the hypothesis that the regular endurance exercise combined with daily curcumin ingestion lowers the age-related increase in left ventricular (LV) afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women using a randomized, double-blind, placebo-controlled, parallel manner.
METHODS
Forty-five women were randomly assigned to four interventions: "placebo ingestion" (n = 11), "curcumin ingestion" (n = 11), "exercise training with placebo ingestion" (n = 11), or "exercise training with curcumin ingestion" (n = 12). Curcumin or placebo pills (150 mg/day) were administered for 8 weeks. Aortic blood pressure (BP) and augmentation index (AIx), an index of LV afterload, were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms.
RESULTS
There were no significant differences in baseline hemodynamic variables among four groups. After the interventions, brachial systolic BP (SBP) significantly decreased in both exercise-trained groups (P &lt; 0.05 for both), whereas aortic SBP significantly decreased only in the combined-treatment (e. g., exercise and curcumin) group (P &lt; 0.05). Heart rate (HR) corrected aortic AIx significantly decreases only in the combined-treatment group.
CONCLUSIONS
These findings suggest that regular endurance exercise combined with daily curcumin ingestion may reduce LV afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women.

Previous research has established that both aging and obesity trigger elevation of arterial stiffness and that such elevation is an independent risk factor for cardiovascular morbidity and mortality. Changes in arterial stiffness are known to be caused by alterations in the balance of hormones, inflammatory, nervous system-related, and endothelium-derived vasoactive factors, and levels of oxidative stress - all of which are known to strongly affect vasoconstriction and vasodilation. Lifestyle modifications that promote the restriction of energy intake, maintenance of nutrient balance, and performance of regular aerobic exercise, can decrease arterial stiffness in elderly and obese individuals. In this review, we discuss the lifestyle strategies found effective in decreasing arterial stiffness in elderly and obese individuals via improvement of vasoactive functional factors.

Macroautophagy (autophagy) is an intracellular catalytic process. We examined the effect of running exercise, which stimulates cardiac work physiologically, on the expression of microtubule-associated protein 1 light chain 3 (LC3)-II, an indicator of autophagy, as well as some autophagy-related proteins in rat cardiac muscle. The left ventricles were taken from rats immediately (0 h), and at 0.5 h, 1 h or 3 h after a single bout of running exercise on a treadmill for 30 min and also from rats in a rest condition. In these samples, we evaluated the level of LC3-II and p62, and the phosphorylation level of mammalian target of rapamycin (mTOR). Akt and AMP-activated protein kinase alpha (AMPK alpha) by Western blotting. The exercise produced a biphasic change in LC3-II, with an initial decrease observed immediately after the exercise and a subsequent increase 1 h thereafter. LC3-II then returned to the rest level at 3 h after the exercise. A negative correlation was found between the LC3-II expression and mTOR phosphorylation, which plays a role in inhibiting autophagy. The exercise increased phosphorylation of AMPK alpha, which stimulates autophagy via suppression of mTOR phosphorylation, immediately after exercise. The level of p62 and phosphorylated Akt was not altered significantly by the exercise. These results suggest for the first time that a single bout of running exercise induces a biphasic change in autophagy in the cardiac muscle. The exercise-induced change in autophagy might be partially mediated by mTOR in the cardiac muscle. (C) 2011 Elsevier Inc. All rights reserved.

The relation between ACTN3 R577X polymorphism and muscle mass in women has been reported, but its relation to age remains unclear. We investigated the relationship between ACTN3 R577X polymorphism and muscle mass in both middle-aged and elderly women. Two age groups (middle-aged and older) were formed among 162 healthy, nontraining Japanese women (mean +/- SE, 58.6 +/- 0.8 year). Their midthigh-muscle cross-sectional area (CSA) was assessed using magnetic resonance imaging, revealing no difference in thigh-muscle CSA among ACTN3 R577X genotypes in the middle-aged group (XX, 87.3 +/- 2.5 cm(2); RR&RX, 86.1 +/- 1.7 cm(2), p = 0.7). In contrast, the XX genotype in the older group had a smaller thigh-muscle CSA adjusted to body weight than the RR&RX genotypes (XX, 67.8 +/- 2.0 cm(2); RR&RX, 72.5 +/- 1.2 cm(2), p &lt; 0.05). The present study showed an association between ACTN3 R577X polymorphism and smaller thigh-muscle CSA in a group of elderly women but not in a group of middle-aged women.

It is not known whether local androgen metabolism is involved in the mechanisms underlying the dehydroepiandrosterone (DHEA) administration-induced improvement of bone mineral density (BMD) in an estrogen-deficiency state. The aim of the present study was to clarify whether DHEA administration would improve local androgen metabolism and BMD in cancellous site of tibia of ovariectomized (OVX) rats. Twenty-two female rats, 6 weeks old, were randomized into three groups: sham-operated rats, OVX control rats, and OVX rats that received DHEA treatment. DHEA was administered intraperitoneally at 20 mg/kg body weight for 8 weeks. The concentrations of free testosterone and dihydrotestosterone (DHT) in cancellous site of tibia did not change as a result of ovariectomy, while the DHT concentration increased following DHEA administration. We revealed that DHEA administration improved the reduction of 17 beta- and 3 beta-hydroxysteroid dehydrogenases and clearly reversed the reduction of 5 alpha-reductase types 1 and 2 and androgen receptor in the cancellous site of tibia of OVX rats. DHEA administration suppressed estrogen deficiency relative to the decrease in the cancellous BMD, which was positively associated with local DHT concentration. These findings indicate that DHEA administration enhances local bioactive androgen metabolism in the cancellous tibia of young OVX rats, suggesting that local DHT may play a part in the DHEA administration-induced improvement of cancellous BMD.

Objective: Aerobic exercise on land decreases arterial stiffness, however, the effect of exercise in water on arterial stiffness has not been clear. This study investigated the effect of a 15-mm cycling exercise on land and that in water on pulse wave velocity (PWV) as an index of arterial stiffness. Methods: Nine healthy young men were randomly performed exercise on land and exercise in water equivalent to 50% of each maximum oxygen uptake on separate days. The PWV from carotid to femoral artery (aortic PWV) and femoral to posterior tibial artery (leg PWV) were measured at baseline and 15, 30, 60 min after exercise. Results: The heart rate in water was significantly lower during exercise than that on land. In addition, the carbon dioxide output and respiratory exchange ratio during exercise were significantly greater in water. Body temperature increased after the exercise on land but decreased after the exercise in water. Although the aortic PWV and leg PWV decreased concomitantly with decrease in SBP and DBP after the exercise on land, there were no significant changes after the exercise in water. Conclusion: Although acute exercise on land decreased arterial stiffness after exercise, acute exercise in water of the same exercise load did not. The differences in body temperature and blood pressure after exercise may result in diverse arterial stiffness after exercise. (Jpn. J. Phys. Fitness Sports Med., 60 (3) : 269 similar to 277 (2011))

MIYAKI, A., S. MAEDA, T. OTSUKI, and R. AJISAKA. Plasma Pentraxin 3 Concentration Increases in Endurance-Trained Men. Med. Sci. Sports Exerc., Vol. 43, No. 1, pp. 12-17, 2011. Introduction: Pentraxin 3 (PTX3), which is mainly produced by endothelial cells, macrophages, and smooth muscle cells in the atherosclerotic region, has a cardioprotective effect. Endurance exercise training has also been known to offer cardioprotection. However, the effect of regular endurance exercise on PTX3 is unknown. This study aimed to investigate whether plasma PTX3 concentrations increase in endurance-trained men. Ten young endurance-trained men and 12 age-and gender-matched sedentary controls participated in this study. Methods: We measured plasma PTX3 concentrations of the participants in each group. We also determined systemic arterial compliance (SAC) by using simultaneous M-mode ultrasound and arterial applanation tonometry of the common carotid artery and used HDL cholesterol (HDLC) as an index of cardioprotective effect. Results: Maximal oxygen uptake was significantly higher in the endurance-trained men than that in the sedentary controls. SAC and HDLC were significantly higher in the endurance-trained men than that in the sedentary controls (SAC = 1.74 +/- 0.11 vs 1.41 +/- 0.09 mL.mm Hg(-1), P &lt; 0.05; HDLC = 70 +/- 5 vs 57 +/- 4 mg.dL(-1), P &lt; 0.05). Plasma PTX3 concentrations were markedly higher in the endurance-trained men than that in the sedentary controls (0.93 +/- 0.11 vs 0.68 +/- 0.06 ng.mL(-1), P &lt; 0.05). Relationships between plasma PTX3 concentrations and SAC and HDLC were linear. Conclusions: This is the first study revealing that endurance-trained individuals had higher levels of circulating PTX3 than sedentary controls. PTX3 may play a partial role in endurance exercise training-induced cardioprotection.

Purpose: Endurance training improves skeletal muscular function including energy metabolism and structure. Sex steroid hormones partly contribute to the exercise-induced muscular adaptations. Recently, we demonstrated that skeletal muscle contains steroidogenic converting enzymes to synthesize sex steroid hormones and an acute endurance exercise activates local steroidogenesis in skeletal muscle. However, whether chronic endurance training leads to enhanced steroidogenesis in skeletal muscle is unknown. Here, we examined changes in steroidogenic enzymes and sex steroid hormones in the skeletal muscle after chronic endurance exercise training. Methods: Eleven male rats were divided into two groups: sedentary (n = 6) and trained (n = 5). Endurance training was performed on a treadmill (30 m•min, 30 min) for 5 d•wk for 12 wk. The posttraining harvesting was performed 48 h after the last exercise training. Results: The mRNA expressions of 3β-HSD, aromatase cytochrome P450, and 5α-reductase in the skeletal muscle of trained rats were significantly higher than those of sedentary rats (P &lt
0.05). The protein expressions of aromatase cytochrome P450 and 5α-reductase in the skeletal muscle of trained rats were also significantly higher than those of sedentary rats (P &lt
0.05). The muscular dihydrotestosterone (DHT) concentrations in the skeletal muscle of trained rats were significantly higher than those of sedentary rats (P &lt
0.01), but there was no change in dehydroepiandrosterone, total testosterone, free testosterone, and estradiol. Furthermore, muscle weight corrected for body weight of trained rats was moderately correlated with the level of muscular DHT concentration in trained rats (r = 0.41, P &lt
0.05). Conclusions: Endurance exercise training enhances the muscular DHT concentration through 5α-reductase in the skeletal muscle of rats, suggesting that local bioactive androgen metabolism may participate in exercise training-induced skeletal muscular adaptation. © 2011 by the American College of Sports Medicine.

Introduction: Pentraxin 3 (PTX3), which is mainly produced by endothelial cells, macrophages, and smooth muscle cells in the atherosclerotic region, has a cardioprotective effect. Endurance exercise training has also been known to offer cardioprotection. However, the effect of regular endurance exercise on PTX3 is unknown. This study aimed to investigate whether plasma PTX3 concentrations increase in endurance-trained men. Ten young endurance-trained men and 12 age- and gender-matched sedentary controls participated in this study. Methods: We measured plasma PTX3 concentrations of the participants in each group. We also determined systemic arterial compliance (SAC) by using simultaneous M-mode ultrasound and arterial applanation tonometry of the common carotid artery and used HDL cholesterol (HDLC) as an index of cardioprotective effect. Results: Maximal oxygen uptake was significantly higher in the endurance-trained men than that in the sedentary controls. SAC and HDLC were significantly higher in the endurance-trained men than that in the sedentary controls (SAC = 1.74 ± 0.11 vs 1.41 ± 0.09 mL•mm Hg -1, P &lt
0.05
HDLC = 70 ± 5 vs 57 ± 4 mg•dL, P &lt
0.05). Plasma PTX3 concentrations were markedly higher in the endurance-trained men than that in the sedentary controls (0.93 ± 0.11 vs 0.68 ± 0.06 ng•mL, P &lt
0.05). Relationships between plasma PTX3 concentrations and SAC and HDLC were linear. Conclusions: This is the first study revealing that endurance-trained individuals had higher levels of circulating PTX3 than sedentary controls. PTX3 may play a partial role in endurance exercise training-induced cardioprotection. © 2010 by the American College of Sports Medicine.

Estrogen has widely been credited for cardioprotection in women. However, the exact mechanisms that underlie these beneficial estrogenic effects are not completely understood. Here, we sought to: 1) elucidate estrogen's influence on levels of vascular endothelial growth factor (VEGF), a key regulator of cardiovascular processes, and components of its basic signaling machinery (VEGF receptors, Akt, and eNOS) in the heart, and 2) delineate the specific estrogen receptor signaling pathway that mediates its beneficial effects using mice lacking either estrogen receptor alpha or estrogen receptor beta. We analyzed pattern of VEGF signaling and the associated coronary capillary density in the hearts of wild-type (WT), estrogen receptor alpha knockout (ERalpha-KO), and estrogen receptor beta knockout (ERbeta-KO) female mice. Deletion of estrogen receptor alpha causes a marked decrease in coronary capillary density compared to wild-type (WT) mice, while that of estrogen receptor beta had a minimal effect. Consistent with reduced coronary capillary density, cardiac expression levels of VEGF and its signaling molecules (two receptors, phosphorylated Akt, and eNOS) in ERalpha-KO mice were reduced to half of WT, in contrast to ERbeta-KO mice that only showed a slight decrease. Moreover, activity of eNOS was greatly lowered in ERalpha-KO mice. These data suggest that estrogen acts largely via estrogen receptor alpha to regulate VEGF transcription and possibly components of its basic signaling and ultimately, the development of coronary microvasculature in the heart. This molecular and histological data, in part, sheds some insights into potential mechanisms that may likely underlie estrogen's cardioprotective effects.

BACKGROUND
Peripheral conduit artery endothelium-dependent dilatation decreases with aging in humans. Lactotripeptides (LTPs) and regular exercise can improve endothelium-dependent dilatation, but combining these lifestyle modifications may be more effective than either treatment alone. We conducted a randomized, place-controlled trial with four different intervention arms.
METHODS
A total of 43 postmenopausal women (50-65 years old) were randomly divided into placebo, LTP, exercise and placebo (Ex+placebo), or exercise and LTP (Ex+LTP) groups. LTP or placebo administered orally for 8 weeks. The exercise groups completed an 8-week moderate aerobic exercise (walking or cycling) intervention.
RESULTS
There were no statistically significant differences in baseline flow-mediated dilatation (FMD) and most other key dependent variables among the groups. FMD significantly increased in the LTP, Ex+placebo, and Ex+LTP groups whereas no such changes were observed in the placebo control group. The magnitude of increases in FMD was significantly greater in the Ex+LTP group than other intervention groups.
CONCLUSION
We concluded that LIP ingestion combined with regular aerobic exercise improves endothelium-dependent dilatation to a greater extent than monotherapy with either intervention alone in postmenopausal women.

Androgens, Such as testosterone, play important roles in regulation of diverse physiological process of target tissues. Recently, we reported that steroidogenic enzymes exist in skeletal Muscle and regulate local production of testosterone in response to exercise. Testosterone is transformed into a bioactive androgen metabolite, dihydrotestosterone (DHT) by 5 alpha-reductase. However, it is unclear whether exercise stimulates local bioactive androgen metabolism in the skeletal muscle in both sexes. In the present study, we examined sex differences in the levels of dehydroepiandrosterone (DHEA), free testosterone, DHT, and steroidogenesis-related enzymes 5 alpha-reductase and androgen receptor (AR) in rat&apos;s skeletal muscle before and after a single bout of exercise. Basal muscular free testosterone and DHT levels were higher in males than females, whereas the levels of DHEA did not differ between the sexes. Muscular DHEA, free testosterone, and DHT levels were increased in both sexes after the exercise. There were no differences of 5 alpha-reductase and AR transcripts and proteins between the sexes, and the expression of 5 alpha-reductase was significantly increased in both sexes after the exercise. Finally, the expression of AR was significantly higher in female rats, but not in males after the exercise. These data Suggest that acute exercise enhances the local bioactive androgen metabolism in the skeletal Muscle of both sexes. (C) 2009 Elsevier Inc. All rights reserved.

Muscle mass is an important factor influencing the activity of daily living in older adults. We aimed to investigate whether alpha-actinin-3 (ACTN3) gene R577X polymorphism affects muscle mass in older Japanese women. A total of 109 women (mean +/- SD, 64.1 +/- 6.0 years) were genotyped for the R/X variant of ACTN3. Mid-thigh muscle cross-sectional area (CSA) was assessed using MRI and compared using analysis of covariance models adjusted for body weight. In addition, physical activity and protein intake were measured as the living environmental factors affecting muscle mass. The ACTN3 R577X genotype distributions of the subjects were 19, 63 and 27 for the RR, RX, and XX genotypes, respectively. No differences in physical activity and protein intake were observed among the genotypes. The XX genotype showed lower thigh muscle CSA compared with RR&RX genotype (mean +/- SEM; XX: 69.1 +/- 1.8 cm(2), RR&RX: 73.6 +/- 1.1 cm(2); p &lt; 0.05). The results of the present study suggest that ACTN3 R577X polymorphism influences muscle mass in older Japanese women.

Aim: Obesity is a strong risk factor for cardiovascular morbidity and mortality. In addition, decreased central arterial distensibility is recognized as an independent risk factor for cardiovascular disease (CVD). Obese subjects exhibit low arterial distensibillity; however, the mechanism responsible for the decrease in arterial distensibility in obese subjects has not yet been elucidated. Pentraxin 3 (PTX3), a recently identified member of the pentraxin family of proteins, is produced in areas of atherosclerosis. A recent study has revealed that the PTX3 level may indicate the vascular inflammatory status. The aim of this study was to investigate plasma PTX3 concentrations and arterial distensibility in obese subjects.
Methods: Eleven obese men (age: 44 +/- 2 years, body mass index [BMI]: 32 +/- 1 kg/m(2)) and 14 non-obese men (age: 42 +/- 2 years, BMI: 26 +/- 1 kg/m(2)) participated in this study. We measured arterial compliance (using simultaneous B-mode ultrasound and arterial applanation tonometry of the common carotid artery); beta-stiffness index, an index of arterial compliance adjusted for distending pressure; and plasma PTX3 concentrations.
Results: Arterial compliance was significantly lower and the beta-stiffness index was significantly higher in obese men than in non-obese men. Plasma PTX3 concentration was markedly higher in obese than non-obese men.
Conclusions: Obese men have lower arterial distensibility and higher circulating PTX3 levels than non-obese men; therefore, higher PTX3 levels and decreased arterial distensibility coexist in obese men. The high PTX3 concentrations in obese men may be involved in the mechanism underlying the obesity-induced decrease in arterial distensibility.

Background and aims: Echocardiographic measurement of epicardial fat (EF) seems to be a reliable and diagnostic marker of visceral. adipose tissue (VAT). However, the weight loss-induced changes in EF have not been compared with those in VAT or the truncal. depot. In this study, we aimed to compare the weight loss-induced changes in EF, VAT and other regional fat compartments in obese men.
Methods and results: In this study, 27 moderately obese men (age 45.8 +/- 1.7 years; body mass index 30.5 +/- 0.7 kg/m(2)) followed a daily low-calorie diet as part of a clinical. 12-week weight loss interventional. study. We evaluated the EF thickness by transthoracic echocardiography, assessed the abdominal fat tissues by computed tomography scans, and examined the regional and whole body fat compartments by dual X-ray absorptiometry. An average decrease of 26.8% in the initial calorie intake corresponded to post-program reductions of 17.2%, 11.0%, 16.6%, and 29.8% in EF thickness (P &lt; 0.001), body mass, percentage fat mass, and abdominal fat compartments, respectively. The percentage change in VAT in response to weight loss was twice as high as the substantial. change in EF tissue (P &lt; 0.001).
Conclusion: The results of the study suggest that a low-calorie diet-induced weight toss decreases EF thickness. Moderate diet-induced weight loss alone may represent an effective nonpharmacological strategy for reducing EF, which is a unique, pathogenic fat depot and an emerging marker of VAT. (c) 2009 Elsevier B.V. All rights reserved.

Yoshizawa M, Maeda S, Miyaki A, Misono M, Choi Y, Shimojo N, Ajisaka R, Tanaka H. Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women. Am J Physiol Heart Circ Physiol 297: H1899-H1903, 2009. First published September 25, 2009; doi:10.1152/ajpheart.00433.2009.-Central arterial compliance plays an important role in the functional abilities of the vasculature. Two active tripeptides, valine-proline-proline and isoleucineproline-proline, were isolated from sour milk and were referred to as lactotripeptides (LTP). Because LTP appears to act as an angiotensin-converting enzyme inhibitor, it is plausible to hypothesize that LTP improves arterial compliance. We determined the effects of LTP ingestion alone or in combination with regular aerobic exercise on arterial compliance. A total of 55 postmenopausal women (50-65 yr old) were randomly divided into four groups: placebo, LTP, exercise and placebo (Ex + placebo), or exercise and LTP (Ex + LTP). LTP or placebo was administered orally for 8 wk. The exercise groups completed an 8-wk moderate aerobic exercise intervention. There were no differences in baseline arterial compliance and most other key dependent variables among the groups. Carotid arterial compliance increased significantly in the LTP (0.93 +/- 0.07 vs. 0.99 +/- 0.08 mm(2)/mmHg . 10(-1)), Ex + placebo (0.92 +/- 0.04 vs. 1.00 +/- 0.05 mm2/mmHg . 10(-1)), and Ex + LTP groups (0.86 +/- 0.06 vs. 1.00 +/- 0.06 mm(2)/mmHg . 10(-1)), whereas no such changes were observed in the placebo control group (0.86 +/- 0.06 vs. 0.85 +/- 0.07 mm(2)/mmHg . 10(-1)). The magnitude of increases in carotid arterial compliance was significantly greater in the Ex + LTP group (19 +/- 4%) than in other groups. The improvements in arterial compliance with LTP were associated with the corresponding reductions in arterial blood pressure and plasma angiotensin II concentrations. We concluded that LTP ingestion improves carotid arterial compliance and that the combination of LTP ingestion and regular exercise is additive and synergistic in improving arterial compliance in postmenopausal women.

Several studies indicate that expression of the peroxisome proliferator-activated receptor gamma(PPARG) gene is influenced by calorie restriction. The aim of this study was to investigate whether PPARG gene variations are associated with weight reduction and changes in coronary heart disease (CHD) risk factors in response to a 14-week calorie restriction. In total, 95 middle-aged, Japanese women (BMI &gt;= 25 kg/m(2)) enrolled as subjects for 14 weeks and attended weekly dietary lectures instructing them on how to consume a nutritionally balanced diet of 1,200 kcal/day. Eight single-nucleotide polymorphisms (SNPs) in the PPARG gene (rs1801282 (Pro/Ala), rs2292101, rs2959272, rs1386835, rs709158, rs1175540, rs1175544, and rs1797912) were analyzed. Body weight decreased significantly (-7.7 +/- 3.1 kg; -11.3 +/- 4.4%) during the intervention. Six PPARG SNPs (rs2959272, rs1386835, rs709158, rs1175540, rs1175544, and rs1797912) were significantly associated with the weight reduction, with rs1175544 having the strongest association (P = 0.004). No differences across the rs1175544 genotypes were observed in any of the blood analyses or in blood pressure. In a multiple regression analysis, the rs1175544 genotypes accounted for 7% of the total weight reduction variance. These data suggest that one SNP of the PPARG genotype accounted for a significant portion of the total body weight reduction variance in response to a short-term intervention consisting of calorie restriction; however, no relationship was found between these SNPs and the changes in CHD risk factors which accompanied weight loss.

The effect of habitual exercise on vascular function, including central arterial distensibility and endothelial function, in obese subjects has not yet been clarified. We investigated whether aerobic exercise training affects central arterial distensibility and endothelial function in middle-age overweight and obese men. A total of 21 overweight and obese men (age 50 +/- 2 years, body mass index 30 +/- 1 kg/m(2)) completed a 12-week aerobic exercise intervention. Aerobic exercise training significantly reduced their body weight and resulted in a significant decrease in body mass index. After the weight-reduction exercise program, carotid arterial compliance (determined by simultaneous B-mode ultrasonography and arterial applanation tonometry on the common carotid artery) significantly increased; and the beta-stiffness index, an index of arterial compliance adjusted for distending pressure, significantly decreased. The concentrations of plasma endothelin-1, a potent vasoconstrictor peptide produced by vascular endothelial cells, significantly decreased and plasma nitric oxide (measured as the stable end product [nitrite/nitrate]), a potent vasodilator produced by vascular endothelial cells, significantly increased after the weight-reduction exercise program. In conclusion, weight reduction by aerobic exercise training in overweight and obese men increased the central arterial distensibility. This increase might contribute to the improvement in endothelial function, as assessed by a decrease in endothelin-1 and an increase in nitric oxide, after exercise training-induced weight loss. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:823-828)

The purpose of this study was to investigate the interaction of habitual exercise and candidate gene polymorphisms related to bone on osteo sono-assessment index (OSI) by quantitative ultrasound (QUS) in middle-aged and elderly Japanese. Participants were classified into exercise group (E; n = 172, 62.3 +/- 7.7 yr) and sedentary group (S; n = 65, 58.6 +/- 9.2 yr). The OSI was measured with AOS-100. DNA was extracted from blood, and single nucleotide polymorphism in vitamin D receptor, estrogen receptor a, and transforming growth factor-beta I were genotyped by TaqMan assay. Group E had significantly lower body weight and body mass index (BMI) than Group S. In men, although Group E was older than Group S, Group E had significantly higher OSI rather than Group S. There was no significant interaction between habitual exercise and each gene polymorphism on OSI. These results essentially remained unchanged even when analysis of covariance was applied after adjustment for age, body weight, and BMI. These results suggest habitual exercise and genetic factors have no interaction on OSI in middle-aged and elderly Japanese. Further investigations are needed to prove the interaction of other gene polymorphisms and exercise. (Jpn. J. Phys. Fitness Sports Med. 2009, 58 : 421 similar to 430)

Background: Resistance training has been increasingly incorporated into the overall exercise programme because of its effect on muscle strength, functional capacity and osteoporosis. High-intensity resistance training increases arterial stiffness. However, the effect of moderate-intensity resistance training on arterial stiffness is unknown.
Objective: To determine whether 12 weeks of moderate-intensity resistance training increases arterial stiffness in middle-aged women.
Methods: 35 middle-aged women (age range 32 to 59 years) volunteered to participate. The subjects were randomly assigned to one of three groups: resistance training (RT) group, aerobic exercise training (AET) group or control group. The RT and AET groups performed 12 weeks of moderate-intensity resistance training or aerobic exercise training (two days/week).
Results: In the RT group, one-repetition maximum strength significantly increased after the intervention. Interestingly, aortic (carotid-femoral) pulse wave velocity (PWV; an index of arterial stiffness), and peripheral (femoral-ankle) PWV did not change with moderate-intensity resistance training. In contrast, in the AET group, carotid-femoral PWV significantly decreased after the intervention. Resistance training and aerobic exercise training did not affect blood pressure.
Conclusions: This study found that moderate-intensity resistance training did not increase arterial stiffness in middle-aged women, which may have great importance for health promotion with resistance training.

The purpose of this study was to investigate the interaction of habitual exercise and candidate gene polymorphisms related to bone on osteo sono-assessment index (OSI) by quantitative ultrasound (QUS) in middle-aged and elderly Japanese. Participants were classified into exercise group (E; n=172, 62.3 ± 7.7 yr) and sedentary group (S; n=65, 58.6 ± 9.2 yr). The OSI was measured with AOS-100. DNA was extracted from blood, and single nucleotide polymorphism in vitamin D receptor, estrogen receptor α, and transforming growth factor-βI were genotyped by TaqMan assay. Group E had significantly lower body weight and body mass index (BMI) than Group S. In men, although Group E was older than Group S, Group E had significantly higher OSI rather than Group S. There was no significant interaction between habitual exercise and each gene polymorphism on OSI. These results essentially remained unchanged even when analysis of covariance was applied after adjustment for age, body weight, and BMI. These results suggest habitual exercise and genetic factors have no interaction on OSI in middle-aged and elderly Japanese. Further investigations are needed to prove the interaction of other gene pol

Objective Hypertension is a major risk factor for cardiovascular disease. Polymorphism in the beta(2)-adrenergic receptor (ADRB2) and nitric oxide synthase 3 (NOS3) genes is associated with clinical cardiovascular phenotypes. The Arg16Gly and Glu298Asp polymorphisms of ADRB2 and NOS3 genes, respectively, have been reported to be associated with hypertension. We hypothesized that a combination of these two polymorphisms increases the risk for hypertension. Hence, we examined the effect of this combination of single-nucleotide polymorphisms on the risk for hypertension.
Methods Our cross-sectional study comprised 402 middle-aged and elderly human participants. We determined the genotypes of Arg16Gly and Glu298Asp single-nucleotide polymorphisms in ADRB2 and NOS3, respectively, by TaqMan PCR method; we also measured the resting blood pressure.
Results The odds ratio for the presence of hypertension in individuals having the Gly/Gly genotype of ADRB2 compared with those having the other genotypes (Arg/Arg and Arg/Gly) was 2.87. With regard to the Glu298Asp polymorphism in NOS3, the odds ratio for the presence of hypertension in individuals having the Glu/Glu genotype of NOS3 when compared with those having the other genotypes (Asp/Asp and Asp/Glu) was 2.79. Interestingly, the odds ratio was 7.64 for individuals having a combination of the Gly/Gly genotype of ADRB2 and Glu/Glu genotype of NOS3 when compared with those having a combination of Arg/Arg and Arg/Gly genotypes of ADRB2 and Asp/Asp and Asp/Glu genotypes of NOS3.
Conclusion We revealed that a combination of the Arg16Gly and Glu298Asp polymorphisms in ADRB2 and NOS3, respectively, remarkably increased the risk for hypertension in middle-aged and elderly humans. J Hypertens 27:1377-1383 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background: Regular aerobic exercise improves large artery compliance in middle-aged and older humans. However, the underlying mechanisms are unknown. We tested the hypothesis that the improved central arterial compliance with endurance training is mediated by decreased a-adrenergic tone and/or increased endothelial function.
Methods: Seven sedentary healthy adults (60 +/- 3 years) underwent systemic a-adrenergic blockade (phentolamine) and nitric oxide synthase (NOS) inhibition using N(G)-monomethyl-L-arginine in sequence before and after a 3-month moderate endurance training (walk/jog, 4-5 days/week). Phentolamine was given first to isolate the contribution of nitric oxide to arterial compliance by minimizing reflex suppression of sympathetic tone resulting from systemic NOS inhibition as well as to assess the a-adrenergic receptor-mediated modulation of arterial compliance.
Results: Baseline arterial compliance (via simultaneous ultrasound and applanation tonometry on the carotid artery) increased 34 +/- 12% after exercise training (P &lt; 0.01). When alpha-adrenergic blockade was performed, arterial compliance increased 37 +/- 6% (P &lt; 0.01) before the exercise training but did not change significantly after the training. Decreases in arterial compliance from the a-adrenergic blockade to the subsequent additional NOS blockade were not different before and after exercise training.
Conclusion: Our results suggest that the reduction in a-adrenergic receptor-mediated vascular tone contributes to the improved central arterial compliance with endurance training. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Obesity and reduction in central arterial distensibility, respectively, have been identified as powerful and independent risk factors for cardiovascular disease. However, the effect of weight reduction on central arterial function in obese Subjects has not yet been clarified. We investigated whether low-calorie diet-induced weight reduction affects central arterial distensibility and endothelial function in middle-aged Obese men. Twelve obese men (age: 45 +/- 2 yrs, BMI: 30 +/- 1 kg/m(2)) completed a 12-week dietary intervention. Caloric restriction induced significantly weight loss and decrease in BMI. After the program, carotid arterial compliance significantly increased and beta-stiffness index and aortic pulse-wave velocity remarkably decreased. Concentrations of plasma endothelin-1 (ET-1) significantly decreased and plasma nitric oxide (NO) markedly increased after the program. Weight reduction by low-calorie diet in obese men increases central arterial distensibility, which may contribute to the improvement in endothelial function, as noted by a decrease in ET-I and an increase in NO.

Habitual aerobic exercise results in a significant increase in central arterial compliance. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide and could play a role in mediating the habitual aerobic exercise-induced increase in central arterial compliance. The aim of the present study was to examine whether ET-1 is involved in the mechanisms underlying the increase in central arterial compliance with aerobic exercise training.
Seven apparently healthy middle-aged and older (60 +/- 3 years) adults underwent systemic endothelin-A/B (ET(A/B))-receptor blockade (500 mg of Tracleer((R))) before and after 12 weeks of aerobic exercise training (70 +/- 1% of maximal heart rate, 44 +/- 2 min day(-1), 4.4 +/- 0.1 days week(-1)).
Basal carotid arterial compliance (via simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) increased significantly after exercise training. Resting plasma ET-1 concentration decreased significantly after exercise training. Before exercise intervention, carotid arterial compliance increased significantly with the administration of the ET(A/B)-receptor blockade. After training, however, increases in carotid arterial compliance previously observed with the ET(A/B)-receptor blockade before training were abolished.
Regular aerobic exercise training enhances central arterial compliance in middle-aged and older humans. The increase in arterial compliance was associated with the corresponding reduction in plasma ET-1 concentration as well as the elimination of ET-1-mediated vascular tone. These results suggest that reductions in ET-1 may be an important mechanism underlying the beneficial effect of exercise training on central artery compliance.

Kim MK, Tomita T, Kim MJ, Sasai H, Maeda S, Tanaka K. Aerobic exercise training reduces epicardial fat in obese men. J Appl Physiol 106: 5-11, 2009. First published October 16, 2008; doi:10.1152/japplphysiol.90756.2008. -The purpose of this study was to determine the effects of exercise training on ventricular epicardial fat thickness in obese men and to investigate the relationship of the change in epicardial fat thickness to changes in abdominal fat tissue following exercise training. Twenty-four obese middle-aged men [ age, 49.4 +/- 9.6 yr; weight, 87.7 +/- 11.2 kg; body mass index (BMI), 30.7 +/- 3.3 kg/m(2); peak oxygen consumption, 28.4 +/- 7.2 ml (.) kg(-1) (.) min(-1); means +/- SD] participated in this study. Each participant completed a 12-wk supervised exercise training program (60-70% of the maximal heart rate; 60 min/day, 3 days/wk) and underwent a transthoracic echocardiography. The epicardial fat thickness on the free wall of the right ventricle was measured from both parasternal long- and short-axis views. The visceral adipose tissue ( VAT) and subcutaneous adipose tissues were measured by computed tomography. Following exercise training, the epicardial fat thickness was significantly decreased ( P &lt; 0.001). The percentage change of epicardial fat thickness was twice as high compared with those of waist, BMI, and body weight of original values ( P &lt; 0.05). There was a significant relationship (r = 0.525, P = 0.008) between changes in the epicardial fat thickness and VAT with exercise training. Stepwise multiple regression analysis revealed that the change in VAT, change in systolic blood pressure, and change in quantitative insulin sensitivity check index were independently related to the change epicardial fat thickness ( P &lt; 0.05). The ventricular epicardial fat thickness is reduced significantly after aerobic exercise training and is associated with a decrease in VAT. These results suggest that aerobic exercise training may be an effective nonpharmacological strategy for decreasing the ventricular epicardial fat thickness and visceral fat area in obese middle-aged men.

Epidemiological studies have reported an association between arterial calcification and bone loss after menopause. However, the underlying mechanism of the association remains unclear. Therefore, to explore the possible mechanisms of the association, we tried to develop a new combined model rat of ovariectomy (OVX, an animal model of osteoporosis) and vitanlin D-3 plus nicotine (VDN rate an animal model of arterial calcification). We tested them by using sham-operated control rats (SC), OVX control rats (OC), and OVX plus VDN-treated rats (OVN). Dissections were performed twice at 4 (4SC. 40C, and 4OVN) and 8 (8SC, 80C, and SOVN) weeks after treatment. 8OVN showed bone loss and arterial calcification. although 80C showed only bone loss. Moreover, arterial clacium content was associated with indexes of bone loss at 8 weeks. Thus, the OVN rat is considered a good model to examine the relationship of the two disorders after menopause. Additionally, the arterial endothelin-1 (ET-1, a potent regulator of arterial calcification) levels increased in both 4OVN and 8OVN, and the level was associated with arterial calcium content at 8 weeks. Furthermore, the arterial endothelial nitric oxide synthase (eNOS) protein, which is an enzyme that produces nitric oxide (an antiatherosclerotic substance), was significantly reduced in only 8OVN. Estrogens affect the alterations of the eNOS and ET-1 proteins. Therefore, we suggest that impairment of the ET-1- and NO-producing system in arterial tissue during periods of rapid bone loss by estrogen deficiency might be a mechanism of the relalionship between the two disorders seen in postmenopausal women.

Post high-intensity exercise lymphocytopenia is well documented, but its underlying mechanisms have not been fully elucidated. A possible mechanism is a reactive oxygen species-induced DNA damage after high-intensity exercise. Furthermore, lymphocyte apoptosis related to DNA damage might contribute to exercise-induced lymphocytopenia. Purpose: This study examined lymphocytopenia, lymphocyte oxidative DNA damage, and apoptosis in young healthy sedentary males after acute high-intensity exercise. Method: Fifteen subjects exercised on bicycle ergometers for 1 h at 75% of their VO(2max). Venous blood samples were taken before exercise (PRE) and hourly after exercise until 4 h (P0-P4). Lymphocyte counts, oxidative DNA damage evaluated using the Comet assay with human 8-oxoguanine DNA glycosylase, and serum lipid peroxide (LPO) concentration were measured. Furthermore, lymphocyte superoxide, Fas receptor (CD95), and Annexin-V-positive lymphocyte apoptosis cells were measured in 10 subjects who exercised and gave blood samples as described above. Results: Lymphocyte counts became significantly lower than the PRE value (P &lt; 0.05): 20.4% at P 1, 24.3% at P2, and 16.3% at P3. Moreover, LPO significantly increased by P2 (P &lt; 0.05): 1.6-fold. The % DNA in tail, indicating oxidative DNA damage, was significantly higher at P3 (54.3 +/- 12.8%) than at PRE (42.6 +/- 11.1 %, P &lt; 0.05). The lymphocyte superoxide level was significantly higher (51.3%) than the PRE value (P &lt; 0.05). Neither CD95 nor Annexin-V-positive cells were significantly different than the PRE value. Conclusion: Results of this study suggest that lymphocyte oxidative DNA damage can relate to lymphocytopenia, although DNA damage was not associated with apoptosis in healthy young sedentary mates.

The spontaneously hypertensive rat (SHR) is a model of cardiomyopathy that displays a genetic defect in cardiac fatty acid (FA) translocase/CD36, a plasma membrane long-chain FA transporter. Therapy with medium-chain FAs, which do not require CD36-facilitated transport, has been shown to improve cardiac function and hypertrophy in SHRs despite persistent hypertension. However, little is known about the underlying molecular mechanisms. The aim of this study was to document the impact of medium-chain triglyceride (MCT) therapy in SHRs on the expression level and activity of metabolic enzymes and signaling pathways. Four-week-old male SHRs were administered MCT (SHR-MCT) or long-chain triglyceride (SHR-LCT) for 16 wk. We used Wistar-Kyoto (WKY) rats as controls (WKY-MCT and WKY-LCT). The SHR-MCT group displayed improved cardiac dysfunction [as assessed by left ventricular (LV) end-diastolic pressure and the positive and negative first derivatives of LV pressure/P value], a shift in the beta-myosin heavy chain (MHC)-to-alpha-MHC ratio, and cardiac hypertrophy compared with the SHR-LCT group without an effect on blood pressure. Administration of MCT of SHRs reversed the LCT-induced reduction in the cardiac FA metabolic enzymatic activities of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD). In the SHR-MCT group, the protein expression and transcriptional regulation of myocardial peroxisome proliferator-activated receptor-alpha, which regulates the transcription of LCHAD and MCAD genes, corresponded to the changes seen in those enzymatic activities. Furthermore, MCT intake caused an inhibition of JNK activation in SHR hearts. Collectively, the observed changes in the myocardial activity of metabolic enzymes and signaling pathways may contribute to the improved cardiac dysfunction and hypertrophy in SHRs following MCT therapy.

Systemic arterial compliance ( C) and vascular resistance ( R) regulate effective arterial elastance ( Ea), an index of artery load. Increases in Ea during exercise are due primarily to reductions of C and maintain optimal ventricular-arterial coupling. Because C at rest and left ventricular functional reserve are greater in endurance-trained ( ET) compared with sedentary control (SC) humans, we hypothesized that reductions of C and increases in Ea are greater in ET than SC individuals. The aim of this study was to investigate C, R, and Ea during exercise in ET and SC humans. C, R, Ea, and cardiac cycle length ( T) were measured at rest and during exercise of 40, 60, and 80% maximal oxygen uptake using Doppler ultrasonography in 12 SC and 13 ET men. C decreased in an exercise intensity-dependent manner in both groups, but its reductions were greater in the ET than SC subjects. Consequently, although C at rest was greater in the ET than SC group, the intergroup difference in C disappeared during exercise. Exercise-related changes in R/T were relatively slight and R/T was lower in the ET than the SC group, both at rest and during exercise. Although Ea at rest was lower in the ET than SC group, there were no intergroup differences in Ea at 40, 60, or 80% maximal oxygen uptake. We conclude that the reductions of C from rest to exercise are more marked in ET than SC humans. This may be related to the exercise-associated disappearance of the difference in Ea between ET and SC humans.

Aim: Loss of oestrogen synthesis capacity after menopause contributes to increases in arterial stiffness and calcification. Exercise training improves arterial stiffness and calcification. However, the mechanism of exercise training-induced improvement of arterial stiffness and calcification remains unclear.
Method: We examined the mechanism by using aortas of sham-operated rats (sham control; SC), ovariectomized rats (OVX control; OC), OVX plus treatment with vitamin D-3 plus nicotine (VDN) rats (OV sedentary; OVSe), which is an animal model of endothelial dysfunction and arterial calcification, and voluntary running wheel exercise for 8 weeks plus OVX plus VDN rats (OV exercise; OVEx).
Results: The arterial tissue calcium and endothelin-1 (ET-1: a vasoconstrictor peptide and a potent regulator of arterial calcification) levels were significantly higher in OVSe rats compared with the SC and OC rats, whereas these levels in the OVEx rats were significantly lower than in the OVSe rats. Additionally, arterial expression of endothelial nitric oxide synthase (eNOS), which is an enzyme that produces nitric oxide (NO: a vasodilator substance), was reduced in OVSe rats. However, exercise training prevented the decrease in eNOS expression. Moreover, there was a significant positive correlation between arterial calcium level and arterial ET-1 level.
Conclusion: These findings suggest that exercise training-induced improvement of ET-1 and NO prevents the impairment of endothelial function after menopause in females, and this improvement may result in less arterial calcification.

An increase in arterial stiffness with advancing age is associated with several pathological states, including hypertension and arteriosclerosis. Regular exercise improves the aging-induced increase in arterial stiffness and has a protective effect against these diseases. However, not all individuals respond to exercise to the same extent. Atrial natriuretic peptide (ANP) is involved in the regulation of basal blood pressure, blood flow, and vascular tone. The present study was designed to clarify whether gene polymorphisms in ANP-related genes affect exercise-induced improvements in arterial stiffness. We performed a cross-sectional study of 291 healthy middle-aged and older Japanese subjects (63 +/- 1 years), examining the relationship between daily physical activity-induced improvements in arterial stiffness, estimated by brachial-ankle arterial pulse wave velocity (baPWV), and the gene polymorphisms of valine32methionine (V32M: 664G&gt;A) in exon 1 of ANP and asparagine521 aspartic acid (N521 D: 1780A&gt;G) in exon 8 of the ANP clearance receptor (NPR-C). The baseline baPWV was significantly lower in the active group, but no differences were seen in blood pressure. Active subjects with the ANP-VV genotype had significantly lower baPWV and higher plasma ANP levels compared with inactive subjects, but there were no variations related to the VM+MM genotype. Additionally, baPWV and plasma ANP levels were negatively correlated in ANP-VV genotype subjects, but were not correlated in VM+MM individuals. Our results suggest that ANP polymorphism in older Japanese subjects may affect the cardiovascular response to regular exercise.

Purpose: Females have been reported to have greater resistance to skeletal muscle fatigue than males. Blood flow, which plays an important role in supplying oxygen and nutrients to working muscles, may play an important role in the mechanisms of gender difference. We hypothesized that females would have greater conduit artery blood flow supplying working muscles than males during intermittent maximal handgrip exercise. Methods: Healthy adult (22-31 yr old) males (N = 8) and females (N = 8), lying in a supine position, repeated static maximal voluntary contractions (MVC) with a handgrip device in an intermittent pattern. Mean brachial arterial blood flow (MBABF) was continuously monitored using Doppler ultrasonography during the 5-s muscle-relaxation phase, when intramuscular pressure does not impede measurement of muscle blood flow during the 4-min exercise period, and continuously during the 10-min recovery period. Vascular conductance (VC) was calculated from the MBABF normalized by forearm volume and mean blood pressure (MBP). Results: Females achieved higher relative muscle force (%MVC) than males throughout both the exercise and the recovery periods (P &lt; 0.05); females tended to exhibit smaller declines in muscle force (i.e., less fatigue). Exercise-induced increases in MBABF normalized to forearm volume were greater in females compared with males during the relaxation phases (P &lt; 0.05), during which females also exhibited greater VC than males (P &lt; 0.05). Conclusion: Our findings suggest that the normalized MBABF and VC in females, who experience less muscle fatigue, are greater during intermittent maximal voluntary handgrip exercise.

High physical activity or aerobic exercise training increases central arterial distensibility in older humans. However, the effect of a single bout of exercise on central arterial distensibility in older humans is unknown. Furthermore, the effect of exercise training on central arterial distensibility during exercise is unclear. We investigated whether systemic arterial compliance (SAC) changes after acute exercise in older humans, and, if so, whether this change in SAC is enhanced by aerobic exercise training. Seven untrained older women (61-69 years old) participated in a 6-month exercise intervention study. We measured SAC after acute exercise (cycling exercise at 80% of their individual ventilatory threshold for 30 min) before and after 6 months of aerobic exercise training. After exercise training, the individual ventilatory threshold was significantly increased. In addition, both the SAC at rest and that 30 min after acute exercise were significantly increased after the exercise training program. Before exercise training, there was no significant increase in SAC after acute exercise, whereas, after exercise training, the SAC was significantly increased 30 min after acute exercise. The present study suggests that, after aerobic exercise training, SAC increases after acute exercise in older humans, and that the SAC at rest and after acute exercise is enhanced by aerobic exercise training, thereby causing an effective adaptation in increase in cardiac output during exercise.

Purpose: Arterial stiffness, an independent risk factor for cardiovascular disease, increases with advancing age. Arterial stiffness is improved by regular exercise, but individual responses to exercise training are variable. Given that estrogen and estrogen receptor-alpha (ER-alpha) can induce vasodilation and can exert an antiatherosclerotic effect in vessels, we hypothesized that gene polymorphisms of ER-alpha might influence the ability of regular exercise to improve arterial stiffness in postmenopausal women. Methods: One hundred ninety-five healthy postmenopausal women (62 +/- 6 yr, mean +/- SD) participated in our cross-sectional study. We determined the genotype of single-nucleotide polymorphisms (SNP) at -401T/C of intron 1 of the ER-alpha gene. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV), and daily physical activity was estimated by a uniaxial accelerometer. Subjects were divided into active and inactive groups according to the median value (200 kcal.d(-1)) of energy expenditure. Results: baPWV in individuals with the TT variant of -401T/C genotype were significantly higher than for individuals with the TC+CC genotype. No significant differences in mean baPWV values were found between the active group and the inactive group (P = 0.09). A significant reduction of baPWV secondary to increased daily physical activity was observed in individuals with the TC+CC genotype but not in individuals with the TT genotype (TT/active: 1470 +/- 36 cm.s(-1); TT/inactive: 1457 +/- 34 cm.s(-1); TC+CC/active: 1359 +/- 21 cm.s(-1); TC+CC/inactive: 1433 +/- 24 cm.s(-1)). Conclusion: These results suggest that ER-alpha polymorphism affects the regular exercise-related reduction in arterial stiffness in healthy postmenopausal women.

Sex steroid hormones, such as testosterone and estradiol, play important roles in developing both strength and mass of skeletal muscle. Recently, we demonstrated that skeletal muscle can synthesize sex steroid hormones. Whether there are sex differences in basal steroidogenesis or acute exercise-induced alterations of steroidogenesis in the skeletal muscle is unknown. We examined sex differences in the levels of testosterone, estradiol, and steroidogenesis-related enzymes, such as 17 beta-hydroxysteroid dehydrogenase (HSD), 3 beta-HSD, and aromatase cytochrome P-450 (P450arom), in the skeletal muscle at rest and after exercise. We studied the gastrocnemius muscles of resting rats (10 wk old) and exercised rats (10 wk old, treadmill running, 30 m/min, 30 min). Basal muscular testosterone levels were higher in males than females, whereas estradiol did not differ between sexes. Additionally, 17 beta-HSD, 3 beta-HSD, and P450arom transcript and protein expression were greater in females. After acute exercise, testosterone levels and 17 beta-HSD expression increased in muscle in both sexes. By comparison, muscular estradiol levels increased in males following exercise but were unchanged in females. Expression of P450arom, which regulates estrogen synthesis, increased after acute exercise in males but decreased after exercise in females. Thus a single bout of exercise can influence the steroidogenic system in skeletal muscle, and these alterations differ between sexes. The acute exercise-induced alteration of steroidogenic enzymes may enhance the local steroidogenesis in the skeletal muscle in both sexes.

Adiponectin is an adipocytokine that is involved in insulin sensitivity. The adiponectin gene contains a single nucleotide polymorphism (SNP) at position 276 (G/T). The GG genotype of SNP276 (G/T) is associated with lower plasma adiponectin levels and a higher insulin resistance index. Therefore, we examined the influence of SNP276 (G/T) on the plasma level of adiponectin in response to exercise training. Thirty healthy Japanese (M12/F18; 56 to 79 years old) performed both resistance and endurance training, 5 times a week for 6 months. The work rate per kg of weight at double-product break-point (DPBP) was measured. Blood samples were obtained before and after the experiment. Plasma concentrations of adiponectin, HbA1c, insulin, glucose, total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, and triglyceride were measured. Genotypes of SNP276 were specified. Student's t-test for paired values and unpaired values was used. After the 6-month training period, the work rate per kg of weight at DPBP and the plasma HDL-cholesterol level were significantly improved (P&lt;0.05), while no change was observed in the total plasma adiponectin level. However, the plasma adiponectin level in those with the GT + TT genotype had significantly increased (P&lt;0.05). Additionally, the degree of the decrease in the HOMA-R level was significantly greater in the subjects with the GT + TT genotype than those with the GG genotype (p&lt;0.05). Our results suggest that subjects with the genotype GT + TT at SNP276 (G/T) have a greater adiponectin-related response to exercise training than those with the GG genotype.

Stroke-prone spontaneously hypertensive rats (SHRSP) often suffer from spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age-dependent stages of hypertension. The profile of VEGF and its receptor, Flk-1, was dependent on age and stage of hypertension (i.e., down regulated at pre-hypertensive and malignant hypertensive stages, but up regulated at typical hypertensive stage), while that of its downstream components, pAkt and eNOS, were down regulated in a time-dependent manner in the frontal cortex of SHRSP compared to age-matched genetic control, normotensive WKY rats. On the other hand, the expression of endothelin-1 and its type A receptor (endothelin ETA receptor) were up regulated, depending on age and stage of hypertension. In contrast, levels of endothelin type B receptor were down regulated. The regional cerebral blood flow decreased during the development of malignant hypertension. Thus, subsequent experiments were designed to investigate whether endothelin-1 receptor antagonism, using endothelin-A/-B dual receptor antagonist SB209670, could normalize the molecular profile of these factors in SHRSP brain. Interestingly, blockage of endothelin-1 receptor restored to normal, levels of cerebral endothelin-1, endothelin ETA receptor and endothelin ETB receptor; VEGF and Flk-l; endothelial nitric oxide synthase (eNOS) and pAkt, in SHRSP, compared to age-matched WKY. Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats. (c) 2007 Elsevier B.V All rights reserved.

Background: We examined the relationships of endurance and strength exercise training and the adolescent duration of training to arterial stiffness in young adult men. We hypothesized that young adults participating in endurance sports would have decreased arterial stiffness, whereas those in strength-based sports would have increased arterial stiffness. In addition, we predicted that these trends would be more pronounced with an increase in the duration of sport participation.
Methods: Subjects were male endurance-trained men with short (current age, 20 years; age at beginning of competitive sport, 15 years; sport careers, 5 years; n = 7, S-ET) and long (current age, 20 years; age at beginning of competitive sport, 12 years; sport careers, 8 years; n = 7, L-ET) competitive sport careers, strength-trained men with short (current age, 20 years; age at beginning of competitive sport, 16 years; sport careers, 4 years; n = 7, S-ST) and long (current age, 22 years; age at beginning of competitive sport, 15 years; sport careers, 7 years; n = 7, L-ST) careers, and sedentary control men (aged, 20 years; n = 7, C).
Results: The exercise training was associated with aortic pulse wave velocity (PWV), a traditional index of arterial stiffness, and the associations were statistically independent of blood pressure (BP). Aortic PWV was lower in L-ET than C and ST. Aortic PWV in L-ST was greater than that of C. The associations of exercise training with systemic arterial compliance (SAC), which inversely correlates with arterial stiffness, were also positive and BP independent. The SAC was greater in the ET groups compared with C and ST groups. The SAC in L-ST was lower than in C.
Conclusions: These results suggest that changes in arterial stiffness associated with different training programs appear in young adults as well as in older humans, and these changes may begin in adolescence.

Endurance training improves endothelium-dependent vasodilation, yet it does not increase basal blood flow in the legs. We determined the effects of a 3-mo aerobic exercise intervention on basal leg blood flow and alpha-adrenergic vasoconstriction and nitric oxide (NO) release in seven apparently healthy middle-aged and older adults (60 +/- 3 yr). Basal femoral artery blood flow (via Doppler ultrasound) (pretraining: 354 +/- 29; posttraining: 335 +/- 34 ml/min) and vascular conductance did not change significantly with the exercise training. Before the exercise intervention, femoral artery blood flow increased 32 +/- 16% with systemic alpha-adrenergic blockade (with phentolamine) (P &lt; 0.05), and the addition of nitric oxide synthase (NOS) inhibition using N-G-monomethyl-L-arginine (L-NMMA) did not affect femoral artery blood flow. After training was completed, femoral artery blood flow increased 47 +/- 7% with alpha-adrenergic blockade (P &lt; 0.01) and then decreased 18 +/- 7% with the subsequent administration of L-NMMA (P &lt; 0.05). Leg vascular conductance showed a greater alpha-adrenergic blockade-induced vasodilation (+ 1.7 +/- 0.5 to + 3.0 +/- 0.5 units, P &lt; 0.05) as well as NOS inhibition-induced vasoconstriction (-0.8 +/- 0.4 to -2.7 +/- 0.7 units, P &lt; 0.05) after the exercise intervention. Resting plasma norepinephrine concentration significantly increased after the training. These results suggest that regular aerobic exercise training enhances NO bioavailability in middle-aged and older adults and that basal limb blood flow does not change with exercise training because of the contrasting influences of sympathetic nervous system activity and endothelium-derived vasodilation on the vasculature.

Although endothelin-1 (ET-1) stimulates vascular endothelial growth factor (VEGF) expression in a variety of cells, including endothelial cells and vascular smooth muscle cells, the effects of ET-1 on expression of VEGF and its receptors in cardiomyocytes are unknown. In the present study, we found that treatment of neonatal rat cardiomyocytes with ET-1 for 24 h resulted in upregulation of VEGF and its two principal receptors, fetal liver kinase 1 and fms-like tyrosine kinase 1, in a concentration-dependent manner (10(-12) to 10(-6) M). ET-1 treatment also caused significant cardiomyocyte hypertrophy, as indicated by increases in cell surface area and [C-14] leucine uptake by cardiomyocytes. Treatment with TA-0201 (10(-6) M), an ETA-selective blocker, eliminated ET-1-induced overexpression of VEGF and its receptors as well as cardiomyocyte hypertrophy. Treatment with VEGF neutralizing peptides (5-10 mu g/ ml) partially but significantly inhibited ET-1-induced cardiomyocyte hypertrophy. These results suggest that ET-1 treatment of cardiomyocytes promotes overexpression of VEGF and its receptors via activation of ETA receptors, and consequently the upregulated VEGF signaling system appears to contribute, at least in part, to ET-1-induced cardiomyocyte hypertrophy.

Background: Increased arterial stiffness is an independent risk factor for cardiovascular disease. The estrogen system (estrogen and estrogen receptor-alpha [ER-alpha]) has potent vasodilator and antiatherosclerotic activity in vascular tissue and therefore was implicated in the regulation of arterial stiffness. We hypothesized that the relationship between arterial stiffness and gene polymorphisms in ER-alpha has a sex-specific component in older humans.
Methods: Two hundred healthy older subjects, comprised of 85 men and 115 postmenopausal women (men, 66 +/- 5 years old; women, 64 +/- 7 years old; mean +/- SD) participated in a cross-sectional study. We determined the genotypes of single-nucleotide polymorphisms (SNPs) at -401T/C of intron 1 and at 30T/C of exon 1 of ER-alpha, using a TaqMan-polymerase chain reaction method. Arterial stiffness was estimated by brachial-ankle pulse-wave velocity (baPWV).
Results: Polymorphisms of both -401T/C and 30T/C in ER-alpha affected baPWV values in postmenopausal women but did not affect men. The baPWV in women was significantly lower in the CC genotype at both -401T/C and 30T/C than in the TT genotype (both P &lt; .05), and the CC genotype of two SNPs in women was significantly lower than in men.
Conclusions: The present study suggests that the relationship between arterial stiffness and -401T/C or 30T/C polymorphisms in ER-alpha is different between sexes in older humans. These polymorphisms may be important in the health and clinical care of cardiovascular function and disease in older women.

Stiffening of large elastic arteries impairs the buffering function of the arterial system and contributes to cardiovascular disease. The aim of this study was to determine whether endothelium-derived nitric oxide (NO) modulates the stiffness of large elastic arteries in humans. Seven apparently healthy adults (60 +/- 3 years, 2 males and 5 females) underwent systemic a-adrenergic blockade (phentolamine) and systemic NO synthase inhibition using N-G-Monomethyl-L-arginine (L-NMMA) in sequence. Phentolamine was given first to isolate contribution of NO to arterial stiffness by preventing reflex changes in sympathetic tone that result from systemic NO synthase inhibition, and also to compare arterial stiffness at a similar mean arterial pressure. Mean arterial blood pressure decreased (p&lt;0.05) after phentolamine infusion but returned to baseline levels after L-NMMA infusion. The carotid beta-stiffness index (via simultaneous ultrasound and applanation tonometry on the common carotid artery) did not change after the restraint of systemic alpha-adrenergic nerve activity (9.8 +/- 1.2 vs. 9.1 +/- 1.1 U) but increased (p&lt;0.05) after NO synthase inhibition (12.6 +/- 2.0 U). These results suggest that NO appears to modulate central arterial stiffness in humans.

Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts. Am J Physiol Endocrinol Metab 292: E1030-E1040, 2007. First published December 5, 2006; doi:10.1152/ajpendo.00517.2006. - Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the presence of pharmacological intervention on these defects in diabetes remains unsettled. Here, we studied the effect of endothelin (ET) receptor blockade on cardiac VEGF signaling pathways and cardiac function in Sprague-Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age-matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with the ET receptor antagonist SB-209670 (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric-oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real-time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with SB-209670 reversed these alterations to the control levels and ameliorated impairment of cardiac function. From a molecular point of view, the present study is the first to indicate the potential usefulness of an ET receptor antagonist in the treatment of cardiac dysfunction in type I diabetes.

High-sensitivity C-reactive protein (CRP) is a novel risk factor for coronary artery disease. It is well known that body weight loss is effective in reducing serum CRP concentration : however, the effect of exercise training on serum CRP concentration has not been fully elucidated. The purpose of this study was to examine the effect of a 24-week exercise training program on serum CRP concentration in 169 healthy middle-aged and elderly subjects (65.9 +/- 6.4 years) Each subject Underwent baseline testing (peak oxygen Uptake, daily physical activity, body weight, and serum CRP levels), and repeated these tests on completion of the training program. The subjects were classified into 2 groups based on initial CRP levels : normal &lt; 1.0 mg/L, n=139, and high &gt;= 1.0 mg/L, n = 30. On completion of the program, both daily physical activity and peak oxygen uptake increased significantly (+33.9 +/- 72.4%, p &lt; 0.0001, +5.4 +/- 14.7%, p= 0.014, respectively). However, body weight did not change significantly. In addition, CRP levels of the entire group did not change significantly. However, CRP levels significantly decreased among the high baseline CRP group (from 1.82 +/- 0.81 mg/L to 0.98 +/- 0.59 mg/L, p &lt; 0.0001). it was concluded that serum CRP levels are reduced without body weight loss in response to exercise training in healthy middle-aged and elderly subjects with high initial CRP levels.

Arterial stiffness is higher in strength-trained humans and lower in endurance-trained humans. However, the mechanisms underlying these different adaptations are unclear. Vascular endothelium-derived factors, such as endothelin-1 ( ET-1) and nitric oxide ( NO), play an important role in the regulation of vascular tonus. We hypothesized that endogenous ET-1 and NO participate in the adaptation of arterial stiffness in different types of exercise training. The purpose of this study was to investigate plasma ET-1 and NO concentrations and arterial stiffness in strength- and endurance-trained men. Young strength-trained athletes ( SA; n = 11), endurance-trained athletes ( EA; n = 12), and sedentary control men ( C; n = 12) participated in this study. Maximal handgrip strength in SA and maximal oxygen uptake in EA were markedly greater than in C. Aortic pulse-wave velocity, which is an established index of arterial stiffness, was higher in SA and lower in EA than in C. Additionally, we measured systemic arterial compliance ( SAC) using carotid artery applanation tonometry and Doppler echocardiography, because arterial stiffness is a primary determinant of the compliance. SAC was lower in SA and higher in EA compared with that in C. Plasma ET-1 concentrations were higher in SA compared with C and EA. We did not find significant differences in plasma NO concentrations ( measured as the stable end product of NO, i.e., nitrite/nitrate). The relationships of plasma ET-1 concentrations to aortic pulse-wave velocity and SAC were linear. These results suggest that differences in endogenous ET-1 may partly participate in the mechanism underlying different adaptations of arterial stiffness in strength- and endurance-trained men.

The left ventricle morphologically adapts to endurance exercise training (eccentric cardiac remodeling) and strength exercise training (concentric remodeling). In addition, the acceleration of vagally mediated heart rate (HR) recovery after exercise is one of the functional adaptations of the heart in endurance-trained humans. However, the effect of strength training on HR recovery is unclear. Purpose: The purpose of this study was to investigate whether postexercise HR recovery accelerates in strength-trained athletes. Methods: Subjects were young strength-trained athletes (ST; N = 12), endurance-trained athletes (ET; N = 12), and age-matched sedentary control men (C; N = 12). HR and oxygen uptake were measured during submaximal exercise (cycling exercise, 40% maximal oxygen uptake for 8 min) and 30 s after the exercise (the postexercise period). Results: Left ventricular end-diastolic dimension was higher in both types of athletes compared with C, but greater in ET than in ST (C, 4.3 +/- 0.1 cm; ET, 5.0 +/- 0.1 cm; ST, 4.8 +/- 0.1 cm). Left ventricular average wall thickness was greater in ST in comparison with ET, although it was higher in both trained men compared with C (C, 0.85 +/- 0.02 cm; ET, 0.90 +/- 0.02 cm; ST, 1.00 +/- 0.02 cm). The time constant of postexercise HR decay, an index of vagally mediated postexercise HR recovery, was lower in ST and ET compared with C (C, 94.4 +/- 9.2 s; ET, 65.9 +/- 4.3 s; ST, 69.1 +/- 4.0 s). Oxygen pulse was greater in ST and ET than in C (C, 9.4 +/- 0.6 mL per beat; ET, 13.0 +/- 0.9 mL per beat; ST, 12.8 +/- 0.4 mL per beat), and it results in increased oxygen debt for both types of athletes (C, 0.257 +/- 0.024 L; ET, 0.343 +/- 0.030 L; ST, 0.331 +/- 0.017 L). We did not find significant differences in these indices between ST and ET. Conclusions: These results suggest that the HR recovery immediately after exercise is accelerated in both strength- and endurance-trained athletes.

Objective Increased aortic and carotid arterial augmentation index (AT) has been directly linked with cardiovascular disease risk, mortality and morbidity. The aim of this study was to examine whether Al obtained directly from radial artery pressure waveforms (radial Al) can provide information comparable with carotid arterial Al measurements.
Methods In a cross-sectional study of 204 apparently healthy subjects (88 men and 116 women) aged 19-76 years (51 +/- 15 years, mean +/- SD), carotid Al [(second peak carotid systolic pressure-first peak carotid systolic pressure)/carotid pulse pressure*100] and radial Al [(second peak radial systolic pressure-diastolic pressure)/(first peak radial systolic pressure-diastolic pressure)*100] were measured using applanation tonometry.
Results Radial Al was strongly correlated with carotid Al (r=0.86, P &lt; 0.0001, SD of difference 10.0%), although radial Al was consistently approximately 66% higher than carotid Al. In 16 apparently healthy young adults (11 men and five women, aged 23 +/- 3 years) handgrip exercise was immediately followed by post-exercise muscle ischaemia (PEMI) to compare changes in carotid and radial Al during increased sympathetic nervous activity PEMI caused parallel increases in carotid and radial Al (26 and 19%). Accordingly, changes in radial Al with PEMI were strongly correlated with corresponding changes in carotid Al (r=0.86, P &lt; 0.0001, SD of difference 7.3%).
Conclusion These results suggest that Al obtained directly from radial arterial pressure waveforms could provide equivalent information to carotid arterial Al, and has potential as a surrogate marker of cardiovascular disease. J Hypertens 25:375-381 (c) 2007 Lippincott Williams & Wilkins.

High-sensitivity C-reactive protein (CRP) is a novel risk factor for coronary artery disease. It is well known that body weight loss is effective in reducing serum CRP concentration : however, the effect of exercise training on serum CRP concentration has not been fully elucidated. The purpose of this study was to examine the effect of a 24-week exercise training program on serum CRP concentration in 169 healthy middle-aged and elderly subjects (65.9 +/- 6.4 years) Each subject Underwent baseline testing (peak oxygen Uptake, daily physical activity, body weight, and serum CRP levels), and repeated these tests on completion of the training program. The subjects were classified into 2 groups based on initial CRP levels : normal &lt; 1.0 mg/L, n=139, and high &gt;= 1.0 mg/L, n = 30. On completion of the program, both daily physical activity and peak oxygen uptake increased significantly (+33.9 +/- 72.4%, p &lt; 0.0001, +5.4 +/- 14.7%, p= 0.014, respectively). However, body weight did not change significantly. In addition, CRP levels of the entire group did not change significantly. However, CRP levels significantly decreased among the high baseline CRP group (from 1.82 +/- 0.81 mg/L to 0.98 +/- 0.59 mg/L, p &lt; 0.0001). it was concluded that serum CRP levels are reduced without body weight loss in response to exercise training in healthy middle-aged and elderly subjects with high initial CRP levels.

The engaging &gt; 30 minutes of physical activity (PA) at 4-6 METs has been recommended for the prevention of cardiovascular disease. We determined whether relatively low intensity (i.e., 3-5 METs) PA inhibits the age-related central arterial stiffening, a risk of cardiovascular disease. In the cross-sectional study, the association between carotid arterial properties (via ultrasound system) and daily PA (via electric accelerometer) were studied in 172 normotensive people (41-82 yrs). People engaging &gt; 30 min/day of PA corresponding to 3-5 METs had a significantly lower beta-stiffness index than sedentary peers after adjusting for covariates (i.e., age and PA time at more than 6 METs). In the interventional study, beta-stiffness index of nine normotensive postmenopausal women was significantly decreased after the 12-week aerobic training (cycling at 80% of ventiratory threshold, approximate to 4 METs, 30 min/day, 5 days/week). These results suggest that the increase in daily PA at 3-5 METs inhibits the age-related carotid arterial stiffening.

Skeletal muscle is comprised of multiple fiber types. Slow-twitch oxidative muscle fibers have greater capillary density compared with fast-twitch glycolytic fibers of skeletal muscle. To gain insight into the molecular mechanism underlying the difference of capillary density, we investigated whether the basal gene expression of vascular endothelial growth factor (VEGF), a major angiogenesis-related factor, and its transcriptional factors (hypoxia-inducible factor-1 alpha, transforming growth factor-beta 1, c-jun, and c-fos) differs between these two fiber types of rat skeletal muscle. The mRNA expression of VEGF and its transcriptional factors was significantly higher in slow type fiber of muscle (soleus muscle) compared with fast type fiber of muscle (plantaris and tibialis anterior muscles). These results suggest that the difference of basal gene expression of VEGF and its transcriptional factors between slow and fast fiber types of skeletal muscle may partly contribute to the difference in capillary density between these two fiber types.

Background: Aerobic exercise training is associated with lower central arterial stiffness, but little information exists on the effects of physical activity intensity or duration on central arterial stiffness. Using a cross-sectional and interventional approach, we tested the hypothesis that both moderate and vigorous physical activity reduce central arterial stiffness in postmenopausal women.
Methods: Carotid arterial stiffness (via ultrasound and applanation tonometry) and duration of physical activity at low, moderate, and vigorous intensities (via electronic accelerometer) were measured in 103 apparently healthy sedentary or recreationally active women 47 to 82 years of age. Moderate intensity physical activity was defined as 4.0 to 6.0 metabolic equivalents (MET) in subjects aged &lt; 65 years and as 3.0 to 5.0 MET in subjects &gt;= 65 years. A subgroup of 17 sedentary subjects was randomly assigned to moderate (n = 8) or vigorous (n = 9) intensity cycling exercise training (900 kcal/week, three to five sessions per week, for 12 weeks). Carotid arterial stiffness was measured before and after training.
Results: Carotid beta-stiffness index was significantly correlated with the duration of moderate and vigorous intensity physical activity (r = -0.25 and r = -0.22) even after adjustment for age, height, and mean BP. Carotid beta-stiffness index significantly decreased after moderate and vigorous intensity cycling training. There were no significant group differences in the magnitude of beta-stiffness index change even after adjustment for expected confounders (eg, baseline beta-stiffness index, height, body mass index, heart rate, and post-training body mass, body mass index, and mean BP).
Conclusions: These results suggest that both moderate and vigorous physical activities have favorable effects on central arterial stiffness in postmenopausal women.

Background: Little information is available on the effect of strength training on vascular function, particularly in older people.
Objective: To determine the effect of resistance training on arterial stiffness and endothelial function in older adults.
Method: Eleven healthy men ( mean (SEM) age 64 ( 1) years) performed 12 weeks of resistance training involving knee flexion and extension ( three sets a day, two days a week).
Results: Resistance training increased maximal muscle power by 16% (p&lt; 0.0001). Arterial stiffness as assessed by aortic pulse wave velocity did not change with resistance training. Plasma concentration of nitric oxide ( NO), measured as its stable end product (nitrite/nitrate), had increased ( p&lt; 0.05) after resistance training (61.2 (10.4) v 39.6 (3.2) mmol/l). There was no change in plasma concentration of endothelin-1.
Conclusion: The results suggest that short term resistance training may increase NO production without stiffening central arteries in healthy older men.

A decrease in systemic arterial compliance (SAC) increases left ventricular load along with the demand for excessive myocardial oxygen consumption when the age-related reduction of SAC reaches a marked level, and consequently may depress left ventricular pump function. Reduced left ventricular pump function decreases aerobic capacity, and some study groups have shown that SAC and/or central arterial distensibility is correlated with maximal aerobic capacity in humans. We thus hypothesize that, once the age-related reduction of SAC reaches a marked level, the participation of SAC in aerobic capacity will be significant even during sub-maximal exercise. Thirty young humans and 46 elderly humans participated in this study. SAC, oxygen uptake at the ventilatory threshold (Vo(2 VT)), and the ratio of increase in oxygen uptake, in cardiac output, and in effective arterial elastance to increase in work rate (Delta Vo(2)/Delta WR, Delta CO/Delta WR and Delta E-a/Delta WR) were measured. SAC was significantly higher in young subjects compared with elderly subjects, and was significantly related to Vo(2 VT) in elderly subjects. SAC also significantly correlated with Delta Vo2/Delta WR, Delta CO/Delta WR and Delta E-a/Delta WR in elderly subjects. When total subjects were divided by the value of SAC into 6 groups, the Vo(2 VT) values in the 3 groups with lower SAC were significantly lower than those in the 3 groups with higher SAC, and gradually decreased with the reduction of SAC. There were no changes in Vo(2 VT) among the 3 groups with higher SAC. These results suggest that the participation of SAC in aerobic capacity is significant even during sub-maximal exercise in individuals who show a pronounced age-related reduction of SAC.

The engaging &gt; 30 minutes of physical activity (PA) at 4-6 METs has been recommended for the prevention of cardiovascular disease. We determined whether relatively low intensity (i.e., 3-5 METs) PA inhibits the age-related central arterial stiffening, a risk of cardiovascular disease. In the cross-sectional study, the association between carotid arterial properties (via ultrasound system) and daily PA (via electric accelerometer) were studied in 172 normotensive people (41-82 yrs). People engaging &gt; 30 min/day of PA corresponding to 3-5 METs had a significantly lower beta-stiffness index than sedentary peers after adjusting for covariates (i.e., age and PA time at more than 6 METs). In the interventional study, beta-stiffness index of nine normotensive postmenopausal women was significantly decreased after the 12-week aerobic training (cycling at 80% of ventiratory threshold, approximate to 4 METs, 30 min/day, 5 days/week). These results suggest that the increase in daily PA at 3-5 METs inhibits the age-related carotid arterial stiffening.

To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ETA) receptor (vasoconstrictive) and ET type B (ETB) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT,) receptor increased over time after LPS injection, those of Ang II type 2 (AT(2)) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other. (c) 2006 Elsevier Inc. All rights reserved.

Background: Effective arterial elastance (Ea), an index of arterial load, increases with elevations in left ventricular elastance to maximize the efficiency of left ventricular stroke work during exercise. Systemic arterial compliance (C) and vascular resistance (R) are the primary components contributing to Ea, and R plays a greater role in determining Ea at rest. We hypothesized that the contribution of C to Ea increases during exercise to maintain an optimal balance between arterial load and ventricular elastance, and that the increase in Ea is due primarily to a reduction in C.
Aim: The aim of this study was to investigate the contributions of C and R to Ea during exercise.
Methods: Ea (0.9 x systolic blood pressure/stroke volume), C (stroke volume/pulse pressure), R (mean blood pressure/cardiac output), and cardiac cycle length (T) were measured at rest and during exercise of 40%, 60% and 80% maximal oxygen uptake (VO2max) using Doppler echocardiography in 45 healthy men.
Results: Ea did not differ between rest and 40% VO2max, but it was greater at 60% and 80% VO2max. C markedly decreased during exercise in an exercise intensity-dependent manner. The changes in R/T during exercise were small, whereas it decreased at 40% VO2max and gradually increased at 60% and 80% VO2max.
Conclusions: The present results suggest that the contribution of systemic arterial compliance to effective arterial elastance increases during exercise. Therefore, we propose that the increase in arterial load during exercise is mainly driven by a reduction in systemic arterial compliance.

The cardiovascular benefit of fish oil in humans and experimental animals has been reported. Endothelin (ET)-1 is a well-known cardiac hypertrophic factor. However, although many studies link a fish oil extract, eicosapentaenoic acid (EPA), to cardiac protection, the effects of EPA on cardiac hypertrophy and underlying mechanism(s) are unclear. The present study investigated whether EPA prevents ET-1-induced cardiomyocyte hypertrophy; the potential pathways likely to underlie such an effect were also investigated. Cardiomyocytes were isolated from neonatal rat heart, cultured for 3 days, and then treated for 24 h with vehicle only (control), treated with 0.1 nM ET-1 only, or pretreated with 10 mu M EPA and then treated with 0.1 nM ET-1. The cells were harvested, and changes in cell surface area, protein synthesis, expression of a cytoskeletal (alpha-actinin) protein, and cell signaling were analyzed. ET-1 induced a 97% increase in cardiomyocyte surface area, a 72% increase in protein synthesis rate, and an increase in expression of alpha-actinin and signaling molecule [transforming growth factor-beta 1 (TGF-beta 1), c-Jun NH2-terminal kinase (JNK), and c-Jun]. Development of these ET-1-induced cellular changes was attenuated by EPA. Moreover, the hypertrophied cardiomyocytes showed a 1.5- and a 1.7-fold increase in mRNA expression of atrial and brain natriuretic peptides, the classical molecular markers of cardiac hypertrophy, respectively; these changes were also suppressed by EPA. Here we show that ET-1 induces cardiomyocyte hypertrophy and expression of hypertrophic markers, possibly mediated by JNK and TGF-beta 1 signaling pathways. These ET-1-induced effects were blocked by EPA, a major fish oil ingredient, suggesting that fish oil may have beneficial protective effects on cardiac hypertrophy.

To investigate a relationship between gender differences in recovery from skeletal muscle fatigue and muscle oxygenation, we examined whether there is a difference in oxygen supply and consumption of the working muscles after intermittent handgrip exercise between young males and females using near-infrared spectroscopy (NIRS). Healthy young subjects (25.8 +/- 3.9 years; males, n=10; females, n=10) repeated static maximal voluntary contractions (MVC) with a handgrip for 5 seconds followed by 5 seconds rest for a period of 4 minutes in Study 1. The MVC force was measured before, each minute during the handgrip exercise, and 2, 5, and 10 minutes following the exercise. In Study 2, the selected 10 subjects (males, n=5; females, n=5) performed the same exercise and their total- and deoxy- hemoglobin/myoglobin level was measured using the venous occlusion NIRS method; and O-2 supply index (OSI) and O-2 consumption index (OCI) calculated before and after the exercise. In Study 1, females exhibited higher %MVC force at the end of the exercise and during the recovery period than males (p &lt; 0.05). In Study 2, the %OSI was significantly lower in females than in males at 5 and 10 minutes in the recovery period (p &lt; 0.05), but no significant differences were detected in %OCI. Furthermore, %MVC of the recovery period correlated with %OCI of the recovery period in females (r=0.724, p=0.015), but not in males. These findings suggest that female working muscles can convert consumed oxygen more effectively after an intermittent handgrip exercise, and therefore, be able to recover muscle force faster.

Since exercise training causes cardiac hypertrophy and a single bout induces mechanical stress to the heart, the present study aimed to characterize the activation patterns of multiple MAPK signaling pathways in the heart after a single bout of exercise or chronic exercises. The hearts of untrained rats received 5, 15, and 30 min of treadmill running exercise (Ex5 to Ex30) and rested for 0.5, 1, 3, 6, 12, and 24 h (PostEx0.5 to PostEx24) before subjecting them to the following different experiments. Activation of MAPKs (ERK, JNK, and p38) and MAPKKs (MEK1/2, SEK, and MKK3/6) increased immediately after acute exercise in a time-dependent manner, with ERK, JNK, and p38 peaking at Ex15, Ex15, and Ex30, respectively. Expression of immediate early genes (c-fos, c-jun, and c-myc) was augmented and activator protein-1 DNA binding activity was enhanced in untrained rats immediately after a single bout of exercise. The elevated levels of MAPKs declined to the resting levels within 24 h after exercise. In another set of experiments, following 4, 8, and 12 wk of exercise training, the rats exhibited significant cardiac hypertrophy by week 12. Activation of MAPKs in the 4-wk-trained rats increased after a 30-min single bout of exercise but decreased in the 8-wk group. Finally, the activity of MAPKs signaling in the 12-wk-trained rats exposed to an acute bout of exercise was unaltered. We conclude that exercise induces the activation of multiple MAPK (ERK, JNK, and p38) pathways in the heart, an effect that gradually declines with the development of exercise-induced cardiac hypertrophy.

Endothelin (ET)-1 is produced by endothelial cells and cardiac myocytes. ET-1 has positive inotropic and chronotropic effects on the heart and causes myocardial cell hypertrophy. Exercise training induces a physiologic cardiac hypertrophy. To study whether myocardial ET-1 is involved in the formation of exercise training-induced cardiac hypertrophy, we investigated time-course alterations of myocardial ET-1 gene expression and ET-1 peptide level in the heart of rats during a formative process of exercise training-induced cardiac hypertrophy. We used the hearts of rats that had been exercise-trained for 4 weeks (4WT) or 8 weeks (8WT) and sedentary control rats for 4 weeks (4WC) or 8 weeks (8WC). Exercise-trained rats performed treadmill running for 5 days/week (60 mins/day). Left ventricular mass index and wall thickness and stroke volume index, measured using echocardiography, in the 8WT group were significantly greater than in the 8WC group, although there were no differences between the 4WC and 4WT groups in these parameters. These results indicated that the 8WT rats developed physiologic cardiac hypertrophy, whereas the 4WT rats did not yet have cardiac hypertrophy. Myocardial ET-1 gene expression and tissue ET-1 concentration in the heart were significantly higher in the 8WT group than in the 8WC group, whereas these values did not differ between the 4WC and 4WT groups. The present study suggests that an alternation of myocardial ET-1 production corresponds with the formation of exercise training-induced cardiac hypertrophy. Therefore, the exercise training-induced change in myocardial ET-1 production may participate in a mechanism of exercise training-induced cardiac adaptation (e.g., cardiac hypertrophy).

The cardiovascular benefit of fish oil, including eicosapentaenoic acid (EPA), in humans and experimental animals has been reported. The role of endothelin-1 (ET-1) in cardiac hypertrophy is well known. Endothelin-1 stimulates prepro-ET-1 mRNA expression in cardiomyocytes, and the autocrine/paracrine system of ET-1 is important for cardiomyocyte hypertrophy. Although many studies link EPA to cardiac protection, the effect of EPA on cardiac hypertrophy has yet to be clarified. Recently, we demonstrated that ET-1-induced cardiomyocytic change could be prevented by pretreatment with EPA. The present study investigated the changes of different components of the ET system at the mRNA level in ET-1-administered cardiomyocytes, and examined the effect of EPA pretreatment. Ventricular cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats, cultured in Dulbecco's modified Eagle's medium and Ham F12 supplemented with 0.1% fatty acid-free bovine serum albumin for 3 days. At Day 4 of culture, the cardiomyocytes were divided into 3 groups: control group, ET-1-treated (0.1 nM) group, and ET-1-treated group pretreated with EPA (10 mu M). Twenty-four hours after treatment, the gene expressions of different components of the endothelin system in three experimental groups were evaluated by real-time polymerase chain reaction. Prepro-ET-1 mRNA expression was 53% upregulated in ET-1-induced hypertrophied cardiomyocytes and suppressed in the EPA-pretreated group. Endothelin-converting enzyme-1 (ECE-1) was also increased in ET-1 -administered cardiomyocytes by 42% compared with the control group and was reversed in the EPA-pretreated group. The two receptors of ET system, ETA and ETB, tended to be increased in the ET-1-treated group, but no statistical significance was seen among study groups. Endothelin-1 increased prepro-ET-1 and ECE-1 mRNA expression in hypertrophied-neonatal cardiomyocytes, and this was reversed with EPA pretreatment. Thus, EPA may play a crucial role in the regression of ET-1-induced cardiomyocyte hypertrophy, partly through the suppression of ET-1 and ECE-1 expression.

Cardiovascular complications are an important feature of diabetes mellitus (DM). Abnormal and decreased coronary collateral development has been implicated in the pathogenesis of cardiac complications in DM. More recently, decreased expression of vascular endothelial growth factor (VEGF) and its receptors has been found in diabetic heart. To our knowledge, no study has focused on the therapeutic improvement associated with VEGF in diabetic heart. DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats, while control rats received only citrate buffer. After 1 week, the streptozotocin-treated rats were randomly divided into two groups: one group received the selective endothelin (ET) type A receptor antagonist TA-0201 at a dose of 1 mg/kg/day for 2 weeks by osmotic mini-pump, and the vehicle group received saline only. The plasma glucose level was 504 +/- 75 mg/dl in the diabetic rats and was unchanged by treatment with ET antagonist. The body weight was decreased in the diabetic rats compared with the control rats, but the left ventricular (LV)-body weight ratio was increased in the diabetic group and was unaffected by treatment with ET antagonist. mRNA expression of VEGF and its receptors (Flt-1 and Flk-1) in the LV tissues was assessed using real-time polymerase chain reaction. VEGF expression was significantly decreased in diabetic heart and was greatly improved by treatment with ET antagonist. The expression of VEGF receptors was downregulated in early diabetic heart but was not recovered by treatment with ET antagonist. ET and its receptor A might have differential regulation on the gene expressions of VEGF and its receptors in early diabetic heart.

The effects of calcium channel blockers (CCBs) on complications associated with diabetes mellitus (DM) have been well studied in clinical and basic science investigations. Cardiovascular complications are a common feature of type 2 DM, and insulin resistance is an early clinical manifestation of type 2 DM. CCBs are widely used to treat cardiovascular diseases in patients with DM. In this study, we used a spontaneous type 2 diabetic rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, at a highly insulin-resistant stage with modest hyperglycemia. We examined cardiac expression of transforming growth factor-beta(1) (TGF beta(1)) and endothelin-1 (ET-1) in male OLETF rats. At 8 weeks of age, OLETF rats were treated for 12 weeks with the long-acting CCB benidipine (1 mg/kg/day or 3 mg/kg/day, po, n = 12), with hydralazine hydrochloride (3 mg/kg/day, po, n = 12), or with vehicle (OLETF, n = 12), and male age-matched genetic control Long-Evans Tokushima Otsuka (LETO, n = 12) rats were used. Blood pressure was significantly higher in OLETF rats than in LETO rats, and benidipine treatment at both dosages in OLETF rats for 12 weeks did not significantly reduce blood pressure, whereas hydralazine treatment significantly lowered blood pressure in OLETF rats. Hydralazine and both dosages of benidipine significantly reduced upregulated cardiac ET-1 levels in OLETF rats. Plasma and cardiac TGFP, levels were remarkably higher in OLETF rats compared with LETO rats and were normalized by treatment with benidipine (3 mg/kg/day). Our results suggest that CCBs are effective in normalizing upregulated cardiac TGFP, and ET-1 levels at the insulin-resistant stage in OLETF rats, which may improve cardiac morphology and function in this rat model without altering blood pressure and plasma glucose levels. In contrast, hydralazine treatment also normalizes cardiac ET-1 levels while significantly reducing blood pressure.

Cardiomyocytes release (or metabolize) several diffusible agents (e.g., nitric oxide [NO], endothelin-1 [ET-1], and angiotensin 11) that exert direct effects on myocyte function under various pathologic conditions. Although cardiac hypertrophy is a compensatory mechanism in response to different cardiovascular diseases, there can be a pathologic transition in which the myocardium becomes dysfunctional. Recently, NO has been found to be an important regulator of cardiac remodeling. Specifically, NO has been recognized as a potent antihypertrophic and proapoptotic mediator in cultured cardiomyocytes. We demonstrated that ET-1-induced hypertrophic remodeling in neonatal cardiomyocytes was arrested by pretreatment with eicosapentaenoic acid (EPA), a major component of fish oil. In some recent studies, EPA has demonstrated cardioprotective effects by modulating NO. This study investigated the changes in NO synthase (NOS) in ET-1-induced hypertrophied cardiomyocytes and in total levels of nitrates and nitrites. Ventricular cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats and were cultured in D-MEM/Ham F12 supplemented with 0.1% fatty acid-free bovine serum albumin for 3 days. At Day 4 of culture, the cardiomyocytes were divided into three groups: control group, ET-1 (0.1 nM) group, and ET-1 pretreated with EPA (10 mu M) group. NOS gene expression was evaluated 24 hrs after treatment using real-time polymerase chain reaction. Endothelial NOS (eNOS) mRNA expression was decreased in the ET-1 group compared with controls and was unchanged by pretreatment with EPA. mRNA expression of inducible NOS (iNOS) was significantly increased in ET-1-treated cardiomyocytes and was suppressed by EPA pretreatment. Neuronal NOS gene expression and total NO level did not exhibit a statistically significant change in any of the groups. There may be some interaction between ET-1, eNOS, and iNOS in ET-1-induced and EPA-regressed hypertrophied cardiomyocytes that suppress iNOS expression without modulating total NO level or eNOS gene expression.

Endothelin-1 (ET-1) has been implicated in hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all these conditions, plasma immunoreactive ET-1 levels are elevated, and tissue ET-1 expression is increased. Clinical trials have demonstrated potentially important benefits of ET antagonism among patients with essential hypertension, pulmonary hypertension, and heart failure. It is unknown whether ET antagonism affects the production of ET-1 in stroke-prone spontaneously hypertensive rat (SHRSP) heart at the typical hypertensive stage. The objective of this study was to investigate the effects of ET blockade on the expression levels of plasma and cardiac ET-1 in SHRSPs. SHRSPs were treated for 3 months with SB209670 (ETA/ETB dual receptor antagonist) or with saline (vehicle) commencing at the prehypertensive stage (age 6 weeks). Plasma and left ventricular ET-1 peptide levels were measured using enzyme-linked immunoabsorbent assay. Compared with age-matched control Wistar-Kyoto rats, peptide levels of ET-1 were significantly upregulated in vehicle-treated SHRSP heart; this upregulation was reversed by long-term ET antagonism. Plasma ET-1 levels were also significantly increased in vehicle-treated SHRSPs and were normalized by ET antagonism. mRNA expression of preproET-1, which is the source of ET-1 peptide production, was significantly increased in vehicle-treated SHRSP heart and was normalized by ET antagonism. Marked cardiac hypertrophy and fibrosis at the histologic level in SHRSPs were ameliorated by ET antagonism, and left ventricular hypertrophy as seen on echocardiography in SHRSPs was suppressed by ET blockade. After ET antagonism, systolic blood pressures were reduced in SHRSPs; diastolic blood pressures were unchanged. The reversal effect of the upregulated ET system in SHRSP heart by ET antagonism might be independent of blood pressure change. By suppressing the upregulated ET system, ET antagonism might be beneficial in arresting cardiac remodeling.

Human heart failure is preceded by a process called cardiac remodeling, in which heart chambers progressively enlarge and contractile function deteriorates. Programmed cell death (apoptosis) of cardiac muscle cells has been identified as an essential process in the progression to heart failure. The execution of the apoptotic program entails complex interactions between and execution of multiple molecular subprograms. Endothelin (ET)-1, a potent vasoconstrictor peptide, is synthesized and secreted by cardiomyocytes and induces hypertrophy of cardiomyocytes. The cardiovascular benefit of fish oil containing eicosapentaenoic acid (EPA) in humans and experimental animals was reported. Recently, we found that ET-1-induced cardiomyocytic remodeling could be prevented by pretreatment with EPA. The aim of the present study is to investigate whether there would be any alteration in the expression of important apoptosis-related molecules in ET-1-administered hypertrophied cardiomyocytes. We also sought to determine, if there are alterations in apoptotic molecules, what type of role for EPA would then exist. Ventricular cardiomyocytes were isolated from 2-day-old Sprague-Dawley rats and were cultured for 3 days. At Day 4 of culture, the cardiomyocytes were divided into three groups: control, the ET-1 (0.1 nM)- treated group, and the ET-1 group pretreated with EPA (10 mu M). Twenty-four hours after the treatment, the gene expressions of three important molecules related to apoptosis (caspase-3, Bax, and Bcl-2) in three experimental groups were evaluated by real-time polymerase chain reaction. The present study could not demonstrate any significant or representative alteration in any of the above three apoptosis-related important markers in either ET-1-induced hypertrophied cardiomyocytes with or without EPA pretreatment. The present study would at least be able to exclude the involvement of some representative molecules related to apoptosis in ET-1-induced hypertrophied cardiomyocytes. In addition, the present study demonstrates that the antihypertrophic effect of EPA to ET-1-administered cardiomyocytes appears not to modulate the apoptosis signaling cascade.

Septic shock is characterized by hypotension and a hyporeactive response to vasopressor agents. The pathogenesis is due to vascular leaks and an increased synthesis of cytokines and nitric oxide (NO). The present study examined the time-dependent alterations of endothelin-1 (ET-1) and the expression of NO synthase (NOS) in lung tissue in a septic rat model. Normal Sprague-Dawley (SD) rats aged 10 weeks received 15 mg/kg lipopolysaccharide (LPS) and then were sacrificed at different time points (1, 3, 6, and 10 hrs). Rats that did not receive LPS were considered to be controls. Both systolic and diastolic pressure decreased in SD rats after LPS administration. Time-dependent onset of features of acute lung injury, such as the infiltration of inflammatory cells and thickening of alveolar septa, were seen in rats that received LPS. A 2.8-fold increase in the expression of preproET-1 level was observed in lung tissue 6 hrs after LPS administration. The expression of endothelial NOS (eNOS) was also altered in lung tissue in a time-dependent fashion. After the administration of LPS, there was a 16-fold increase in the expression of eNOS mRNA. The peak expression of inducible NOS (iNOS) in lung tissue specimens obtained from rats that received LPS was 45-fold higher than that in control rats. ET-1 is a potent vasoconstrictor and thereby may play an important role in the pathogenesis of acute lung injury in a septic rat model. The increased expression of NOS may result in excess NO production and may also play a role in the pulmonary complications of endotoxemia.

Erectile dysfunction (ED) affects approximately 50% of male patients with diabetes mellitus (DM) and is possibly due to the vascular and neuropathic complications of DM. Recently, apoptosis has been regarded as a downstream event in ED. More recently, the importance of alterations in apoptosis-related molecules in the mechanism of DM-induced ED has begun to be appreciated. Endothelin-1 (ET-1) plays a role via ETA and ETB receptors in the regulation of cavernosal smooth-muscle tone in penile tissues. We found that the ET-1 level in the penis of rats with DM was higher than that in the penis of control animals. The present study investigated a rat model in which DM was induced by a 3-week regimen of streptozotocin (STZ) to assess the expression of several apoptosis-related molecules in penile tissue and, concomitantly, the effects of ET antagonism on these changes. Male Sprague-Dawley rats (weight [+/- SD], 450 +/- 26 g) received a citrate saline vehicle or STZ (65 mg/kg ip). DM was confirmed by the presence of hyperglycemia. Diabetic animals were further separated into two treatment groups 1 week after onset of disease: one group received ETA/B dual receptor antagonist (SB209670) by means of osmotic minipump at a dosage of 1 mg/day, and the other group received saline. Rats in both groups were treated for 2 weeks and then sacrificed. Plasma glucose levels (+/- SD) in rats with DM were significantly higher than those in rats without DM (506 +/- 70 vs. 111 +/- 11 mg/dl). In the penile tissue of rats with DM, a 35% decrease in the expression of Bcl-2 protein (an important antiapoptotic marker detectable by immunoblotting) was seen, and ETA/B dual antagonist was observed to significantly counteract this decrease. Real-time polymerase chain reaction revealed that the expression of Bcl-2 mRNA was consistent with Bcl-2 protein expression. Levels of Bax and caspase-3, two important proapoptotic markers, were not significantly altered in the present study. Thus, we conclude that, in the penis of rats with early stage DM, the protection against apoptosis has decreased but can be improved by ET antagonism.

Obesity is associated with endothelial dysfunction that may contribute to the development of diabetes, hypertension, and atherosclerosis. Endothelin-1 (ET-1), which is produced mostly by vascular endothelial cells, has potent vasoconstrictor and proliferative activity in vascular smooth muscle cells and, therefore, has been implicated in regulation of vascular tonus and the progression of atherosclerosis, suggesting that ET-1 may be important in endothelial dysfunction. We studied whether diet-induced weight loss (i.e., lifestyle modification) affects plasma ET-1 concentration in obese individuals. We measured plasma ET-1 concentration in seven obese men (age: 48 +/- 4 years old, body mass index: 27.7 +/- 0.5 kg/m(2)) before and after a 3-month, diet-induced weight reduction program (i.e., lifestyle modification program). Caloric restriction reduced body weight from 78 +/- 3 to 68 +/- 2 kg (P &lt; 0.001) and resulted in 12.1 +/- 1.2% reduction in body mass index (24.3 +/- 0.3 kg/m(2), P &lt; 0.0001). After the weight reduction program, systolic and diastolic blood pressure significantly decreased (128 +/- 7 vs. 115 +/- 4 mm Hg, P &lt; 0.05 and 88 +/- 4 vs. 77 +/- 2 min Hg, P &lt; 0.01, respectively). The plasma level of ET-1 significantly decreased after the program (5.1 +/- 0.4 vs. 4.0 +/- 0.3 pg/ml, P &lt; 0.05). The percentage systolic blood pressure reduction and percentage plasma ET-1 concentration reduction was in a linear relationship (r = 0.86, P &lt; 0.05). Furthermore, the relationship between percentage weight reduction and percentage plasma ET-1 concentration reduction was linear (r = 0.87, P &lt; 0.05). We conclude that weight loss by low-calorie diet (i.e., lifestyle modification) reduces plasma ET-1 concentration in obese individuals. This reduction may contribute to the improvement of obesity-induced endothelial dysfunction.

The retinal ischemia-reperfusion model is used in the study of transient ischemia-related diseases, such as central retinal artery occlusion, angle-closure glaucoma, and others. There are two methods for experimentally producing an ischemia-reperfusion model in the rat retina: (i) the intraocular pressure is greatly raised by increasing the height of the infusion bottle connected with the needle in the anterior chamber; or (ii) the blood vessel that accompanies the optic nerve in retina is ligated. However, each method has some drawbacks. For example, in the first method, the needle must be fixed in the anterior chamber for 1 hr, thus, the technique is not stable and mechanical damage to ocular structures sometimes occurs. In the second method, because of the unavoidable involvement of the optic nerve, damage to the nerve induces retinal changes unrelated to ischemia. In this study, we injected endothelin (ET)-1 under the conjunctiva of the eyeball (subconjunctival injection), and evaluated whether a retinal ischemia-reperfusion model could be generated by this method, simply and noninvasively. We injected 4 X 10(-5) M ET-1 solution into the right eye of the rat and injected a control vehicle (artificial tears) into the left eye. From 5-60 mins after the injection, 50 mg/ml fluorescein isothiocyanate (FITC)-dextran was injected to the left ventricle of heart. Then, the retina was removed and flat mounted. We compared the perfusion conditions of the FITC-dextran to each retina in the right and left eye. There was a complete perfusion of FITC-dextran in the retinal main artery, vein, and the capillary vessels in all of the control eyes. However, perfusion could not be completely observed in the ET-1 injected eye from 5-35 mins after injection; afterwards, the flow was returned. This method of subconjunctival injection of ET-1 is, thus, a feasible technical option for producing a retinal ischemia-reperfusion model in rat.

Diabetic retinopathy (DR), one of the most serious causes of blindness, is often associated with the upregulation of vascular endothelial growth factor (VEGF) in retina. Recently, leukocyte adhesion (leukostasis) is blamed for the occlusion of retinal capillary vascularity, which ultimately contributes to the progression of diabetic retinopathy. In addition, intercellular adhesion molecule-1 (ICAM-1), a representative factor for leukostasis, is increased in the diabetic retina. Endothelin (ET)-1, a potent vasoconstrictor peptide, is deeply linked to the pathogenesis of diabetic retinopathy. Different therapeutic interventions concerning VEGF have already been proposed to prevent diabetic retinopathy. However, no study yet has reported whether ET-1 dual receptor antagonist could alter the upregulated VEGF and ICAM-1 levels in the diabetic retina. The present study investigated the effect of ETA/B dual receptor antagonist (SB209670; 1 mg/rat/day) on the expression of VEGF and ICAM-1 in the diabetic rat retina. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in Sprague-Dawley rats, whereas control rats (non-DM control) received only citrate buffer. After 1 week, the STZ-administered rats were randomly divided into two groups: one group (DM+SB209670) received ETA/B dual receptor antagonist for 2 weeks, and a vehicle group (DM+vehicle) was treated only with saline. After the treatment period, the retinas were removed from the eyeballs. In DM+vehicle group, the VEGF expression of the retinas was significantly increased (32.8 pg/mg) in comparison to that in the non-DM control group (26.2 pg/mg); this upregulation of VEGF was reversed in the DM+SB209670 group (28.6 pg/mg). The expression of retinal ICAM-1 was increased in the DM+vehicle group (152.2 pg/mg) compared with the non-DM control group (121.6 pg/mg). However, SB209670 treatment did not alter the expression of retinal ICAM-1 level (154.8 pg/ml) in DM rats. Thus we conclude that an ETA/B dual receptor antagonist could reverse the expression level of VEGF in the diabetic retina while failing to normalize the upregulated ICAM-1 expression.

Sepsis involves a heterogeneous class of syndromes, and septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs. The present study examined the time-dependent alterations of endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) levels in liver tissue in a septic rat model. Healthy male Wistar rats aged 15 weeks received 15 mg/kg lipopolysaccharide (LPS) and were sacrificed at different time points (1, 3, 6, and 10 hrs after treatment). Rats that did not receive LPS were considered to be controls. A 28-fold increase in the ET-1 level was observed in liver tissue 10 hrs after LPS administration. VEGF was also altered in hepatic tissue in a time-dependent manner. A gradual increase of VEGF expression in liver tissue after LPS administration was observed. Expression of Flt-1, the vascular permeability receptor of VEGF, was also increased in liver tissue after LPS administration. ET-1 is a potent vasoconstrictor and, therefore, may play a role in the regulation of hepatic perfusion in a sepsis model. On the other hand, VEGF may be involved in capillary leakage in liver tissue after LPS administration. The present findings suggest that there might be a loss of balance between the ET-1 and VEGF levels in the septic liver at different time points, which could contribute to the pathogenesis of acute liver injury in endotoxemia.

Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin ( ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations ( ie, gene polymorphisms) in ET- related gene might affect exercise- induced improvement in arterial stiffness with age in human subjects. The present study provides a cross- sectional investigation of 191 healthy middle- aged and older ( 65 +/- 1 years) human subjects to clarify the relationship between the regular exercise- induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme ( ECE)- 1, ECE- 2, ET- A receptor ( ET- A), and ET- B receptor ( ET- B). The study subjects were divided into active and inactive groups based on the median value ( 186 kcal/ d) of energy expenditure. Brachial- ankle arterial pulse wave velocity ( baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013( + 289) A/ G in intron 17 of ECE- 1, 669( + 17) T/ C in intron 5 of ECE- 2, 958A/ G in exon 6 of ET- A, and 831A/ G in exon 4 of ET- B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE- 1 influenced basal blood pressure. Polymorphisms in ECE- 1 and ECE- 2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET- A and ET- B affected baPWV in the 2 groups. The present results suggest that differences in ET- A and ET- B polymorphisms may influence the response of the vascular wall to exercise whereas ECE- 1 polymorphisms may affect basal blood pressure.

Reduction of systemic arterial compliance (SAC) with aging increases left ventricular afterload. The present study was designed to examine whether age-related reduction of SAC is related to excessive myocardial oxygen consumption during sub-maximal aerobic exercise. We studied elderly (60-69 years; n = 25) and senior (70-82 years; n = 25) subjects. We measured SAC immediately before the start of the ramp-fashion exercise (Le., at the end of the 20 W warm-up exercise) and the double product (DP: systolic blood pressure x heart rate) during the ramp-fashion exercise (20-50 W). SAC was significantly lower in senior subjects (0.76 +/- 0.25 ml mmHg(-1) m(-2)) compared with elderly subjects (0.95 +/- 0.22 ml mmHg(-1) m(-2)). DP was higher in senior subjects (20 W: 14.3 +/- 3.1; 30 W: 15.9 +/- 4.2; 40 W: 17.7 +/- 4.9; 50 W: 20.6 +/- 5.6 [x 10(3) mmHg bpm]) than in elderly subjects (12.8 +/- 3.0, 14.0 +/- 3.5, 15.1 +/- 4.0, 17.1 +/- 4.3 [x 10(3) mmHg bpm]). In total subjects, SAC correlated significantly with DID (r = -0.64, r = -0.64, r = -0.64, r = -0.64). In senior subjects, SAC was related significantly to DP (r = -0.83, r = -0.78, r = -0.76, r = -0.74). In elderly subjects, SAC tended to correlate with DP although its relationships were not statistically significant (r = -0.34, r = -0.36, r = -0.33, r = -0.31). Correlation coefficients at each respective exercise intensity were significantly higher in senior subjects compared with elderly subjects. These results suggest that the age-related reduction of SAC is related to excessive myocardial oxygen consumption during sub-maximal aerobic exercise in older humans, but this relation does not become significant until the SAC reduction becomes pronounced.

Reduction of systemic arterial compliance (SAC) with aging increases left ventricular afterload. The present study was designed to examine whether age-related reduction of SAC is related to excessive myocardial oxygen consumption during sub-maximal aerobic exercise. We studied elderly (60-69 years; n = 25) and senior (70-82 years; n = 25) subjects. We measured SAC immediately before the start of the ramp-fashion exercise (Le., at the end of the 20 W warm-up exercise) and the double product (DP: systolic blood pressure x heart rate) during the ramp-fashion exercise (20-50 W). SAC was significantly lower in senior subjects (0.76 +/- 0.25 ml mmHg(-1) m(-2)) compared with elderly subjects (0.95 +/- 0.22 ml mmHg(-1) m(-2)). DP was higher in senior subjects (20 W: 14.3 +/- 3.1; 30 W: 15.9 +/- 4.2; 40 W: 17.7 +/- 4.9; 50 W: 20.6 +/- 5.6 [x 10(3) mmHg bpm]) than in elderly subjects (12.8 +/- 3.0, 14.0 +/- 3.5, 15.1 +/- 4.0, 17.1 +/- 4.3 [x 10(3) mmHg bpm]). In total subjects, SAC correlated significantly with DID (r = -0.64, r = -0.64, r = -0.64, r = -0.64). In senior subjects, SAC was related significantly to DP (r = -0.83, r = -0.78, r = -0.76, r = -0.74). In elderly subjects, SAC tended to correlate with DP although its relationships were not statistically significant (r = -0.34, r = -0.36, r = -0.33, r = -0.31). Correlation coefficients at each respective exercise intensity were significantly higher in senior subjects compared with elderly subjects. These results suggest that the age-related reduction of SAC is related to excessive myocardial oxygen consumption during sub-maximal aerobic exercise in older humans, but this relation does not become significant until the SAC reduction becomes pronounced.

Diabetic retinopathy, a cause of blindness, is often associated with the upregulation of vascular endothelial growth factor (VEGF) in the retina. Recently, leukocyte adhesion (leukostasis) is claimed for the occlusion of retina] capillary vascularity, which ultimately assists in the progression of diabetic retinopathy. In addition, intercellular adhesion molecule-1 (ICAM-1), a representative factor for leukostasis, is increased in diabetic retina. Endothelin (ET)-1, a potent vasoconstrictor peptide, is closely linked to the pathogenesis of diabetic retinopathy. Different therapeutic interventions concerning VEGF have already been proposed to prevent diabetic retinopathy. However, no study has yet reported concerning the effects of ET-I receptor antagonist on the upregulated VEGF and ICAM-1 in morphologically intact diabetic retina. The current study investigated the effect of ETA receptor antagonist (TA-0201; 1 mg kg(-1) day(-1)) on the expressions of VEGF and ICAM-I in rat diabetic retina. Diabetes was induced by intraperitoneal injection of streptozotocin (70 mg/kg) in Sprague-Dawley rats, whereas control rats (Cont) received only citrate buffer. After I week, the streptozotocin-administered rats were randomly divided into two groups: ETA receptor antagonist-treated group (DM+TA-0201) and saline-treated group (DM+vehicle). After the treatment for 4 weeks, the retina was removed from the eyeball. In DM+vehicle group, the VEGF expression of retina was significantly increased (33.5 pg/mg) in comparison with that in the Cont group (25.1 pg/mg), and the upregulation of VEGF was reversed in DM+TA-0201 group (26.9 pg/mg), a phenomenon consistent with the change in VEGF mRNA levels. The expression of retinal ICAM-I was increased in DM+vehicle group (55.1 pg/mg) compared with Cont group (43.8 pg/mg), and ET antagonism completely blocked this increase (43.8 pg/mg). Moreover, an increased leukostasis by 3.3-fold in DM+vehicle retina was returned to the control level by ET antagonism. In the current study, there was no obvious retinal morphological alteration from both the hematoxylin and eosin staining and the FITC-dextran angiography. Thus, ETA receptor antagonist might be useful in preventing the progression of diabetic retinopathy, as evidenced by suppressing the increase in VEGF and ICAM-1 levels as well as leukostasis in morphologically intact diabetic retina.

The aim of this study was to assess the usefulness of the break-point in the heart rate/work rate relationship (HRBP). Ninety-seven middle-aged and elderly people performed a ramp-fashion incremental exercise test on a cycle ergometer. Breath-by breath O2 consumption and CO2 production data and beat-to-beat systolic blood pressure and heart rate data were obtained during the test, and work rate and heart rate corresponding to ventilatory threshold (VT), double product break point (DPBP), and HRBP were obtained by a linear regression analysis. Work rate and heart rate at HRBP correlated significantly with the corresponding values at VT (r=0.773, r=0.858, both P<0.0001), as work rate and heart rate at DPBP did (r=0.873, r=0.905, both P<0.0001). Work rate at DPBP and HRBP (60±13 and 61±13 watts) did not significantly differ from work rate at VT (61±13 watts), whereas heart rates at DPBP and HRBP (105±14 and 106±13 bpm) were significantly lower than that at VT (108±14 bpm, P<0.05). However, there was no significant difference in error from heart rate at VT between heart rate at DPBP and heart rate at HRBP. These results suggest that, in middle-aged and elderly people, HRBP could

In our previous study, we demonstrated that an increase in the amount of daily physical activity might produce beneficial effects on aging-induced reduction of systemic arterial compliance. Regular physical activity, especially vigorous activity levels, inhibits age-related decrease in sytemic or central arterial compliance. However, the effect of mild to moderate intensity of physical activity has not been fully elucidated. The purpose of the present study was to investigate which intensity level of physical activity would be effective to improve systemic arterial compliance. We examined the relationship between systemic arterial compliance and intensity levels of daily physical activity (activity time corresponding to <3 METs [low], <3 METs and <6 METs [mild-moderate], and >6 METs [high]) in 413 middle-aged and elderly subjects (46∼85 y). Multiple regression analysis detected age and time of mild-moderate intensity of daily physical activity as significant independent determinants of systemic arterial compliance. The time of mild-moderate intensity of daily physical activity was significantly related to age and amount of daily physical activity. After age and amount of daily ph

Exercise training causes some physiological cardiovascular adaptations, which act to enhance cardiac and vascular functions at rest and during exercise. However, the molecular mechanisms of these adaptations are unclear. We investigated gene expression profiles of exercise training-induced cardiovascular adaptations. In the experiment, rats exercised on a treadmill for 4 or 8 weeks (4WT and 8WT). The differences in expression levels of 3,800 genes in the heart and abdominal aorta of sedentary control and exercise-trained rats were compared by the microarray analysis. Of the 3,800 genes analyzed in the microarray analyses, in the heart, a total of 45 genes (upregulation of 3 genes and downregulation of 42 genes) in the 4WT and 74 genes (upregulation of 50 genes and downregulation of 24 genes) in the 8WT displayed altered gene expression with exercise training. In the aorta, a total of 57 genes (upregulation of 35 genes and downregulation of 24 genes) in the 4WT and 31 genes (upregulation of 12 genes and downregulation of 19 genes) in the 8WT displayed altered gene expression with exercise training. Thus exercise training caused an alteration of many genes expression in the heart and

Regular exercise training brings about desirable physical effects, including an increase in both endurance capacity and muscle strength/volume and an improvement in arterial stiffness that regulate blood pressure. However, these effects vary greatly between individuals. In addition to environmental factors, the genetic backgrounds causing those individual variations are inferred. Research exploring genes which regulate physical capabilities and training-induced effects is widely being implemented. These studies will encourage an individually tailored prescription of lifestyle/exercise for health. This review focused on individual variations of exercise training-induced effects on physical endurance capacity, muscle strength/volume and arterial stiffness. The relation between these effects and the gene and genetic factors, and future perspectives were discussed. Concerning endurance capacity, many studies have been carried out on ACE genotype, and also the relation to polymorphisms of mtDNA, UCP gene or HIF1A gene. In our studies, the polymorphisms of mitochondria-related genes were explored, revealing a suggestion that polymorphism is related to the endurance capacity and the pheno

Exercise training improves aging-induced deterioration of angiogenesis in the heart. However, the mechanisms underlying exercise-induced improvement of capillary density in the aged heart are unclear. Vascular endothelial growth factor (VEGF) is implicated in angiogenesis, which activated angiogenic signaling cascade through Akt and endothelial nitric oxide synthase (eNOS)-related pathway. We hypothesized that VEGF angiogenic signaling cascade in the heart contributes to a molecular mechanism of exercise training-induced improvement of capillary density in old age. With the use of hearts of sedentary young rats (4 mo old), sedentary aged rats (23 mo old), and exercise-trained aged rats (23 mo old, swim training for 8 wk), the present study investigated whether VEGF and VEGF-related angiogenic molecular expression in the aged heart is affected by exercise training. Total capillary density in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats, whereas that in the exercise-trained rat was significantly higher than the sedentary aged rats. The mRNA and protein expressions of VEGF and of fms-like tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1), which are main VEGF receptors, in the heart were significantly lower in the sedentary aged rats compared with the sedentary young rats, whereas those in the exercise-trained rats were significantly higher than those in the sedentary aged rats. The phosphorylation of Akt protein and eNOS protein in the heart corresponded to the changes in the VEGF protein levels. These findings suggest that exercise training improves aging-induced downregulation of cardiac VEGF angiogenic signaling cascade, thereby contributing to the exercise training-induced improvement of angiogenesis in old age. Copyright © 2006 the American Physiological Society.

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg.kg(-1).day(-1)). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ET(A) and ET(B) receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.

Aims: Exercise training causes physiological cardiac hypertrophy, which acts to enhance cardiac function during exercise. However, the underlying molecular mechanisms are unclear. We investigated gene expression profile of exercise training-induced cardiac hypertrophy using left ventricle (LV) excised from exercise-trained and sedentary control rats (12-week old).
Method: Rats in the training group exercised on a treadmill for 8-week.
Results: Left ventricular mass index and wall thickness in the exercise-trained group were significantly greater than that in the control group, indicating that the trained rats developed cardiac hypertrophy. Of the 3800 genes analysed in the microarray analyses, a total of 75 relevant genes (upregulation of 33 genes and downregulation of 42 genes) displayed alterations with exercise training. Among these genes, we focused on glycogen synthase kinase (GSK)-3 beta, calcineurin-inhibitor (Cain), and endothelin (ET)-1 for their implicated roles in pathological cardiac hypertrophy, and confirmed the results of microarray analysis at mRNA and protein/peptide levels using quantitative PCR, Western blot, and EIA analyses. The gene expression of GSK-3 beta decreased significantly and those of Cain and ET-1 increased significantly with exercise training. Furthermore, LV mass index was significantly correlated with GSK-3 beta protein activity (r = -0.70, P &lt; 0.01) and tissue ET-1 concentration (r = 0.52, P &lt; 0.05). There were no changes in gene expressions in brain natriuretic peptide (BNP), angiotensin-correcting enzyme (ACE), interleukin-6, and vascular cell adhesion molecule (VCAM)-1.
Conclusion: These findings suggest that physiological and pathological LV hypertrophy may share some of the same molecular mechanisms in inducing LV hypertrophy (e.g. GSK-3 beta, Cain, and ET-1) and that other genes (e.g. BNP, ACE) may differentiate physiological from pathological LV hypertrophy.

Introduction/Purpose: Regular aerobic exercise reduces aortic stiffness. However, the mechanisms by which chronic exercise lowers arterial stiffness are not known. To determine the molecular mechanisms of these changes, the alteration of gene expression in the aorta by aerobic exercise training was measured with the microarray technique. Methods/Results: The differences in expression levels of 3800 genes in the abdominal aorta of sedentary control rats (8 wk old) and exercise-trained rats (8 wk old, treadmill running for 4 wk) were compared by the microarray analysis. Aortic pulse wave velocity (PWV) was lower and systemic arterial compliance was higher (both P &lt; 0.05) in the exercise-trained group than in the control group. Of the 323 genes that displayed differential expression (upregulation of 206 genes and downregulation of 117 genes), a total of 29 genes (24 upregulated and 5 downregulated genes) were identified as potential candidate genes that may be involved in vasodilation and arterial destiffening. Using real-time quantitative polymerase chain reaction, we confirmed the results of microarray analysis that prostaglandin EP2 receptor (PGE-EP2R), prostaglandin EP4 receptor (PGE-EP4R), C-type natriuretic peptide (CNP), and endothelial nitric oxide synthase (eNOS) genes were differentially expressed. Furthermore, there were modest correlations between arterial stiffness and levels of these factors. Differential expression of eNOS gene was further verified at protein level by using Western blot analysis. Conclusion: These results suggest that exercise training induces the altered expression in several genes including prostaglandin, CNP, and nitric oxide in the aorta and that these molecular changes (particularly eNOS as its protein expression was altered) may contribute, at least in part, to the beneficial effect of exercise training on aortic stiffness.

Aims: Initially, the renin-angiotensin system (RAS) produced through the classical endocrine pathway was well known for its regulation of blood pressure. However, it was revealed that a local autocrine and/or paracrine RAS may exist in a number of tissues (such as kidney). Exercise causes a redistribution of tissue blood flow, by which the blood flow is greatly increased in active muscles, whereas it is decreased in the splanchnic circulation (such as in the kidney). We hypothesized that exercise causes an enhancement of tissue RAS in the kidney.
Methods: We studied whether exercise affects expression of angiotensinogen and angiotensin-converting enzyme (ACE) and tissue angiotensin II level in the kidney. The rats performed treadmill running for 30-min. Immediately after this exercise, kidney was quickly removed. Control rats remained at rest during this 30-min period.
Results: The expression of angiotensinogen mRNA in the kidney was markedly higher in the exercise rats than in the control rats. ACE mRNA in the kidney was significantly higher in the exercise rats than in the control rats. Western blot analysis confirmed significant upregulation of ACE protein in the kidney after exercise. Tissue angiotensin II level was also increased by exercise.
Conclusion: The present study suggests that the exercise-induced enhancement of tissue RAS in the kidney causes vasoconstriction and hence decreases blood flow in the kidney, which are helpful in increasing blood flow in active muscles, thereby contributing to the redistribution of blood flow during exercise.

Aortic pulse wave velocity (PWV) significantly decreased after 16 weeks of moderate-intensity exercise training (walking/jogging) in 17 sedentary middle-aged men, whereas leg PWV did not. These results suggest that in contrast with central arterial stiffness, peripheral arterial stiffness is difficult to change with aerobic exercise training.

A reduction in central arterial compliance has been identified as an independent risk factor for future cardiovascular disease. The aim of the present study was to determine the influence of age-related carotid arterial enlargement on carotid arterial compliance in postmenopausal females, using a cross-sectional study design. Carotid arterial properties were measured with applanation tonometry and ultrasound system in 113 normotensive females (aged 50-78). Brachial-ankle pulse wave velocity (baPWV) measured by a plethysmographic technique was used as an index of arterial stiffness. In comparisons among the three age groups (50-59, 60-69, and 70-78 years old), baPWV (F=11.9, p &lt; 0.001) and carotid systolic (F=4.5, p &lt; 0.05) and pulse pressures (F=9.6, p &lt; 0.0001), and lumen diameter (F=5.6, p &lt; 0.01) increased with advancing age. Carotid arterial compliance gradually decreased with age, but not significantly. A stepwise regression analysis revealed that carotid systolic pressure and lumen diameter and age were independent correlates of carotid arterial compliance. After carotid lumen diameter was taken into account (ANCOVA), the differences in carotid arterial compliance among the three age groups became significant (F=3.8, p &lt; 0.05). These results suggest that an increase in arterial lumen diameter might compensate for the age-related increase in arterial stiffness and limit the deterioration of the buffering capacity of the central artery in normotensive postmenopausal females.

近年、国内外で心臓・血管疾病による死亡率が増加している。その原因として、高血圧症、高脂肪血症、糖尿病などの生活習慣病の急増が問題視されており、継続的な運動はこれらの予防や改善に対して、極めて有効な手段とされている。 ...

KAKIYAMA, T., J. SUGAWARA, H. MURAKAMI, S. MAEDA, S. KUNO, and M. MATSUDA. Effects of Short-Term Endurance Training on Aortic Distensibility in Young Males. Med. Sci. Sports Exerc., Vol. 37, No. 2, pp. 267-271, 2005. Background: Short-term endurance exercise training can increase aortic distensibility. The effect of exercise on arterial distensibility, however, may not last long term. Purpose: We evaluated the effects of short-term exercise training and detraining on aortic distensibility in 10 sedentary young males (21.0 +/- 0.6 yr. mean +/- SE; range 19-24 yr). Methods: The subjects underwent 8 wk of endurance training on a cycle ergometer at 70% of maximal oxygen consumption (VO2max), for 60 min at a time and on alternate days (3-4 d(.)wk(-1)). The detraining period consisted of a return to sedentary days for 8 wk. The aortic pulse wave velocity (APWV) was measured before and immediately after training and during the detraining period. Results: The VO2max was significantly increased after training (pre: 2240.0 +/- 71.4 mL, after: 2729.9 +/- 82.5 mL, mean +/- SE, P &lt; 0.0001) and remained at increased levels during the detraining period (after 4 wk: 2671.2 +/- 73.6 mL, P &lt; 0.001; after 8 wk: 2628.0 +/- 85.0 mL, P &lt; 0.001). The APWV was significantly decreased after training (pre: 5.80 +/- 0.15 m(.)s(-1), after: 5.50 +/- 0.21 m-s(-1), P &lt; 0.01) but returned close to the baseline after detraining for 4 wk (5.66 +/- 0.13 m(.)s(-1), P &lt; 0.18). Conclusion: Our data suggest that short-term exercise training can improve aortic distensibility, but the effect cannot be maintained without continuing physical exercise.

Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and is thought to have antiatherosclerotic properties. Therefore, it has also been proposed that NO may be useful to regulate vascular tonus and prevent progression of atherosclerosis. On the other hand, NO activity reduces with aging. We previously reported that the plasma nitrite/nitrate (NOx: the stable end product of NO) concentration was significantly increased by intense aerobic exercise training in healthy young humans. We hypothesized that lifestyle modification (e.g., even mild regular exercise training) can increase NO production in previously sedentary older humans. We measured the plasma NOx concentration before and after a mild aerobic exercise training regimen (cycling on a leg ergometer at 80% ventilatory threshold for 30 min, 5 days/week) for 3 months in elderly women. In addition, we assessed the plasma concentration of cyclic guanosine monophosphate (cGMP), a second messenger of NO, in the same samples. The individual ventilatory threshold increased significantly after the 3-month exercise training. The blood pressure at rest significantly decreased after exercise training. These results suggest that the 3-month exercise training in the older women produced favorable physiological effects. The plasma concentration of NOx significantly increased by the exercise training, and the plasma concentration of cGMP also increased by the exercise training. The present study suggests that even a mild regular aerobic-endurance exercise increases NO production in previously sedentary older humans, which may have beneficial effects (Le., anti hypertensive and antiatherosclerotic effects by endogenous NO) on the cardiovascular system.

We previously reported that even low-intensity, short-duration acute aerobic exercise decreases arterial stiffness. We aimed to test the hypothesis that the exercise-induced decrease in arterial stiffness is caused by the increased production of NO in vascular endothelium with exercise. Nine healthy men (age: similar to22-28 yr) performed a 5-min single-leg cycling exercise ( 30 W) in the supine position under an intravenous infusion of N-G-monomethyl-L-arginine (L-NMMA; 3 mg/kg during the initial 5 min and subsequent continuous infusion of 50 mug . kg(-1) . min(-1) in saline) or vehicle (saline) in random order on separate days. The pulse wave velocity (PWV) from the femoral to posterior tibial artery was measured on both legs before and after the infusion at rest and 2 min after exercise. Under the control condition, exercised leg PWV significantly decreased after exercise (P &lt; 0.05), whereas nonexercised leg PWV did not show a significant change throughout the experiment. Under L-NMMA administration, exercised leg PWV was increased significantly by the infusion (P &lt; 0.05) but decreased significantly after the exercise (P &lt; 0.05). Nonexercised leg PWV increased with L-NMMA administration and maintained a significantly higher level during the administration compared with baseline ( before the infusion, all P &lt; 0.05). The NO synthase blockade x time interaction on exercised leg PWV was not significant (P = 0.706). These results suggest that increased production of NO is not a major factor in the decrease of regional arterial stiffness with low-intensity, short-duration aerobic exercise.

The effects of long-term administration of YM598, a selective endothelin-A antagonist, on improving the exercise tolerance of chronic heart failure model rats were examined using a treadmill exercise loading test. Rats were acclimatized to the treadmill apparatus and the coronary artery was ligated to prepare a myocardial infarction-induced congestive heart failure (CHF) model. Starting 10 days postoperatively, when the acute phase of infarction was over, YM598 was administered orally once daily for approximately 25 weeks at a dose of 1 mg/kg. At weeks 20 and 24 the treadmill test was performed. YM598 prolonged running tune, which had been shortened as a result of heart failure. The weights, relative to the body weight, of the left and right ventricles and lungs of surviving rats with CHF were significantly greater than those of sham-operated rats, suggesting hypertrophy of the ventricles and congestion of the lungs. Administration of YM598 markedly reduced ventricular hypertrophy and pulmonary congestion. Examination of cardiac function revealed that, in surviving CHF rats, the peak positive first derivative of left ventricular pressure was significantly lower, and left ventricular end-diastolic pressure, right ventricular systolic pressure and central venous pressure were significantly higher in comparison to sham-operated rats. These data demonstrate that, in rats with CHF, the contractile and diastolic capacity of the left ventricle decreased and pulmonary hypertension and systemic congestion occurred. Long-term administration of YM598 improved left ventricular function of CHF rats to the level of sham-operated rats, and reduced the workload placed on the right side of the heart. Histological examination revealed that long-term treatment with YM598 prevented fibrosis of the surviving left ventricular myocardium. In conclusion, long-term administration of YM598 to rats with CHF improved exercise tolerance and inhibited remodeling of cardiac muscles, leading to marked improvement of cardiac function.

In spontaneously hypertensive rats a decrease occurs in myocardial energy supply from long-chain triglyceride (LCT) by CD36 gene mutation-induced dysfunction. We investigated whether long-term intake of medium-chain triglyceride, which enters into cells without CD36, upregulates fatty acid metabolic capacity in the heart of spontaneously hypertensive rats, and whether this upregulation improves cardiac hypertrophy and molecular markers. Male 4-week-old spontaneously hypertensive rats were given medium-chain triglyceride (SHR-MCT) or LCT (SHR-LCT) for 16 weeks. After hemodynamic measurement, we determined myocardial fatty acid metabolic enzyme activity and mRNA expression of molecular markers (endothelin-1, alpha-skeletal actin, angiotensin-converting enzyme and brain natriuretic peptide) for cardiac hypertrophy. We used Wistar-Kyoto rats (WKY-MCT and WKY-LCT) as controls. When compared with SHR-LCT rats, SHRMCT rats showed an increase in myocardial fatty acid metabolic enzyme activity and improvement in cardiac function (left ventricular end-diastolic pressure and +dP/dt/P) and cardiac hypertrophy. Blood pressure did not differ between them. The mRNA expression of endothelin-1, alpha-skeletal actin, angiotensin-converting enzyme and brain natriuretic peptide in the heart was significantly higher in SHR-LCT than in WKY-MCT and WKYLCT rats, and there was no significant difference between SHRLCT and SHR-MCT. These findings suggest that medium-chain triglyceride application to spontaneously hypertensive rats improves decreased cardiac function and cardiac hypertrophy without affecting blood pressure and myocardial mRNA expression of molecular markers. Because mechanical stress to the heart is similar between SHR-LCT and SHR-MCT, this may be a reason for the lack of difference in expression of molecular markers.

Exercise causes an integrated physiological response (e.g., an increase in cardiac output and a significant redistribution of tissue blood flow), which greatly increases blood flow in active muscles but decreases it in the splanchnic circulation. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. We hypothesized that exercise causes a tissue-specific change in ET-1 production in various organs. We studied whether a bout of exercise alters the expression of preproET-1 mRNA in various tissues of rats. The rats were randomly divided into exercise rats and control rats. Exercise rats performed treadmill running for 30 minutes at a speed of 30 m/minute. Control rats remained at rest during the same period (30 minutes). Immediately after the exercise and rest, the abdominal artery, liver, muscles (tibialis anterior muscle, plantar muscle and soleus) and adipose tissue were quickly removed and the expression of preproET-1 mRNA in these tissues was determined by real-time quantitative polymerase chain reaction analysis. The expression of preproET-1 mRNA in these tissues was changed in a different manner by acute exercise (i.e., increased, decreased, or unchanged). The expression of preproET-1 mRNA in the aorta was significantly decreased by exercise, whereas that in the plantar muscle was significantly increased by exercise. There were no significant differences in the expression of preproET-1 mRNA in the liver, tibialis anterior muscle, soleus and adipose tissue between the exercise rats and the control rats. These results show that the expression of preproET-1 mRNA was changed tissue-specifically by acute exercise. We demonstrate that acute exercise causes tissue-specific changes in the production of ET-1 and that these alterations may participate in the integrated physiological response during exercise.

Endothelin-1 (ET-1), which is produced by vascular endothelial cells, has potent vasoconstrictor and proliferative activity in vascular smooth muscle cells, and therefore has been implicated in regulation of vascular tonus and progression of atherosclerosis. We recently demonstrated that the plasma ET-1 concentration was significantly decreased by aerobic exercise training in healthy young humans and healthy older humans. However, it is unclear whether the production of ET-1 is altered by resistance exercise training. We measured the plasma ET-1 concentration before and after resistance exercise training in healthy young humans. Six healthy young men (26 +/- 1 years old) performed 8 weeks of resistance exercise training (3 days/week). There were no significant differences in body composition, blood pressure, heart rate, and maximal oxygen consumption before and after resistance exercise training. The girths of the arm and thigh significantly increased after resistance exercise training. The maximal muscle powers in the arm and leg increased after resistance exercise training. After resistance exercise training, the plasma concentration of ET-1 significantly decreased. The present study suggested that resistance exercise training, as well as aerobic exercise training, reduces the plasma ET-1 concentration in healthy young humans, and that this reduction in plasma ET-1 concentration may have beneficial effects on the cardiovascular system.

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects in the heart and causes myocardial cell hypertrophy. We investigated the alteration of gene expression of ET-1 in the heart of rats during acute exercise and 24 hour post-exercise periods. Sprague-Dawley rats performed treadmill running for 30 minutes at a speed of 30 m/minute. We determined the expression ofpreproendothelin-1 mRNA in the rat hearts of resting (control) and 0, 0.5, 1, 3, 6, 12, and 24 hour post-exercise time points, respectively. The percent changes in expression of preproendothelin-1 mRNA in the heart from resting control rats were significantly increased at the time point of 1 hour post-exercise (199.0 +/- 33.6%, P &lt; 0.05), and this enhancement returned to the level of resting control rats at the time points of 6, 12, and 24 hours post-exercise. These results suggest that a bout of exercise causes time-related enhancement of gene expression of ET-1 in the rat hearts during acute exercise and 24 hour post-exercise periods. Therefore, an exercise-induced change of ET-1 gene expression in the heart may participate in mechanisms of exercise-induced and/or training-induced adaptive responses of the heart.

Exercise training improves the aging-induced downregulation of myosin heavy chain (MHC) and sarcoplasmic reticulum (SR) Ca(2+)-ATPase, which participate in the regulation of cardiac contraction and relaxation. Thyroid hormone receptor (TR), a transcriptional activator, affected the regulation of gene expression of MHC and SR Ca(2+)-ATPase. We hypothesized that myocardial TR signaling contributes to a molecular mechanism of exercise training-induced improvement of MHC and SR Ca(2+)-ATPase genes with cardiac function in old age. We investigated whether TR signaling and gene expression of MHC and SR Ca(2+)-ATPase in the aged heart are affected by exercise training, using the hearts of sedentary young rats (4 mo old), sedentary aged rats (23 mo old), and trained aged rats (23 mo old, swimming training for 8 wk). Trained aged rats showed improvement in cardiac function. Expression of TR-alpha(1) and TR-beta(1) proteins in the heart were significantly lower in sedentary aged rats than in sedentary young rats and were significantly higher in trained aged rats than in sedentary aged rats. The activity of TR DNA binding to the transcriptional regulatory region in the alpha-MHC and SR Ca(2+)-ATPase genes and the mRNA and protein expression of alpha-MHC and SR Ca(2+)-ATPase in the heart and plasma 3,3&apos;-triiodothyronine and thyroxine levels were altered in association with changes in the myocardial TR protein levels. These findings suggest that exercise training improves the aging-induced downregulation of myocardial TR signaling-mediated transcription of MHC and SR Ca(2+)-ATPase genes, thereby contributing to the improvement of cardiac function in trained aged hearts.

Vascular endothelial cells produce endothelin (ET)-1, a potent vasoconstrictor peptide, and nitric oxide ( NO), a potent vasodilator substance. There are interactions between ET-1 and NO. Exercise results in a marked decrease in renal blood flow. We previously reported that exercise causes an increase of ET-1 production in the kidney, whereas production of NO in the kidney is decreased. Furthermore, we recently revealed that the magnitude of decrease in blood flow to the kidney during exercise was significantly attenuated by the administration of the endothelin-A (ETA) receptor antagonist, strongly suggesting that endogenously increased ET-1 participates in the decrease of blood flow in the kidney during exercise. Because it was demonstrated that ET-1 depresses NO synthase (NOS) activity of cultured cells in vitro, we hypothesized that an increase of ET-1 production in kidney during exercise contributes to a decrease of NO production in kidney in vivo. We studied whether administration of the ETA receptor antagonist attenuates the decreases of NOS activity and NO production in the kidney during exercise. Rats performed treadmill running for 30 min after pretreatment with an ETA receptor antagonist ( TA-0201, 0.5 mg/kg; TA-0201-treated exercise group) or vehicle (vehicle-treated exercise group). Control rats remained at rest ( vehicle-treated sedentary group). Blood flow in the kidney was decreased by this exercise, but the magnitude of the decrease after pretreatment with TA-0201 was significantly smaller than that after pretreatment with vehicle. NOS activity in kidney was significantly lower in the vehicle-treated exercise group than in the vehicle-treated sedentary group, whereas that in the TA-0201-treated exercise group was significantly higher than that in the vehicle-treated exercise group. Expressions of endothelial NOS protein and NOx, the stable end product of NO, i.e., nitrite/nitrate, concentration in the kidney were significantly lower in the vehicle-treated exercise group than in the vehicle-treated sedentary group, whereas those in the TA-0201-treated exercise group were significantly higher than those in the vehicle-treated exercise group. The data suggest that increased ET-1 production in the kidney during exercise contributes to the decreases of NOS activity and NO production. Therefore, the present study provides a possibility that the exercise-induced increase in production of ET-1 in the kidney causes a decrease in blood flow in the kidney through two pathways, i.e., vasoconstrictive action and the action of attenuating NO production.

The distensibility of the arterial wall progressively decreases with age, and the aging of the arterial wall may be responsible for the decrease of central arterial compliance and the consequent rise of systolic blood pressure (SBP) in the elderly. We hypothesized that an increase in daily physical activity (DPA) might have a favorable effect on systemic arterial compliance (SAC : an index of central arterial compliance) and lower SBP in the elderly. We therefore investigated relationships among DPA, SAC and SBP cross-sectionally in 92 middle-aged and elderly individuals (30 males, 62 fe- males ; aged 64 ± 8 years, mean ± SD). DPA was estimated by using an accelerometer as expended calories. SAC was calculated from the finger pulse pressure waveform recorded by using a Portapres and the stroke volume obtained from the same pressure waveform based on the volume-clamp method. Preliminarily in 37 subjects (17 male, 20 females ; aged 25-97 years), we confirmed a significant negative correlation between the simultaneously measured SAC and aortic pulse wave velocity (r=-0.68, p<0.0001). Correlation analysis and path analysis applied to the hypothetical model demonstrated that SBP was d

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects in the heart and causes myocardial cell hypertrophy. We investigated the alteration of gene expression of ET-1 in the heart of rats during acute exercise and 24 hour postexercise periods. Sprague-Dawley rats performed treadmill running for 30 minutes at a speed of 30 m/minute. We determined the expression of preproendothelin-1 mRNA in the rat hearts of resting (control) and 0, 0.5, 1, 3, 6, 12, and 24 hour post-exercise time points, respectively. The percent changes in expression of preproendothelin-1 mRNA in the heart from resting control rats were significantly increased at the time point of 1 hour post-exercise (199.0 +/- 33.6%, P < 0.05), and this enhancement returned to the level of resting control rats at the time points of 6, 12, and 24 hours post-exercise. These results suggest that a bout of exercise causes time-related enhancement of gene expression of ET-1 in the rat hearts during acute exercise and 24 hour post-exercise periods. Therefore, an exercise-induced change of ET-1 gene expression in the heart may participate in mechanisms of ex

The purpose of this research was to study the effects of exercise program participation on the personal factors of exercise adherence promotion in the middle-aged and elderly by comparing a group and individual exercise program. The personal factors for promoting exercise adherence, the four domains (i.e. initiative attitude, achievement satisfaction, self-recognition, and intrinsic motivation), were hypothesized. Two groups of middle-aged and elderly subjects, who volunteered to participate in different 6-month exercise programs, were examined. Group 1, 33 subjects (aged 67.7±4.3 years : mean±SD), participated in a program consisting of an individual exercise program (combination of endurance and resistance exercise, e.g. cycling exercise, dumbbell and machine exercise, once a week) and group exercise program (e.g. dance and ball game, once a week). Group 2, 27 subjects (aged 65.2±4.0 years), participated in the same individual exercise program twice a week. After the 6-month exercise program, significant improvements in group 1 were found in the self-assessment of activity score of the initiative attitude domain, the achievement satisfaction score including enjoyment, achievem

Arterial compliance progressively decreases with aging. This aging-induced reduction of arterial compliance causes an increase of systolic blood pressure (SBP), whereas regular exercise increases arterial compliance. We hypothesized that an increase in daily physical activity (DPA) produces a beneficial effect on systemic arterial compliance (SAC : an index of central arterial compliance) and this phenomenon could decrease SBP in the elderly. We investigated the relationship among DPA, SAC, SBP, diastolic blood pressure (DBP), and some other risk factors for cardiovascular and/or cerebrovascular events (total cholesterol, HDL-cholesterol, and HOMA-R) cross-sectionally in 127 elderly persons (42 male, 85 female : aged 71±4 years). The DPA was estimated by expended calories using an accelerometer. The SAC was calculated from a finger pulse pressure wave form recorded by using PORTAPRES ; and stroke volume obtained from the same pressure wave form based on the volume-clump method. The analyses demonstrated that SBP was directly and decreasingly affected by SAC, and that DPA had an increasing effect on SAC. Furthermore, SBP was directly and increasingly affected by DBP, and DBP was di

Endothelial function deteriorates with aging. On the other hand, exercise training improves the function of vascular endothelial cells. Endothelin-1 (ET-1), which is produced by vascular endothelial cells, has potent constrictor and proliferative activity in vascular smooth muscle cells and, therefore, has been implicated in regulation of vascular tonus and progression of atherosclerosis. We previously reported significantly higher plasma ET-1 concentration in middle-aged than in young humans, and recently we showed that plasma ET-1 concentration was significantly decreased by aerobic exercise training in healthy young humans. We hypothesized that plasma ET-1 concentration increases with age, even in healthy adults, and that lifestyle modification ( i.e., exercise) can reduce plasma ET-1 concentration in previously sedentary older adults. We measured plasma ET-1 concentration in healthy young women ( 21 - 28 yr old), healthy middle-aged women ( 31 - 47 yr old), and healthy older women ( 61 - 69 yr old). The plasma level of ET-1 significantly increased with aging (1.02 +/- 0.08, 1.33 +/- 0.11, and 2.90 +/- 0.20 pg/ml in young, middle-aged, and older women, respectively). Thus plasma ET-1 concentration was markedly higher in healthy older women than in healthy young or middle-aged women ( by similar to3- and 2-fold, respectively). In healthy older women, we also measured plasma ET-1 concentration after 3 mo of aerobic exercise ( cycling on a leg ergometer at 80% of ventilatory threshold for 30 min, 5 days/wk). Regular exercise significantly decreased plasma ET-1 concentration in the healthy older women (2.22 +/- 0.16 pg/ml, P &lt; 0.01) and also significantly reduced their blood pressure. The present study suggests that regular aerobic-endurance exercise reduces plasma ET-1 concentration in older humans, and this reduction in plasma ET-1 concentration may have beneficial effects on the cardiovascular system (i.e., prevention of progression of hypertension and/or atherosclerosis by endogenous ET-1).

We examined the effect of low-intensity single-leg exercise (20 or 30 watt, 5 min) on pulse wave velocity from the femoral to the ankle arteries in 18 young men. After the exercise, the velocity significantly decreased in the exercised leg, but not in the counterpart, suggesting that the decrease in arterial stiffness in the exercised leg was induced mainly by exercise-related regional factors. [The Japanese Journal of Physiology 53: 239-241, 2003].

Hypertension-induced pathological cardiac hypertrophy (hypertensive heart) and exercise training-induced physiological cardiac hypertrophy (athletic heart) have differences in cardiac properties. We hypothesized that gene expression of energy metabolic enzymes differs between these two types of cardiac hypertrophy. To investigate whether mRNA expression of key enzymes in the long-chain fatty acid (FA), glucose, and lactic acid metabolic pathways differs between these two types of cardiac hypertrophy, we used the hearts of spontaneously hypertensive rats (SHR; 19 weeks old) as a model of the hypertensive heart, swim-trained rats (Trained; 19 weeks old, swimming training for 15 weeks) as a model of the athletic heart, and sedentary Wistar-Kyoto rats (Control; 19 weeks old). SHR developed hypertensive cardiac hypertrophy, of which cardiac function was deteriorated, whereas Trained rats developed an athletic heart, of which cardiac function was enhanced. The mRNA expression of CD36, which involved in uptake of long-chain FA, in the heart was almost never detected in the SHR group. Furthermore, the mRNA expression of key enzymes in the long-chain FA metabolic pathway (acyl CoA synthase

Large arteries (central arteries such as aortas) and medium-sized arteries (peripheral arteries such as upper limb arteries) provide buffer function to level off fluctuations in blood pressure and blood flow. When upper limb arterial stiffness increases, buffer functions deteriorate, thereby increasing the blood pressure and reducing the blood flow efficiency. Intense aerobic exercise training helps to decrease stiffness in central arteries and peripheral arteries. We have demonstrated whether continuous aerobic exercise in elderly women can help to reduce stiffness in peripheral arteries, even when the exercise is relatively mild. Arterial pulse wave velocity (PMV) method was used to measure peripheral (upper arm- forearm) arterial stiffness in test subjects; eight healthy elderly women (age 62±1) who perform moderate exercises continuously and six healthy women (age 61±3) who do not exercise regularly. Findings demonstrate that stiffness in peripheral arteries is significantly lower in the elderly women who participate in continuous aerobic exercise training compared to those with no such exercise routine. These findings show that aerobic exercise on cycle ergometer that mainly uses lower limbs helps to reduce stiffness in upper limb arteries. Therefore, this study suggests that aerobic exercise training in peripheral arteries may have an effect on arteries where lower loads are to be applied.

Systemic arterial compliance (SAC) for the aged is a very important index in hemodynamics during exercise. In this study, the blood pressure waveform used for calculation of SAC was noninvasively recorded at finger artery by volume clamp method (VC) and compared with the method recorded by applanation tonometry (AT) at carotid artery, and usefulness and validity of this method were investigated. Continuous blood pressure waveform was recorded using VC at finger artery and AT at carotid artery during the light exercise for 22 elderly patients. The blood pressure waveform by VC was transformed by transfer function into the waveform of brachial artery. The ratio of the subjects recorded with stable waveform was 64% by AT while that of VC is 100%. Significantly high correlationship (r=0.89) between the measured values of the ratio of the area under the arterial blood pressure waveform at one heart beat cycle and at left ventricular diastole by VC and AT was observed, and its agreement was very good. As a consequence, it is supposed to be valid to use the method using blood pressure waveform recorded at peripheral artery by VC as a noninvasive estimate method of SAC for the elderly people during light exercise.

We evaluated the effects of endurance training on systolic blood pressure (SBP) in elderly people individually, by using a single-case study design and a statistical technique, e.g., the randomization test. Six people (4 females and 2 males, 60-77 yr) participated in 12-week endurance exercise training (cycling at 80% of the work rate corresponding to the ventilatory threshold, 30-min, 5-day/wk) and recorded their own daily SBP. The mean SBP in all subjects was significantly lower than the baseline after the 7th training week (P<0.05). Individual changes in SBP with training varied among subjects. The earliest and latest occurrences of significant training effects were in the 3rd training week (-6 mmHg) and the 11th training week (-5 mmHg). In the subject who had the highest SBP at the baseline, SBP decreased 12 mmHg in the 12th training week. The subject who had the lowest SBP at the baseline (99 mmHg) did not show significant changes in SBP throughout training. We concluded that the randomization test in the single-case study design was useful to evaluate individual training effects on SBP.

Nitric oxide (NO) is produced in the vascular endothelium. and is a potent vasodilator substance that participates in the regulation of local vascular tone. Exercise causes peculiar changes in systemic and regional blood flow, i.e., an increase of systemic blood flow and a redistribution of local tissue blood flow, by which the blood flow is greatly increased in the working muscles, whereas it is decreased in some organs such as the kidney and intestine. Thus we hypothesized that exercise causes a tissue-specific change of NO production in some internal organs. We studied whether exercise affects expression of NO synthase (NOS) mRNA and protein, NOS activity, and tissue level of nitrite/nitrate (stable end products of NO) in the kidneys (in which blood flow during exercise is decreased) and lungs (in which blood flow during exercise is increased with the increase of cardiac output) of rat. Rats ran on a treadmill for 45 min at a speed of 25 m/min. Immediately after this exercise, kidneys and lungs were quickly removed. Control rats remained at rest during this 45-min period. Expression of endothelial NOS (eNOS) mRNA in the kidneys was markedly lower in exercise rats than in control rats, whereas that in the lungs was significantly higher in exercise rats than in control rats. Western blot analysis confirmed down- and upregulation of eNOS protein in the kidney and lung, respectively, after exercise. On the other hand, neither expression of neuronal NOS (nNOS) mRNA and nNOS protein nor inducible NOS (iNOS) mRNA and iNOS protein in the kidneys and lungs differed between exercise and control rats. NOS activity in the kidney was significantly lower in exercise rats than in control rats, whereas that in the lung was significantly higher in exercise rats than in control rats. On the other hand, the iNOS activity in the kidneys and lungs did not differ between exercise rats and control rats. Tissue nitrite/nitrate level in the kidneys was markedly lower in exercise rats, whereas that in the lungs was significantly higher in exercise rats. The present results show that production of NO is markedly and tissue-specifically changed in the kidney and lung by exercise.

Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group
19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group
19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of β1-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of β1-adrenergic receptor kinase mRNA, which inhibits β1-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.

We studied the effects of aerobic exercise training and detraining in humans on post-exercise vagal reactivation. Ten healthy untrained men trained for 8 weeks using a cycle ergometer [70% of initial maximal oxygen uptake (VO2max) for 1 h, 3-4 days·week-1] and then did not exercise for the next 4 weeks. Post-exercise vagal reactivation was evaluated as the time constant of the beat-by-beat decrease in heart rate during the 30 s (t30) immediately following 4 min exercise at 80% of ventilatory threshold (VT). The VO2max and the oxygen uptake at VT had significantly increased after the 8 weeks training programme (P&lt
0.0001, P&lt
0.001, respectively). The t30 had shortened after training, and values after 4 weeks and 8 weeks of training were significantly shorter than the initial t30 (P&lt
0.05, P&lt
0.01, respectively). The change in the t30 after 8 weeks of training closely and inversely correlated with the initial t30 (r=-0.965, P&lt
0.0001). The reduced t30 was prolonged significantly after 2 weeks of detraining, and had returned almost to the baseline level after a further 2 weeks of detraining. These results suggest that aerobic exercise training of moderate intensity accelerates post-exercise vagal reactivation, but that the accelerated function regresses within a few weeks of detraining.

Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and has been proposed as having antiatherosclerotic property. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictor peptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has been implicated in the progression of atheromatous vascular disease. Because exercise training has been reported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesized that exercise training influences the production of NO and ET-1 in humans. The purpose of the present study was to examine whether chronic exercise could influence the plasma levels of NO (measured as the stable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects (20.3 +/- 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO2max for 1 hour, 3-4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measured before and after (immediately before the end of 8-week exercise training) the exercise training, and also after the 4th and 8t

The effects of endurance training and detraining on cardiac autonomic nervous system activity were studied by using the power spectral analysis of heart rate (HR) variability. Twenty-one sedentary male subjects were trained for 8 weeks using cycle ergometer exercise [70% of maximal oxygen uptake (VO(2)max), 60 min, 3-4 times/wk]. Resting RR for 5 min was recorded before the training, after the 8-week training period, and after the 2-week and 4-week detraining period. The indices of cardiac parasympathetic and sympathetic nervous system activity were determined by Mem-Cale method, as the high frequency power (HF:0.15-0.50 Hz) and the ratio of the low frequency power (LF:0.04-0.15 Hz) to the HF (LF/HF), respectively. The VO(2)max after the training and 4 weeks detraining period were significantly higher than the initial value (before training: 41+/-1 ml/kg/min; after training: 48+/-2, P&lt;0.0001; after detraining: 46+/-2, P&lt;0.001). The HF was significantly increased by the training (P&lt;0.05), and maintained the increased level for the 2-week detraining period (before training: 6.4+/-0.3 ln ms(2); after training: 7.0+/-0.2, P&lt;0.01; after 2-week detraining: 7.0+/-0.2, P&lt;0.05). The increase in the HF, however, disappeared after the 4-week detraining period (6.8+/-0.3 ln ms(2)). The LF/HF did not show any significant changes during the training and detraining period. These results suggest that an endurance exercise with moderate intensity enhances cardiac parasympathetic nervous system activity, but not cardiac sympathetic nervous system activity. The enhanced cardiac parasympathetic nervous system activity, however, may regress rapidly during detraining period.

Cardiac myocytes produce nitric oxide (NO). We studied the effects of intense exercise on the expression of NO synthase (NOS) and the tissue level of nitrite (NO2/-)/nitrate (NO3/-) (i.e., NOx), which are stable end products of NO in the heart. Rats ran on a treadmill for 45 min. Immediately after this exercise, the heart was quickly removed. Control rats remained at rest during the same 45-min period. The mRNA level of endothelial NOS (eNOS) in the heart was markedly lower in the exercised rats than in the control rats. Western blot analysis confirmed downregulation of eNOS protein in the heart after exercise. Tissue NOx level in the heart was significantly lower in the exercised rats than in the control rats. The present study revealed for the first time that production of NO in the heart is decreased by intense exercise. Because NO attenuates positive inotropic and chronotropic responses to β1-adrenergic stimulation in the heart, the decrease in cardiac production of NO by intense exercise may contribute to the acceleration of increase in myocardial contractility and heart rate during intense exercise.

The purpose of the present experiment was to study the pathophysiological roles of endothelin-1 (ET-1) in salt-sensitive hypertension with the use of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. PreproET-1 mRNA expression was determined by reverse transcription- polymerase chain reaction. In the kidney, expression of preproET-1 mRNA was greater in DS rats on a normal salt diet compared with DR rats of the same age. In DS rats, the level of preproET-1 mRNA expression in kidney had a significant correlation with systolic blood pressure. The expression of preproET-1 mRNA in aorta and kidney was increased by 3-week high salt intake in DS rats but not in DR rats. Expression of preproET-1 mRNA and ET-1 levels in left ventricle was exaggerated by high salt intake in DS rats. However, there was no significant difference in plasma ET-1 levels between DS and DR rats regardless of salt intake. Pressor response curves for ET-1 in DS rats with or without high salt intake were significantly shifted to the left compared with those in DR rats. A single oral dose (3 to 10 mg/kg) of J- 104132 (L-753 037), a potent, orally active mixed endothelin A and B (ET(A)/ET(B)) receptor antagonist, reduced blood pressure to normotensive levels in DS rats with high salt intake, and its action was maintained for ≥24 hours. In DS rats with normal salt intake, J-104132 (10 mg/kg) slightly but significantly decreased blood pressure. DR rats did not show obvious depressor responses to J-104132 (10 mg/kg) regardless of salt intake. These results suggest that ET-1 acts as one of the pathophysiological factors in the development and maintenance of salt-sensitive hypertension, and a mixed ET(A)/ET(B) receptor antagonist could be useful in the treatment for salt- sensitive hypertension.

Cardiac myocytes produce endothelin-1 (ET-1). ET-1 has potent positive inotropic and chronotropic effects. We investigated whether production of ET-1 in the heart is altered by prolonged exercise in rats. Rats ran on a treadmill for 45 min. Immediately after this exercise the heart and lungs were quickly removed. Control rats remained at rest during this 45-min period. Expression of preproET-1 mRNA in the heart was markedly higher in the exercised than in the control rats. The peptide level of ET-1 in the heart was also markedly higher in the exercised rats. Expression of endothelin type A- and type B-receptor mRNA and endothelin-converting enzyme mRNA in the heart did not differ between the groups. The peptide level of ET-1 and the preproET-1 mRNA level in the lungs of the exercised rats did not differ from those in the control rats. The present results show that production of ET-1 is markedly increased tissue specifically in the heart by exercise without appreciable changes in endothelin-converting enzyme and endothelin receptor expression. The present study suggests that myocardial ET-1 may participate in modulation of cardiac function during exercise.

Cardiac myocytes produce endothelin-1 (ET-1). ET-1 has potent positive inotropic and chronotropic effects. We investigated whether production of ET-1 in the heart is altered by prolonged exercise in rats. Rats ran on a treadmill for 45 min. Immediately after this exercise the heart and lungs were quickly removed. Control rats remained at rest during this 45-min period. Expression of preproET-1 mRNA in the heart was markedly higher in the exercised than in the control rats. The peptide level of ET-1 in the heart was also markedly higher in the exercised rats. Expression of endothelin type A- and type B-receptor mRNA and endothelin-converting enzyme mRNA in the heart did not differ between the groups. The peptide level of ET-1 and the preproET-1 mRNA level in the lungs of the exercised rats did not differ from those in the control rats. The present results show that production of ET-1 is markedly increased tissue specifically in the heart by exercise without appreciable changes in endothelin-converting enzyme and endothelin receptor expression. The present study suggests that myocardial ET-1 may participate in modulation of cardiac function during exercise.

Cardiac myocytes and vascular endothelial cells produce endothelin (ET)-1, which has potent hypertrophic effects on cardiac myocytes. Although in cultured cardiomyocytes, angiotensin 11 (Ang II) was reported to enhance ET-1 production in vitro, it is not known whether ET-1 production is enhanced by Ang 11 in vivo. We investigated the production and pathophysiologic roles of ET-1 in 20-week-old male transgenic hypertensive mice (THM), in which the renin-angiotensin system (RAS) was markedly activated because of the presence of both human renin and angiotensinogen genes. Systolic blood pressure and the ratio of left ventricular weight to body weight were significantly higher in the THM than in control mice, indicating that THM developed cardiac hypertrophy. ET-1 production was significantly increased in the heart of because both ET-1 mRNA expression and peptide levels were significantly higher than in controls. However, circulating plasma ET-1 levels did not differ between the groups, and blood pressure did not change after i.v. injection with a high dose (3 mg/kg) of the ETA/B-nonselective receptor antagonist SB209670. These findings suggest that increased cardiac ET-1 production may contribute to the progression of cardiac hypertrophy and that endogenous ET-1 may not be involved in the short-term modulation of blood pressure in THM of this age.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, which also potentiates contractions to norepinephrine in human internal mammary and coronary vessels. Exercise causes a redistribution of blood flow, i.e., the increase in working muscles that is partly attributable to a decrease in visceral blood flow. We hypothesized that exercise causes a tissue-specific increase in ET-1 expression in internal organs. We studied whether exercise affects expression of preproET-1 mRNA in the kidneys and lungs. The rats performed treadmill running (0% grade) for 45 min at a speed of 25 m/min. The plasma concentrations of ET-1, epinephrine, and norepinephrine were greater in the exercise rats than in the sedentary control rats. The expression of preproET-1 mRNA in the kidneys was markedly higher in the exercise rats than in the sedentary control rats, whereas that in the lungs did not differ between the two groups. Therefore, the present study provides a possibility that the exercise-induced increase in production of ET-1 in the kidneys causes vasoconstriction and hence decreases blood flow in the kidneys through its direct vasoconstrictive action and/or its indirect effect of enhancing vasoco

In addition to its potent vasocontractile effects, endothelin-1 (ET-1) has potent positive inotropic and chronotropic effects on isolated heart muscles in vitro. However, it is not known whether the production of ET-1 in the heart is altered by exercise. In this study we investigated the production of ET-1 in the heart during exercise. Rats performed treadmill running of 45-min duration. Sedentary rats served as controls. Immediately after exercise, the heart was quickly removed. The peptide level of ET-1 in the heart was measured by a sandwich-enzyme immunoassay. The peptide level of ET-1 in the heart was significantly higher in the exercise group than in the control sedentary group. Therefore, we have demonstrated that production of ET-1 in the heart is increased by exercise. The present study suggests that myocardial ET-1 participates in the modulation of cardiac function during exercise.

Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ETA receptors and ETB receptors. We previously reported that an ETA receptor antagonist greatly ameliorated pulmonary hypertension due to congestive heart failure (CHF) in rats. In the present study of rats with pulmonary congestion secondary to CHF, we determined not only ETA receptor mRNA expression but also ETB receptor mRNA expression in the congestive lung because lung ETB receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-I and circulating ET-I levels. The expression of ETB receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ETA receptor mRNA did not differ between the two groups. The protein level of ETB receptor, determined by Western blot, in the lung was lower in the rats with CHF than in the control rats, while the protein level of ETA receptor did not differ between the two groups. The lung ET-1 level and plasma ET-1 level were significantly higher in the rats with CHF than in the controls by 1.4-fold and 5.3-fold, respectively. Thus, in the rats with CHF, ET-1 was increased to a much greater extent in plasma than in the lung. The present findings suggest that selective down-regulation of ETB receptor, but not ETA receptor, occurs in the congestive lung. Since lung ETB receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ETB receptors partly contributes to marked increases in circulating ET-1 and that increased ET-1 in the circulating plasma as well as in the lung is involved in the progression of pulmonary hypertension in CHF.

It is generally accepted that visually impaired individuals generally have a low aerobic capacity, which may be partly attributed to a lack of physical activity, and have hypothesized that their response to exercise may differ from that of normal-sighted people. In this study, we investigated the effect of exercise on local immunity in the oral cavity in 24 visually impaired males (n = 8
totally blind group, n = 16
partially sighted group) and 8 normal-sighted males. The subjects performed submaximal graded bicycle ergometer exercise to an intensity of 75% heart rate max for 12 min. Before and immediately after exercise, we collected timed saliva samples and measured secretory immunoglobulin A (sIgA). The totally blind group had lower levels of aerobic capacity and a lower sIgA secretion rate compared to the partially sighted and sighted groups. Immediately after exercise, the sIgA secretion rate tended to increase in the totally blind group. It is suggested that the exercise-induced response of local immunity in the totally blind group differed from that in the other groups.

Although it has been established that exercise is useful for health promotion, physical exercise may induce oxidative stress in humans. Our previous study showed that the concentration of plasma protein-bound sulfhydryl groups (p-SHs) was significantly decreased after strenuous exercise, i. e. full-marathon running and participation in an athletic training camp. Reactive oxygen species may cause oxidation of plasma proteins in vitro. To study whether moderate exercise for health promotion, e. g. jogging or walking, induces oxidative stress in human circulating blood, the authors examined the change in plasma p-SHs concentration following ergometric exercise at moderate intensity and of relatively short duration {Exercise 1 : 80% ventilatory threshold (VT), 100% VT, and 110% VT
30 min, Exercise 2 : 90% VT
120 min} in 8 (23-28 yr
Exercise 1) and 6 males (23-28 yr
Exercise 2) respectively. The plasma p-SHs concentration did not changed significantly after Exercise 1 or 2. The data indicated that the exercise did not cause significant modification of plasma proteins, suggesting that it did not induce significant oxidative stress in the circulating blood.

Several studies have indicated that endothelin-1 (ET-1) and endothelin-3 (ET-3) are produced by different cells. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3. The presence of ET-3 in the brain of several species suggests that ET-3 is a novel neuropeptide. It is unclear whether there are differences in the release of ET-1 and ET-3 under various physiological conditions in humans. In the present study, we measured the plasma concentrations of both ET-1 and ET-3 before and after endurance exercise on a cycle ergometer. Male athletes exercised on a cycle ergometer for 30 min at intensity of 130% of their individual ventilatory threshold (VT), which is intense exercise. Plasma ET-1 and ET-3 were greatly elevated by exercise, but there was a marked difference in the time-course of the change in plasma concentration between the two peptides. The level of ET-1 peaked 30 min after exercise, whereas that of ET-3 peaked immediately after exercise. Thus, plasma ET-3 increased faster than plasma ET-1 after exercise. The exercise-induced change in the time course in plasma ET-3, but not in ET-1, is similar to that in plasma norepinephrine which is a ne

Endothelin-1 (ET-1) is an endothelium-derived potent vasoconstrictor peptide that potentiates contractions to norepinephrine in human vessels. We previously reported that the circulating plasma concentration of ET-1 is significantly increased after exercise (S. Maeda, T. Miyauchi, K. Goto, and M. Matsuda. J. Appl. Physiol. 77: 1399-1402, 1994). To study the roles of ET- 1 during and after exercise, we investigated whether endurance exercise affects the production of ET-1 in the circulation of working muscles and nonworking muscles. Male athletes performed one-leg cycle ergometer exercise of 30-min duration at intensity of 110% of their individual ventilatory threshold. Plasma concentrations of ET-1 in both sides of femoral veins (veins in the working leg and nonworking leg) and in the femoral artery (artery in the nonworking leg) were measured before and after exercise. The plasma ET-1 concentration in the femoral vein in the nonworking leg was significantly increased after exercise, whereas that in femoral vein in the working leg was not changed. The arteriovenous difference in ET-1 concentration was significantly increased after exercise in the circulation of the nonworking leg but not of the working leg, which suggests that the production of ET-1 was increased in the circulation of the nonworking leg by exercise. The present study also demonstrated that the plasma norepinephrine concentrations were elevated by exercise in the femoral veins of both the working and nonworking legs, suggesting that the sympathetic nerve activity was augmented in both legs during exercise. Therefore, the present study demonstrates the possibility that the increase in production of ET-1 in nonworking muscles may cause vasoconstriction and hence decrease blood flow in nonworking muscles through its direct vasoconstrictive action or through an indirect effect of ET-1 to enhance vasoconstrictions to norepinephrine and that these responses may be helpful in increasing blood flow in working muscles. We propose that endogenous ET-1 contributes to the exercise-induced redistribution of blood flow in muscles.

We investigated whether dehydration due to exercise contributes to the increase in plasma endothelin-1 (ET-1) concentration. We measured the plasma concentration of ET-1 before and after exercise in a hot environment (about 30 degrees C). Five male intercollegiate Kendo (Japanese fencing) players entered the present study. Each athlete participated in 15 min of Kendo fighting, followed by 5 min of rest and another 15 min of Kendo fighting (i.e., total exercise 30 min), with or without oral intake of 700 ml of water. Body weight and left atrial diameter, a parameter that reflects changes in circulating plasma volume, were significantly decreased after exercise under both conditions. However, the decreases in both values were significantly greater after exercise without water intake than after exercise with water intake, indicating that dehydration and decreased circulating plasma volume were more marked after exercise without water intake. The extent of the increase in plasma ET-1 concentration appeared to be closely related to the extent of exercise-induced dehydration; the greater the dehydration, the greater the increase in plasma ET-1 concentration. These findings suggest that e

A study was carried out to examine the effects of water replacement on cardiovascular function during kendo practice in a hot environment. Five male college kendoists performed moderately severe 30-min kendo practice at a WBGT index of about 27°C with and without water intake. For water replacement, the subjects ingested 700 ml water (500 ml before exercise and 200 ml at 15 min after the start of exercise). Under both conditions, body weight was decreased significantly, and hematocrit and serum total protein concentration were increased significantly after the exercise. With water replacement, the body weight loss induced by the exercise was similar to that under water deprivation. However, the decrease in body weight from the basal body weight, i. e. body weight measured before water intake, was significantly less with water replacement than under water deprivation. There were no significant differences in the percentage increases of hematocrit and serum total protein concentration between the two conditions, although the percentage change in plasma vasopressin concentration was significantly lower with water replacement than without. In the subjects deprived of water, the left ventricular end-diastolic dimension and left atrial dimension were significantly reduced after the exercise, and stroke volume, ejection fraction, and fractional shortening were also decreased significantly. The ratio of left ventricular end-systolic wall stress to left ventricular end-systolic volume index was increased significantly after the exercise without water intake. With water replacement, however, the percentage decreases in cardiac dimensions, stroke volume, ejection fraction, and fractional shortening were significantly lower than those under water deprivation. There was no significant change in the ratio of left ventricular end-systolic wall stress to left ventricular end-systolic volume index before and after the exercise with water intake. It is suggested that 700 ml water replacement before and during kendo exercise in a hot environment prevents depletion of stroke volume and deterioration of cardiovascular function, although it might not improve significantly the plasma volume loss after exercise. © 1995, The Japanese Society of Physical Fitness and Sports Medicine. All rights reserved.

We have previously reported that plasma endothelin-1 (ET-1) levels were significantly increased after exercise in healthy athletes. In the present study, venous plasma ET-1 levels were measured to investigate whether the role of ET-1 during exercise differs between healthy athletes and patients with congenital heart disease. Seven patients (mean age 13 years) performed symptom-limited treadmill exercise (Bruce protocol). All patients were in class I of the NYHA functional classification. The mean end-exercise O-2 utilization was 32 ml/min/kg (166% of ventilatory threshold). Blood sampling was carried out in the seated position. The plasma ET-1 level was 1.21 pg/ml before exercise and did not alter immediately after or 30 min after exercise. The plasma level of norepinephrine was markedly elevated immediately after exercise and returned to the basal level 30 min after exercise. The present study demonstrated that exercise failed to alter plasma ET-1 levels in patients with congenital heart disease.

The purpose of this study was to investigate whether the release of endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by vascular endothelial cells, is induced by exercise. Venous plasma concentrations of ET-1 were measured by sandwich-enzyme immunoassay before and after endurance exercise with a cycle ergometer at different intensities. Male intercollegiate athletes participated in the study and performed cycle ergometer exercise of 30 min duration at intensities of 90 or 130% of their individual ventilatory threshold (VT). The plasma concentration of ET-1 was slightly but significantly increased after exercise at 90% and markedly increased after exercise at 130% of individual VT. The increase in ET-1 was greatest 30 min after exercise at both intensities. It was first demonstrated that the plasma concentration of ET-1 was significantly increased after exercise: the greater the intensity, the greater the extent of the increase in plasma ET-1 concentration. However, the precise physiological roles of ET- 1 during exercise remain to be elucidated.