The present study assessed heat-escape/cold-seeking behavior during thermoregulation in mice and the influence of TRPV1 channels. Mice received subcutaneous injection of capsaicin (50 mg/kg; CAP group) for desensitization of TRPV1 channels or vehicle (control [CON] group). In Experiment 1, heat-escape/cold-seeking behavior was assessed using a newly developed system comprising five temperature-controlled boards placed in a cross-shape. Each mouse completed three 90-min trials. In the trials, the four boards, including the center board, were set at either 36˚C, 38˚C, or 40˚C, while one corner board was set at 32˚C, which was rotated every 5 min. In Experiment 2, mice were exposed to an ambient temperature of 37˚C for 30 min. cFos expression in the preoptic area of the hypothalamus (POA) was assessed. In Experiment 1, the CON group stayed on the 32˚C board for the longest duration relative to that on other boards, and intra-abdominal temperature (Tabd) was maintained. In the CAP group, no preference for the 32˚C board was observed, and Tabd increased. In Experiment 2, cFos expression in the POA decreased in the CAP group. Capsaicin-induced desensitization of TRPV1 channels suppressed heat-escape/cold-seeking behavior in mice during heat exposure, resulting in hyperthermia. In conclusion, our findings suggest that heat sensation from the body surface may be a key inducer of thermoregulatory behaviors in mice.

Regular exercise maintains arterial endothelial cell homeostasis and protects the arteries from vascular disease, such as peripheral artery disease and atherosclerosis. Autophagy, which is a cellular process that degrades misfolded or aggregate proteins and damaged organelles, plays an important role in maintaining organ and cellular homeostasis. However, it is unknown whether regular exercise stimulates autophagy in aorta endothelial cells of mice prone to atherosclerosis independently of their circulating lipid profile. Here, we observed that 16 weeks of voluntary exercise reduced high-fat diet-induced atherosclerotic plaque formation in the aortic root of ApoE deficient mice, and that this protection occurred without changes in circulating triglycerides, total cholesterol, and lipoproteins. Immunofluorescence analysis indicated that voluntary exercise increased levels of the autophagy protein LC3 in aortic endothelial cells. Interestingly, human umbilical vein endothelial cells (HUVECs) exposed to serum from voluntarily exercised mice displayed significantly increased LC3-I and LC3-II protein levels. Analysis of circulating cytokines demonstrated that voluntary exercise caused changes directly relevant to IL-1 signaling (ie, decreased interleukin-1 receptor antagonist [IL-1ra] while also increasing IL-1α). HUVECs exposed to IL-1α and IL-1β recombinant protein significantly increased LC3 mRNA expression, LC3-I and LC3-II protein levels, and autophagy flux. Collectively, these results suggest that regular exercise protects arteries from ApoE deficient mice against atherosclerosis at least in part by stimulating endothelial cell autophagy via enhanced IL-1 signaling.

Surgical masks are widely used for the prevention of respiratory infections. However, the risk of heat stroke during intense work or exercise in hot and humid environment is a concern. This study aimed to examine whether wearing a surgical mask increases the risk of heat stroke during mild exercise in such environment. Twelve participants conducted treadmill exercise for 30 min at 6 km/h, with 5% slope, 35°C ambient temperature, and 65% relative humidity, while wearing or not a surgical mask (mask and control trials, respectively). Rectal temperature (T_rec), ear canal temperature (T_ear), and mean skin temperature (mean T_skin) were assessed. Skin temperature and humidity of the perioral area of the face (T_face and RH_face) were also estimated. Thermal sensation and discomfort, sensation of humidity, fatigue, and thirst were rated using the visual analogue scale. T_rec, T_ear, mean T_skin, and T_face increased during the exercise, without any difference between the two trials. RH_face during the exercise was greater in the mask trial. Hot sensation was greater in the mask trial, but no influence on fatigue and thirst was found. These results suggest that wearing a surgical mask does not increase the risk of heat stroke during mild exercise in moist heat.

The present study aimed to determine the influence of estradiol (E2) and the interaction with circadian phases on thermoregulatory responses to mild heat in female rats. Heat loss and production during 3-h exposure to the environment at an ambient temperature of 28-34 °C were assessed by measuring abdominal temperature (Tabd), tail skin temperature, and oxygen consumption in ovariectomized rats with and without E2 replacement (OVX + E2 and OVX, respectively) and in control rats in the proestrus (P) and diestrus (D) phases. In the light phase, Tabd remained unchanged in all groups. Tabd increased in the dark phase, but was lower in the OVX + E2 and P groups than in the OVX and D groups. Oxygen consumption decreased at 34 °C, but to a lesser extent in the OVX + E2 group than in the OVX group. These results suggest that E2 activates thermoregulation in mild heat in the dark phase.

Chemokines are critical mediators of angiogenesis in several physiological and pathological conditions; however, a potential role for muscle-derived chemokines in exercise-stimulated angiogenesis in skeletal muscle remains poorly understood. Here, we postulated that the chemokine stromal cell-derived factor-1 (SDF-1α/C-X-C motif chemokine ligand 12: CXCL12), shown to promote neovascularization in several organs, contributes to angiogenesis in skeletal muscle. We found that CXCL12 is abundantly expressed in capillary-rich oxidative soleus and exercise-trained plantaris muscles. CXCL12 mRNA and protein were also abundantly expressed in muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α transgenic mice, which have a high proportion of oxidative muscle fibers and capillaries when compared with wild-type littermates. We then generated CXCL12 muscle-specific knockout mice but observed normal baseline capillary density and normal angiogenesis in these mice when they were exercise trained. To get further insight into a potential CXCL12 role in a myofiber-endothelial cell crosstalk, we first mechanically stretched C2C12 myotubes, a model known to induce stretch-related chemokine release, and observed increased CXCL12 mRNA and protein. Human umbilical vein endothelial cells (HUVECs) exposed to conditioned medium from cyclically stretched C2C12 myotubes displayed increased proliferation, which was dependent on CXCL12-mediated signaling through the CXCR4 receptor. However, HUVEC migration and tube formation were unaltered under these conditions. Collectively, our findings indicate that increased muscle contractile activity enhances CXCL12 production and release from muscle, potentially contributing to endothelial cell proliferation. However, redundant signals from other angiogenic factors are likely sufficient to sustain normal endothelial cell migration and tube formation activity, thereby preserving baseline capillary density and exercise training-mediated angiogenesis in muscles lacking CXCL12.

The conscious perception of thermal stimuli is divided into two categories: thermal sensation (i.e., discriminative component) and pleasantness/unpleasantness (i.e., hedonic component). There have been very few studies which clearly dissociated the two components. The aim of the present study was 1) to identify brain regions involved in perception of thermal stimuli per se, dissociating those related to the two components, and additionally 2) to examine brain regions of the explicit evaluation processes for the two components. Sixteen participants received local thermal stimuli of either 41.5 °C or 18.0 °C during whole-body thermal stimuli of 47.0 °C, 32.0 °C, or 17.0 °C. The local stimuli were delivered to the right forearm with the Peltier device. The whole-body stimuli delivered through a water-perfusion suit was aimed to modulate thermal pleasantness/unpleasantness to the local stimulus. The local stimulation at the same temperature was conducted five times with 30-s intervals. Brain activation was assessed by functional magnetic resonance imaging (fMRI), and the participants were asked to report their ratings of thermal sensation and pleasantness/unpleasantness following the cessation of each local stimulus. Local thermal stimulation activated specific brain regions such as the anterior cingulate cortex, insula, and inferior parietal lobe, irrespective of the temperature of local and whole-body stimuli; however, no specific activation for hot or cold sensation was observed. Different brain regions were associated with pleasantness and unpleasantness; the caudate nucleus and frontal regions for pleasantness, and the medial frontal and anterior cingulate cortex for unpleasantness. In addition, the explicit evaluation process for the discriminative and hedonic components immediately following the cessation of local stimulus involved different brain regions; the medial prefrontal cortex extending to the anterior cingulate cortex, insula, middle frontal cortex, and parietal lobes during the explicit evaluation of thermal sensation, and the medial prefrontal cortex, posterior cingulate cortex, and inferior parietal lobes during that of pleasantness/unpleasantness.

The aim of the present study was to clarify physical risks during hot-water bathing by measuring thermal and cardiovascular responses and thermal sensation. Young men and women (n = 7 and 5, respectively) participated in the present study, which consisted of two trials mimicking bathing behavior at room temperature of 25 °C and 15 °C. Participants bathed in 41 °C water for 20 min to the subclavian level. Before bathing, participants rested fully clothed for 15 min and then rested for 15 min without clothes. After bathing, they rested without clothes for 15 min and afterwards rested fully clothed for another 15 min. Tympanic temperature (Tty), heart rates (HR), mean skin temperature (Tsk), mean arterial pressure (MAP), and laser-Doppler flow at the chest and forehead (LDFhead and LDFchest) were evaluated. Thermal perception was assessed with a visual analogue scale. Mean Tsk in the 15 °C trial decreased during the period without clothing while MAP increased. The value remained unchanged in the 25 °C trial. During bathing, Tty, mean Tsk, HR, LDFhead, and LDFchest increased in both trials, and MAP decreased to similar levels. Relative change in LDFchest was greater in the 15 °C trial than in the 25 °C trial. Participants felt cold when they were without clothes at 15 °C; however, the thermal perception during bathing was similar between the two trials. Greater changes in cardiovascular and thermal responses were observed during the bathing behavior. In addition, bathing in cold room augmented the changes, which may induce some physical risks during bathing.

Fasted rats place their tails underneath their body trunks in the cold (tail-hiding behavior), which is a thermoregulatory behavior. The aim of the present study was to investigate the effect of fasting and des-acyl ghrelin, a hormone related to fasting, on tail-hiding behavior and neural activity in the cold. Wistar rats were divided into 'fed', '42-h fasting' and des-acyl ghrelin groups. The rats received an intraperitoneal saline or 30-μg des-acyl ghrelin injection, and were then exposed to 27 °C or 15 °C for 2-h with continuous body temperature (Tb), tail skin temperature (Ttail), and tail-hiding behavior measurements. cFos immunoreactive (cFos-IR) cells in the insula, secondary somatosensory cortex, medial preoptic nucleus, parastrial nucleus, amygdala, and lateral parabrachial nucleus were counted in four segments: seg1, 2, 3, and 4 (bregma -0.36, -1.44, -2.64, and -9.00 mm), respectively. At 15 °C, Tb and Ttail were lower in the 42-h fasting group than in the fed and des-acyl ghrelin groups, and the duration of tail-hiding behavior was longer in the 42-h fasting and des-acyl ghrelin groups than in the fed group. The onset of tail-hiding behavior more advanced in the des-acyl ghrelin group than in the fed group at 15 °C. Only at the insula in seg3 at 15 °C, the number of cFos-IR cells was greater in the 42-h fasting group than in the fed group. Both the 42-h fasting and des-acyl ghrelin groups might modulate the tail-hiding behavior of rats in a cold, and a part of the insula might be involved this response during fasting.

cFos expression in the preoptic area (PO), which is thermoregulatory center increased by both heat and cold exposures; however, the regional difference is unknown yet. We aimed to determine if cFos expression in the PO was regionally different between heat and cold exposures. Mice were exposed to 27, 10, or 38°C for 90min, and body temperature (Tb) was measured. cFos-immunoreactive (cFos-IR) cells in the PO were counted by separating the PO into the ventral and dorsal parts in the rostral (bregma 0.38mm), central (-0.10mm), and caudal (-0.46mm) planes. Tb at 10°C remained unchanged; however, it increased at 38°C. Counts of cFos-IR cells in all areas were greater at 38°C than at 27°C. In the dorsal and ventral parts of the central and the dorsal part of caudal PO, counts of cFos-IR cells were greater at 10°C than at 27°C. In conclusion, the areas of increased cFos expression in the PO in the heat were different that in the cold in mice.

The processes of thermoregulation are roughly divided into two categories: autonomic and behavioral. Behavioral thermoregulation alone does not have the capacity to regulate core temperature, as autonomic thermoregulation. However, behavioral thermoregulation is often utilized to maintain core temperature in a normal environment and is critical for surviving extreme environments. Thermal comfort, i.e., the hedonic component of thermal perception, is believed to be important for initiating and/or activating behavioral thermoregulation. However, the mechanisms involved are not fully understood. Thermal comfort is usually obtained when thermal stimuli to the skin restore core temperature to a regulated level. Conversely, thermal discomfort is produced when thermal stimuli result in deviations of core temperature away from a regulated level. Regional differences in the thermal sensitivity of the skin, hypohydration, and adaptation of the skin may affect thermal perception. Thermal comfort and discomfort seem to be determined by brain mechanisms, not by peripheral mechanisms such as thermal sensing by the skin. The insular and cingulate cortices may play a role in assessing thermal comfort and discomfort. In addition, brain sites involved in decision making may trigger behavioral responses to environmental changes.

We evaluated cold sensation at rest and in response to exercise-induced changes in core and skin temperatures in cold-sensitive exercise trained females. Fifty-eight trained young females were screened by a questionnaire, selecting cold-sensitive (Cold-sensitive, n = 7) and non-cold-sensitive (Control, n = 7) individuals. Participants rested in a room at 29.5°C for ~100 min after which ambient temperature was reduced to 23.5°C where they remained resting for 60 min. Participants then performed 30-min of moderate intensity cycling (50% peak oxygen uptake) followed by a 60-min recovery. Core and mean skin temperatures and cold sensation over the whole-body and extremities (fingers and toes) were assessed throughout. Resting core temperature was lower in the Cold-sensitive relative to Control group (36.4 ± 0.3 vs. 36.7 ± 0.2°C). Core temperature increased to similar levels at end-exercise (~37.2°C) and gradually returned to near preexercise rest levels at the end of recovery (>36.6°C). Whole-body cold sensation was greater in the Cold-sensitive relative to Control group during resting at a room temperature of 23.5°C only without a difference in mean skin temperature between groups. In contrast, cold sensation of the extremities was greater in the Cold-sensitive group prior to, during and following exercise albeit this was not paralleled by differences in mean extremity skin temperature. We show that young trained females who are sensitive to cold exhibit augmented whole-body cold sensation during rest under temperate ambient conditions. However, this response is diminished during and following exercise. In contrast, cold sensation of extremities is augmented during resting that persists during and following exercise.

Rats place their tails underneath their bodies in the cold (tail-hiding behavior), which is a behavioral indicator of thermoregulation. The aim of the present study was to elucidate the effect of estradiol (E2) on tail-hiding behavior and neural activity assessed by immunohistochemistry. Ovariectomized rats were implanted with a silastic tube with or without E2 underneath the dorsal skin (E2(-) and E2(+) groups), and exposed to 27°C, 16°C, and 10°C for 2h with continuous body temperature (Tb), tail skin temperature (Ttail), and behavioral measurements. cFos immunoreactive (cFos-IR) cells in the insula, secondary somatosensory cortex, medial preoptic nucleus, parastrial nucleus, amygdala, and lateral parabrachial nucleus were counted. Tb and Ttail were not different between the E2(-) and E2(+) groups. At 16°C, the duration and the onset of tail-hiding behavior in the E2(+) group were greater than that in the E2(-) group. The number of cFos-IR cells in the insula of the E2(-) group was greater than that of the E2(+) group in rats kept at 16°C. E2 might modulate tail-hiding behavior of female rats at 16°C, and the insula may be involved in the response.

BACKGROUND: The aims of this study were to (1) evaluate whether recently introduced methods of measuring axillary temperature are reliable, (2) examine if individuals know their baseline body temperature based on an actual measurement, and (3) assess the factors affecting axillary temperature and reevaluate the meaning of the axillary temperature. METHODS: Subjects were healthy young men and women (n = 76 and n = 65, respectively). Three measurements were obtained: (1) axillary temperature using a digital thermometer in a predictive mode requiring 10 s (T ax-10 s), (2) axillary temperature using a digital thermometer in a standard mode requiring 10 min (T ax-10 min), and (3) tympanic membrane temperature continuously measured by infrared thermometry (T ty). The subjects answered questions about eating and exercise habits, sleep and menstrual cycles, and thermoregulation and reported what they believed their regular body temperature to be (T reg). RESULTS: T reg, T ax-10 s, T ax-10 min, and T ty were 36.2 ± 0.4, 36.4 ± 0.5, 36.5 ± 0.4, and 36.8 ± 0.3 °C (mean ± SD), respectively. There were correlations between T ty and T ax-10 min, T ty and T ax-10 s, and T ax-10 min and T ax-10 s (r = .62, r = .46, and r = .59, respectively, P < .001), but not between T reg and T ax-10 s (r = .11, P = .20). A lower T ax-10 s was associated with smaller body mass indices and irregular menstrual cycles. CONCLUSIONS: Modern devices for measuring axillary temperature may have changed the range of body temperature that is recognized as normal. Core body temperature variations estimated by tympanic measurements were smaller than those estimated by axillary measurements. This variation of axillary temperature may be due to changes in the measurement methods introduced by modern devices and techniques. However, axillary temperature values correlated well with those of tympanic measurements, suggesting that the technique may reliably report an individual's state of health. It is important for individuals to know their baseline axillary temperature to evaluate subsequent temperature measurements as normal or abnormal. Moreover, axillary temperature variations may, in part, reflect fat mass and changes due to the menstrual cycle.

Background: The aims of this study were to (1) evaluate whether recently introduced methods of measuring axillary temperature are reliable, (2) examine if individuals know their baseline body temperature based on an actual measurement, and (3) assess the factors affecting axillary temperature and reevaluate the meaning of the axillary temperature.
Methods: Subjects were healthy young men and women (n= 76 and n = 65, respectively). Three measurements were obtained: (1) axillary temperature using a digital thermometer in a predictive mode requiring 10 s (Tax-10 s), (2) axillary temperature using a digital thermometer in a standard mode requiring 10 min (Tax-10 min), and (3) tympanic membrane temperature continuously measured by infrared thermometry (T-ty). The subjects answered questions about eating and exercise habits, sleep and menstrual cycles, and thermoregulation and reported what they believed their regular body temperature to be (T-reg).
Results: T-reg, Tax-10 s, Tax-10 min, and T-ty were 36.2 +/- 0.4, 36.4 +/- 0.5, 36.5 +/- 0.4, and 36.8 +/- 0.3 degrees C (mean +/- SD), respectively. There were correlations between T-ty and Tax-10 min, T-ty and Tax-10 s, and Tax-10 min and Tax-10 s (r = .62, r = .46, and r = .59, respectively, P &lt; .001), but not between T-reg and Tax-10 s (r = .11, P = .20). A lower Tax-10 s was associated with smaller body mass indices and irregular menstrual cycles.
Conclusions: Modern devices for measuring axillary temperature may have changed the range of body temperature that is recognized as normal. Core body temperature variations estimated by tympanic measurements were smaller than those estimated by axillary measurements. This variation of axillary temperature may be due to changes in the measurement methods introduced by modern devices and techniques. However, axillary temperature values correlated well with those of tympanic measurements, suggesting that the technique may reliably report an individual's state of health. It is important for individuals to know their baseline axillary temperature to evaluate subsequent temperature measurements as normal or abnormal. Moreover, axillary temperature variations may, in part, reflect fat mass and changes due to the menstrual cycle.

Hyperosmolality in extracellular fluid in humans attenuates autonomic thermoregulation in heat, such as sweating and blood flow in the skin. However, exercise training minimizes the attenuation. The aim of the present study was to clarify the influence of hyperosmolality on thermal perception and to assess the training effect of exercise. Ten sedentary (SED) and 10 endurance-trained (TR) healthy young men were infused with 0.9% (normal saline [NS]) or 3% NaCl (hypertonic saline [HS]) for 120min on two separate days. After infusion for 20min, heat stimulus to the skin of the whole body was produced by a gradual increase in hot water-perfused suit temperature (33°C, 36°C, and 39°C), which was first used in the normothermic condition and then in the mild hyperthermic condition (0.5-0.6°C increase in esophageal temperature) and controlled by immersion of the lower legs in a water bath at 34.5°C and 42°C, respectively. Thermal sensation and comfort were rated at the time of each thermal condition. Plasma osmolality increased by ~10mosmL/kg·H2O in the HS trial. In the mild hyperthermic condition, increases in sweat rate and cutaneous vascular conductance were lower in the HS than in the NS trial in both the SED and TR groups (p<0.05). In the SED group, thermal sensation in the mild hyperthermic condition was lower in the HS than in the NS trial (p<0.05); there was no significant difference between the trials in the TR group. These results might indicate that hyperosmolality attenuates thermal sensation with heat and that exercise training eliminates the attenuation.

Thermoregulation is categorized as either autonomic (i.e., sweating, shivering) or behavioral (i.e., wearing clothes, usage of air conditioner) thermoregulation. Compared to autonomic thermoregulation, the neural pathway of behavioral thermoregulation in cold environments remains unclear. A decrease in ambient temperature is perceived through thermoreceptors for detecting cold, including transient receptor potential (TRP) channels, such as TRPM8 and TRPA1, which are expressed in the sensory nerve endings of the skin. From these receptors, nerves connect to the dorsal root ganglion and dorsal horn in the spinal cord, and arrive at the lateral parabrachial nucleus in the pons, which is the same neural pathway that is used for autonomic thermoregulation. Following this, an unknown neural pathway induces thermoregulatory behavior, such as cold-escape behavior. Both young and climacteric women complain of an unpleasant thermal comfort, which is attributed to &quot;hie-sho&quot; (chill or poor blood circulation). The altered thermal sensation and comfort by an absence or a fluctuation of estrogen (E2) may modulate behavioral thermoregulation in females. This effect is unknown in women. However, in

We assessed the relationship between core temperature (Tc) and sleep rhythms in mice, and examined the effects of ambient temperature and fasting. Tc, electroencephalograms (EEG), electromyograms (EMG), and spontaneous activity in male ICR mice (n=9) were measured by telemetry for 3 days under a 12:12h dark-light cycle. Mice were fed or fasted at an ambient temperature (Ta) of 27°C or 20°C for the final 30h of the experiment. The vigilance state was categorized into a wake state, rapid-eye movement (REM) sleep, and non-REM (NREM) sleep, and the total sleep time (TST) was assessed. Relationships between Tc and TST, NREM periods, and REM sleep were estimated using Pearson's correlation coefficient. During cold exposure, Tc decreased during the dark and light phases, and TST and the periods of NREM and REM sleep decreased during the dark phase. Throughout the fasting period, Tc also decreased during the dark and light phases. Furthermore, the decrease in Tc was augmented when fasting and cold were combined. TST and NREM sleep periods decreased in the light and dark phases, respectively, whereas REM sleep periods decreased in both phases. Negative linear correlations (r=-0.884 to -0.987) were observed between Tc and TST, NREM sleep periods, and REM sleep periods, except for Tc and REM sleep periods where fasting and cold conditions were combined. The correlations between sleep and Tc rhythms were well maintained during cold exposure and fasting. However, when cold and fasting were combined, REM sleep and Tc rhythms were desynchronized.

We investigated the effects of menstrual cycle phase on thermal sensation, thermal pleasantness, and autonomic thermoregulatory responses during mild cold exposure. Eight healthy young women participated. Experiments were conducted in the follicular and luteal phases: 120 min exposure at 23.5 °C after 40-min at a baseline temperature of 29 °C. Body core temperature was higher (P = 0.01) in the luteal phase than in the follicular phase. Thermal sensation of the whole body (P = 0.59), hands (P = 0.46), and toes (P = 0.94), and thermal pleasantness of the whole body (P = 0.79) were no different between phases. In both phases, mean skin temperature decreased (P = 0.00) in the same manner without any change in metabolic rate (P = 0.90). These results suggest the change of body core temperature in the menstrual cycle phases has no effect on thermal perception of cold or on autonomic cold-defense response.

It has been speculated that the control of core temperature is modulated by physiological demands. We could not prove the modulation because we did not have a good method to evaluate the control. In the present study, the control of core temperature in mice was assessed by exposing them to various ambient temperatures (Ta), and the influence of circadian rhythm and feeding condition was evaluated. Male ICR mice (n=20) were placed in a box where Ta was increased or decreased from 27°C to 40°C or to -4°C (0.15°C/min) at 0800 and 2000 (daytime and nighttime, respectively). Intra-abdominal temperature (Tcore) was monitored by telemetry. The relationship between Tcore and Ta was assessed. The range of Ta where Tcore was relatively stable (range of normothermia, RNT) and Tcore corresponding to the RNT median (regulated Tcore) were estimated by model analysis. In fed mice, the regression slope within the RNT was smaller in the nighttime than in the daytime (0.02 and 0.06, respectively), and the regulated Tcore was higher in the nighttime than in the daytime (37.5°C and 36.0°C, respectively). In the fasted mice, the slope remained unchanged, and the regulated Tcore decreased in the nighttime (0.05 and 35.9°C, respectively), while the slopes in the daytime became greater (0.13). Without the estimating individual thermoregulatory response such as metabolic heat production and skin vasodilation, the analysis of the Ta-Tcore relationship could describe the character of the core temperature control. The present results show that the character of the system changes depending on time of day and feeding conditions.

Cold defense mechanisms in mice are attenuated in the light phase during fasting, resulting in hypothermia. The present study examined whether specific neurons and areas in the SCN are related to the response. Mice were fasted over 47h or remained fed, during which they were placed at 20 or 27°C for 3h in the light or dark phases. Body temperature (Tb) was monitored. After the exposure, immunoreactive (IR) cells of cFos, arginine vasopressin (AVP), and vasoactive intestinal polypeptide (VIP) in the SCN were assessed. Tb at 20°C during fasting was lower in the light phase than in the dark phase. Both AVP/cFos-IR and VIP/cFos-IR cells increased when mice were at 20°C during fasting in the light phase. Such increase was observed in the central part of the SCN. These responses in the SCN may be related to the hypothermia in the light phase.

In homeothermic animals, metabolic heat production in the brain is higher than in other tissues. However, cerebral tissue is susceptible to heat. Several animals have mechanisms that selectively cool the brain during hyperthermia (i.e., selective brain cooling [SBC]). Carotid retes have been well documented in artiodactyls (hoofed animals) and felids (cats) as mechanisms of SBC. SBC has also been found in some species without carotid retes, such as horses and squirrel monkeys. However, the presence of SBC in humans remains controversial. Brain temperature cannot be directly measured in healthy subjects; therefore, tympanic temperature has been used to estimate brain temperature. However, tympanic temperature is reportedly affected by facial skin temperature. We recently investigated the effect of facial fanning on tympanic and esophageal temperature in normothermic and hyperthermic humans. The results showed that tympanic temperature is not affected by the facial skin temperature under normothermic conditions and that facial fanning may induce SBC under hyperthermic conditions. Regional differences in thermal comfort are present over the body surface in humans, i.e. humans prefer a cool head in the heat and a warm abdomen in the cold. Therefore, preference for a low facial temperature may activate SBC. Several recent studies have demonstrated that whole-brain temperature can be measured noninvasively with proton magnetic resonance spectroscopy. The existence of a thermal gradient within the brain has been suggested. Studies measuring whole-brain temperature will reveal the details of human SBC.

In a previous study, we investigated the contribution of the surface of the face, chest, abdomen, and thigh to thermal comfort by applying local temperature stimulation during whole-body exposure to mild heat or cold. In hot conditions, humans prefer a cool face, and in cold they prefer a warm abdomen. In this study, we extended investigation of regional differences in thermal comfort to the neck, hand, soles, abdomen (Experiment 1), the upper and lower back, upper arm, and abdomen (Experiment 2). The methodology was similar to that used in the previous study. To compare the results of each experiment, we utilized the abdomen as the reference area in these experiments. Thermal comfort feelings were not particularly strong for the limbs and extremities, in spite of the fact that changes in skin temperature induced by local temperature stimulation of the limbs and extremities were always larger than changes that were induced in the more proximal body parts. For the trunk areas, a significant difference in thermal comfort was not observed among the abdomen, and upper and lower back. An exception involved local cooling during whole-body mild cold exposure, wherein the most dominant preference was for a warmer temperature of the abdomen. As for the neck and abdomen, clear differences were observed during local cooling, while no significant difference was observed during local warming. We combined the results for the current and the previous study, and characterized regional differences in thermal comfort and thermal preference for the whole-body surface.

Fasted mice show torpor-like hypothermia in the cold in their inactive phase. The aim of the present study was to elucidate whether leptin and/or ghrelin are involved in this reaction and to identify its neurophysiological mechanisms. In ob/ob mice, which lack leptin, metabolic heat production (oxygen consumption, Vo(2)) was suppressed in 20°C cold in both the light and dark phases, resulting in hypothermia. When wild-type mice received a systemic injection of 8 µg ghrelin in the early light phase, followed by a 2-h cold exposure to 10°C, their core body temperature (T(b)) decreased by 1.7°C, and they displayed a less marked increase in Vo(2) compared with vehicle-injected mice. However, ghrelin injection in the early dark phase resulted in the maintenance of T(b) and increased Vo(2) in the mice, which was similar to the result observed in the vehicle-injected mice. The number of doubly labeled neurons with cFos and neuropeptide Y (NPY) in the suprachiasmatic nucleus was greater in the light phase in the ghrelin-injected mice, which may suggest that ghrelin activates NPY neurons. On the contrary, in the paraventricular nucleus, the counts became greater only when they were exposed to the cold in the dark phase. These results indicate that ghrelin plays an important role in inducing time-dependent changes in thermoregulation in the cold via hypothalamic pathways.

Rats place their tails underneath their body trunks when cold (tail-hiding behavior). The aim of the present study was to determine whether this behavior is necessary to maintain body temperature. Male Wistar rats were divided into 'fed' and '42-h fasting' groups. A one-piece tail holder (8.4 cm in length) that prevented the tail-hiding behavior or a three-piece tail holder (2.8 cm in length) that allowed for the tail-hiding behavior was attached to the tails of the rats. The rats were exposed to 27°C for 180 min or to 20°C for 90 min followed by 15°C for 90 min with continuous body temperature and oxygen consumption measurements. Body temperature decreased by -1.0 ± 0.1°C at 15°C only in the rats that prevented tail-hiding behavior of the 42-h fasting group, and oxygen consumption increased at 15°C in all animals. Oxygen consumption was not different between the rats that prevented tail-hiding behavior and the rats that allowed the behavior in the fed and 42-h fasting groups under ambient conditions. These results show that the tail-hiding behavior is involved in thermoregulation in the cold in fasting rats.

Most animals can adapt physiologically and biochemically when exposed to altered temperatures for prolonged periods. In humans, marked physiological adjustments are apparent following repeated bouts of core temperature elevation, either from exercise, or high ambient environmental temperatures, or both. In this review, the mechanisms for such adjustments, called "heat acclimation", are discussed. First, the authors focus on thermoregulatory responses in the process of heat acclimation, i.e. how thermoregulation adapts to changes in temperature following repeated exposure to heat and exercise. Once heat acclimation is achieved, skin vasodilation and sweating are initiated at a lower core temperature threshold, and higher sweat rates can be sustained. Second, knowledge regarding the central and peripheral mechanisms for heat acclimation and tolerance is discussed. Recently, two advances - the implication that long-term accommodation to a changing environment involves functional neuronal remodeling associated with transcriptional reprogramming, and the understanding that there is neurogenesis in the hypothalamus - have introduced new concepts to the study of heat acclimation. Although it is still a developing issue, future study will bridge the gap between the classical physiological heat acclimation profile and molecular and cellular mechanisms.

We evaluated the effect of plasma hyperosmolality on behavioral thermoregulation in mice, using a new experimental system. The system consisted of Plexiglas box (dimensions: 50×12×19 cm) with five computer-controlled Peltier boards (dimensions: 10×10 cm) at the bottom. Experiments were conducted in two different settings of the system. An operant behavior setting: each board was first set to 39°C, and the right-end board was changed to 20°C for 1 min when a mouse moved to a specific position. A temperature mosaic setting: each board was randomly set to 15°C, 22°C, 28°C, 35°C, or 39°C with a 6-min interval, but each board temperature was different from the others at a given time point. Mice were injected subcutaneous (s.c.) isotonic or hypertonic saline (154 mM (IS group) or 2,500 mM (HS group), 10 ml/kg body wt), and exposed to either setting for 90 min. In the operant setting, the HS group showed fewer operant behavior counts than the IS group (11±5 and 25±4 counts, respectively; P<0.05) with greater increase in body temperature (1.6±0.4°C vs. 0.0±0.2°C, respectively; P<0.05). In the mosaic setting, the HS group selected the board temperature of 35°C more frequently than the other temperatures (P<0.05) with the same increase in body temperature. These results may suggest that plasma hyperosmolality modulates behavioral thermoregulatory response to heat and induce regulated hyperthermia.

Humans have physiological, intellectual, and cultural capabilities to maintain viable body temperatures under several conditions. We do exercise in daily living for labor, health, and just fun. However, exercise is one of the strong factors disturbing the maintenance of body temperature. Some conditions, such as heavy exercise in thermal extremes, could rapidly lead to dangerous internal temperatures. Body temperature constancy is achieved by two major processes: i) behavioral processes of maintaining or searching for a preferable environment and ii) autonomic processes, e.g. vasodilation of the skin, sweating and shivering. The thermal load posed by the environment or by heavy exercise may be too great for the capacity of the regulators. Or, the regulator could be deranged due to extreme temperatures. Accidents during exercise often involve a compromise of many aspects of thermal balance; and an altered body temperature is very likely. In the present review, recent knowledge is looked at about the thermoregulation system, focusing on its defense mechanisms against the thermal load due to exercise and pathophysiological reasons for incidences of abnormal body temperature during exercise.

The sympathetic thermoregulatory system controls the magnitude of adaptive thermogenesis in correspondence with the environmental temperature or the state of energy intake and plays a key role in determining the resultant energy storage. However, the nature of the trigger initiating this reflex arc remains to be determined. Here, using capsiate, a digestion-vulnerable capsaicin analog, we examined the involvement of specific activation of transient receptor potential (TRP) channels within the gastrointestinal tract in the thermogenic sympathetic system by measuring the efferent activity of the postganglionic sympathetic nerve innervating brown adipose tissue (BAT) in anesthetized rats. Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated BAT sympathetic nerve activity (SNA) over 180 min, which was characterized by an emergence of sporadic high-activity phases composed of low-frequency bursts. This increase in BAT SNA was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of SNA was delimited to BAT and did not occur in the heart or pancreas. These results point to a neural pathway enabling the selective activation of the central network regulating the BAT SNA in response to a specific stimulation of gastrointestinal TRP channels and offer important implications for understanding the dietary-dependent regulation of energy metabolism and control of obesity.

The present study examined the effect of the central administration of estrogen on responses to the cold. Estrogen or cholesterol was applied locally to the medial preoptic nucleus (MPO) or dorsomedial hypothalamic nucleus (DMH) of the hypothalamus in free-moving ovariectomized rats. Forty-eight hours after the application, rats had 2-h exposure at 10 or 25 degrees C. Body temperature (T(b)) and the tail surface temperature (T(tail)) were continuously measured by telemetry and thermography, respectively. The change of T(b) at 10 degrees C from the 25 degrees C baseline was higher in the estrogen application in the MPO than that in the cholesterol application; however, such difference was not observed in the DMH application. The uncoupling 1 protein mRNA level in the interscapular brown adipose tissue involved in non-shivering thermogenesis was not different between the estrogen and cholesterol applications in the MPO and DMH. T(tail) decreased in the cold, which was greater after the estrogen application in the MPO than after the cholesterol application. These results show that estrogen affects the MPO in female rats, changing T(b) in the cold. Moreover, suppression of heat loss from the tail may be involved in the mechanism.

:The present study examined the effect of the central administration of estrogen on responses to the cold. Estrogen or cholesterol was applied locally to the medial preoptic nucleus (MPO) or dorsomedial hypothalamic nucleus (DMH) of the hypothalamus in free-moving ovariectomized rats. Forty-eight hours after the application, rats had 2-h exposure at 10 or 25 degrees C. Body temperature (T(b)) and the tail surface temperature (T(tail)) were continuously measured by telemetry and thermography, respectively. The change of T(b) at 10 degrees C from the 25 degrees C baseline was higher in the estrogen application in the MPO than that in the cholesterol application; however, such difference was not observed in the DMH application. The uncoupling 1 protein mRNA level in the interscapular brown adipose tissue involved in non-shivering thermogenesis was not different between the estrogen and cholesterol applications in the MPO and DMH. T(tail) decreased in the cold, which was greater after the estrogen application in the MPO than after the cholesterol application. These results show that estrogen affects the MPO in female rats, changing T(b) in the cold. Moreover, suppression of heat loss f

Hypohydration caused by exercise in the heat attenuates autonomic thermoregulation such as sweating and skin blood flow in humans. In contrast, it remains unknown if behavioral thermoregulation is modulated during hypohydration. We assume that thermal unpleasantness could drive the behavioral response, and would also be modulated during hypohydration. Nine healthy young men participated in the present study. Body and skin temperatures were monitored. Ratings of thermal sensation and pleasantness were conducted. After approximately 45 min rest at 27 degrees C, they performed 50-min cycling exercise, which was at the level of 40% of heart rate range at 35 degrees C (hypohydration trial) or at the level of 10% of heart rate range at 23 degrees C (control trial), respectively. Subjects returned to the rest at 27 degrees C, and the ambient temperature was then changed from 22 to 38 degrees C. Body weight decreased by 0.9+/-0.1% immediately after exercise in the hypohydration trial and 0.3+/-0.1% in the control trial. In the cold, no significant difference in thermal sensation or pleasantness was observed between trials. There was no significant difference in thermal pleasantness between trials in the heat, although thermal sensation in the heat (32.5-36 degrees C) was significantly lower in the hypohydration trial than in the control trial. In addition, laser Doppler flow of the skin and sweat rate were attenuated in the heat in the hypohydration trial. These results may indicate that mild hypohydration after exercise in the heat has no influence on behavioral responses to the heat.

We would like to emphasize about the system involved with homeostatic maintenance of body temperature. First, the primary mission of the thermoregulatory system is to defend core temperature (T (core)) against changes in ambient temperature (T (a)), the most frequently encountered disturbance for the system. T (a) should be treated as a feedforward input to the system, which has not been adequately recognized by thermal physiologists. Second, homeostatic demands from outside the thermoregulatory system may require or produce an altered T (core), such as fever (demand from the immune system). There are also conditions where some thermoregulatory effectors might be better not recruited due to demands from other homeostatic systems, such as during dehydration or fasting. Third, many experiments have supported the original assertion of Satinoff that multiple thermoregulatory effectors are controlled by different and relatively independent neuronal circuits. However, it would also be of value to be able to characterize strictly regulatory properties of the entire system by providing a clear definition for the level of regulation. Based on the assumption that T (core) is the regulated variable of the thermoregulatory system, regulated T (core) is defined as the T (core) that pertains within the range of normothermic T (a) (Gordon in temperature and toxicology: an integrative, comparative, and environmental approach, CRC Press, Boca Raton, 2005), i.e., the T (a) range in which an animal maintains a stable T (core). The proposed approach would facilitate the categorization and evaluation of how normal biological alterations, physiological stressors, and pathological conditions modify temperature regulation. In any case, of overriding importance is to recognize the means by which an alteration in T (core) (and modification of associated effector activities) increases the overall viability of the organism.

The aim of this study was to determine whether estrogen modulates central and peripheral responses to cold in female rats. In ovariectomized female rats with and without administered estrogen [E(2) (+) and E(2) (-), respectively], the counts of cFos-immunoreactive cells in the medial preoptic nucleus (MPO) and dorsomedial hypothalamic nucleus (DMH) in the hypothalamus were greater in the E(2) (+) rats than in the E(2) (-) rats at 5 degrees C. Examination of the response of normal female rats to exposure to 5 degrees C at different phases of the estrus cycle revealed that counts of cFos-immunoreactive cells in the MPO, DMH, and posterior hypothalamus and the level of uncoupling protein 1 mRNA in the brown adipose tissues were greater in the proestrus phase than on day 1 of the diestrus phase. This result was linked to the level of plasma estrogen. The body temperature during cold exposure was higher in the E(2) (+) rats than in the E(2) (-) rats and was also higher in the proestrus phase than on day 1 of the diestrus phase. We conclude that estrogen may affect central and peripheral responses involved in thermoregulation in the cold.

The circadian rhythm of body temperature (Tb) is a well-known phenomenon. However, it is unknown how the circadian system including the suprachiasmatic nucleus (SCN) and clock genes affects thermoregulation. Food deprivation in mice induces a greater reduction of Tb particularly in the light phase. We examined the role of Clock, one of key clock genes and the SCN during induced hypothermia. At 20 °C with fasting, mice increased their metabolic heat production in the dark phase and maintained Tb, whereas in the light phase, heat production was less, resulting in hypothermia. Under these conditions, neuronal activity in the SCN, assessed by cFos expression, increased only in the light phase. However, such differences in thermoregulatory and neural responses between the phases in Clock mutant mice were less marked. The neural network between the SCN and paraventricular nucleus appeared to be important in hypothermia. These findings suggest that the circadian system per se is influenced by both the feeding condition and environmental temperature and that it modulates thermoregulation. © 2009 IBRO.

Sensations evoked by thermal stimulation (temperature-related sensations) can be divided into two categories, "temperature sensation" and "thermal comfort." Although several studies have investigated regional differences in temperature sensation, less is known about the sensitivity differences in thermal comfort for the various body regions. In the present study, we examined regional differences in temperature-related sensations with special attention to thermal comfort. Healthy male subjects sitting in an environment of mild heat or cold were locally cooled or warmed with water-perfused stimulators. Areas stimulated were the face, chest, abdomen, and thigh. Temperature sensation and thermal comfort of the stimulated areas were reported by the subjects, as was whole body thermal comfort. During mild heat exposure, facial cooling was most comfortable and facial warming was most uncomfortable. On the other hand, during mild cold exposure, neither warming nor cooling of the face had a major effect. The chest and abdomen had characteristics opposite to those of the face. Local warming of the chest and abdomen did produce a strong comfort sensation during whole body cold exposure. The thermal comfort seen in this study suggests that if given the chance, humans would preferentially cool the head in the heat, and they would maintain the warmth of the trunk areas in the cold. The qualitative differences seen in thermal comfort for the various areas cannot be explained solely by the density or properties of the peripheral thermal receptors and thus must reflect processing mechanisms in the central nervous system.

We investigated the effects of alcohol on thermoregulatory responses and thermal sensations during cold exposure in humans. Eight healthy men (mean age 22.3+/-0.7 year) participated in this study. Experiments were conducted twice for each subject at a room temperature of 18 degrees C. After a 30-min resting period, the subject drank either 15% alcohol at a dose of 0.36 g/kg body weight (alcohol session) or an equal volume of distilled water (control session), and remained in a sitting position for another 60 min. Mean skin temperature continued to decrease and was similar in control and alcohol sessions. Metabolic rate was lower in the alcohol session, but the difference did not affect core temperature, which decreased in a similar manner in both alcohol and control sessions (from 36.9+/-0.1 degrees C to 36.6+/-0.1 degrees C). Whole body sensations of cold and thermal discomfort became successively stronger in the control session, whereas these sensations were both greatly diminished after drinking alcohol. In a previous study we performed in the heat, using a similar protocol, alcohol produced a definite, coordinated effect on all autonomic and sentient heat loss effectors. In the current study in the cold, as compared to responses in the heat, alcohol intake was followed by lesser alterations in autonomic effector responses, but increased changes in sensations of temperature and thermal discomfort. Overall, our results indicate that although alcohol influences thermoregulation in the cold as well as in the heat, detailed aspects of the influence are quite different.

Introduction Dehydration attenuates autonomic thermoregulation in the heat such as sweating and skin blood flow in human. Hyperosmolality in the extracellular fluid is thought to be involved in this mechanism. In contrast, behavioral thermoregulation (i.e. heat escape behavior) is augmented after hypertonic saline injection in rats (Nagashima et al., Am J Physiol 2001). However, it remains unknown if human activate behavioral thermoregulation during dehydration. Methods Ten healthy young men participated in the present study. Body and skin temperature were monitored. Rating for thermal sensation and comfort were conducted. After 45 min rest at 27&deg;C, they did 50 min ergometer exercise, which was at the level of 40% peak VO₂ or 15% peak VO₂ at an ambient temperature of 35&deg;C or 24&deg;C, respectively. Subjects returned to the rest at 27&deg;C until body and skin temperature being restored. Ambient temperature was then changed from 22&deg;C to 38&deg;C. Results Body weight decreased by 1.1 &plusmn; 0.1% after the exercise at 35&deg;C and 0.2 &plusmn; 0.1% at 24&deg;C. Plasma osmolality increased by 6 &plusmn; 1 mosmol/kg H₂O at 35&deg;C, but did not change at &sim;24&deg;C. Thermal sensation and comfort in the heat were augmented (i.e. feeling hotter and more uncomfortable) after the exercise at 35&deg;C. Conclusion Dehydration increases thermal sensation and comfort in the heat in human, which are closely related to behavioral thermoregulation. [J Physiol Sci. 2008;58 Suppl:S103]

We tested the hypothesis that peripheral vascular responses (in the lower and upper limbs) to application of lower body positive pressure (LBPP) are dependent on the posture of the subjects. We measured heart rate, stroke volume, mean arterial pressure, leg and forearm blood flow (using the Doppler ultrasound technique), and leg (LVC) and forearm (FVC) vascular conductance in 11 subjects (9 men, 2 women) without and with LBPP (25 and 50 mmHg) in supine and upright postures. Mean arterial pressure increased in proportion to increases in LBPP and was greater in supine than in upright subjects. Heart rate was unchanged when LBPP was applied to supine subjects but was reduced in upright ones. Leg blood flow and LVC were both reduced by LBPP in supine subjects [LVC: 4.8 (SD 4.0), 3.6 (SD 3.5), and 1.4 (SD 1.8) ml.min(-1).mmHg(-1) before LBPP and during 25 and 50 mmHg LBPP, respectively; P < 0.05] but were increased in upright ones [LVC: 2.0 (SD 1.2), 3.4 (SD 3.4), and 3.0 (SD 2.0) ml.min(-1).mmHg(-1), respectively; P < 0.05]. Forearm blood flow and FVC both declined when LBPP was applied to supine subjects [FVC: 1.3 (SD 0.6), 1.0 (SD 0.4), and 0.9 (SD 0.6) ml. min(-1).mmHg(-1), respectively; P < 0.05] but remained unchanged in upright ones [FVC: 0.7 (SD 0.4), 0.7 (SD 0.4), and 0.6 (SD 0.5) ml.min(-1).mmHg(-1), respectively]. Together, these findings indicate that the leg vascular response to application of LBPP is posture dependent and that the response differs in the lower and upper limbs when subjects assume an upright posture.

INTRODUCTION It is well known that body temperature in female is closely linked with menstrual cycle. We reported that estrogen affects thermal regulation in rats: 1) estrogen is involved in circadian body temperature rhythm; 2) estrogen has an important role in thermal regulation in both the heat and cold. Moreover, in human beings, not a small population of females experiences some troubles in thermoregulation such as hot flash or cold sensation. Estrogen replacement therapy is sometimes effective for the females. In this study, we hypothesized that there would be differences in thermoregulation and thermal sensation, depending of menstruation cycle. METHOSDS and RESULTS Eight female subjects with a regular menstruation participated in this study. Experiments were conducted twice for each subject in follicular (F) and luteal (L) phases, determined by basal body temperature. Experimental condition was 120-min exposure at 23.5&deg;C after a 40-min baseline at 29.5&deg;C. Mean skin temperature decreased and body core temperature increased in both F and L during the 23.5&deg;C exposure. Oxygen consumption also increased in F and L. Based on rating scores for thermal sensation and comfort, L enhanced both coldness and unpleasantness when ambient temperature changed from 29.5&deg;C to 23.5&deg;C. COMCLUSION Although the autonomic thermal regulation seems to be similar between F and L, the menstrual phase may have an influence on thermal sensation or comfort. Estrogen may be involved in this mechanism. [J Physiol Sci. 2007;57 Suppl:S183]

Systemic salt loading has been reported to facilitate operant heat-escape/cold-seeking behavior. In the present study, we hypothesized that the median preoptic nucleus (MnPO) would be involved in this mechanism. Rats were divided into two groups (n = 6 each): one group had the MnPO lesion with ibotenic acid (4.0 mug) and the other was the vehicle control. After subcutaneous injection (10 ml/kg) of either isotonic- (154 mM) or hypertonic-saline (2,500 mM), each rat was placed in a behavior box, where the ambient temperature was changed to 26 degrees C, 35 degrees C, and 40 degrees C every 1 h. The position of a rat in the box and the body core temperature (T(core)) were monitored. A rat could trigger 0 degrees C air for 45 s in the 35 degrees C and 40 degrees C heat when moved in a specific area in the box (operant behavior). In the control group, counts of the operant behavior were greater (P < 0.05) in the hypertonic- than in the isotonic-saline injection (17 +/- 2 and 10 +/- 2 at 35 degrees C, 24 +/- 2 and 18 +/- 1 at 40 degrees C). T(core) remained unchanged throughout the exposure, although the level was lower (P < 0.05) in the hypertonic- than in the isotonic-saline trial (36.6 +/- 0.2 degrees C and 37.4 +/- 0.1 degrees C at 26 degrees C and 36.9 +/- 0.2 degrees C and 37.4 +/- 0.1 degrees C at 40 degrees C, respectively). However, in the MnPO-lesion group, counts of the behavior were similar between the hypertonic- and isotonic-saline injection trials (10 +/- 2 and 8 +/- 1 at 35 degrees C, and 17 +/- 1 and 16 +/- 1 at 40 degrees C, respectively). T(core) increased (P < 0.05) in the heat in both trials (36.8 +/- 0.1 degrees C and 37.4 +/- 0.1 degrees C at 26 degrees C and 37.4 +/- 0.2 degrees C and 37.8 +/- 0.2 degrees C at 40 degrees C in the hypertonic- and isotonic-saline injection trials, respectively). These results may suggest that, at least in part, the MnPO is involved in the facilitation of heat-escape/cold-seeking behavior during osmotic stimulation.

We report a new system for monitoring sensations of many body parts as well as comprehensively showing the distribution of overall skin temperature (T(sk)) and temperature-related sensations. The system consists of a console with 52 levers to report temperature-related sensations and software that facilitates the visualization of the distribution of T(sk) and temperature-related sensations by displaying them on a model of the human body. The system's utility was demonstrated with a physiological experiment involving three males and three females. They were exposed to step changes of ambient temperature from 23 degrees C to 33 degrees C. We measured T(sk) at 50 points, and the subjects concurrently provided estimates of local temperature sensation and thermal comfort/discomfort at 25 loci. This system greatly facilitates the perception and analysis of spatial relationships and differences in temperature and sensation in various areas of the body.

Homeothermic animals regulate body temperature by autonomic and behavioral thermoeffector responses. The regulation is conducted mainly in the brain. Especially, the preoptic area (PO) in the hypothalamus plays a key role. The PO has abundant warm-sensitive neurons, sending excitatory signals to the brain regions involved in heat loss mechanisms, and inhibitory signals to those involved in heat production mechanisms. The sympathetic fibers determine tail blood flow in rats, which is an effective heat loss process. Some areas in the midbrain and medulla are involved in the control of tail blood flow. Recent study also showed that the hypothalamus is involved in heat escape behavior in rats. However, our knowledge about behavioral regulation is limited. The central mechanism for thermal comfort and discomfort, which induce various behavioral responses, should be clarified. In the heat, dehydration affects both autonomic and behavioral thermoregulation by non-thermoregulatory factors such as high Na+ concentration. The PO seems to be closely involved in these responses. The knowledge about the central mechanisms involved in thermoregulation is important to improve industrial health, e.g. preventing accidents associated with the heat or organizing more comfortable working environment.

The nature of muscle efferent fibre activation during whole body cooling was investigated in urethane-anaesthetized rats. Multiunit efferent activity to the gastrocnemius muscle was detected when the trunk skin was cooled by a water-perfused jacket to below 36.0 +/- 0.7 degrees C. That efferent activity was not blocked by hexamethonium (50 mg kg(-1), i.v.) and was not associated with movement or electromyographic activity. Cold-induced efferent activity enhanced the discharge of afferent filaments from the isotonically stretched gastrocnemius muscle, demonstrating that it was fusimotor. Fusimotor neurons were activated by falls in trunk skin temperature, but that activity ceased when the skin was rewarmed, regardless of how low core temperature had fallen. While low core temperature alone was ineffective, a high core temperature could inhibit the fusimotor response to skin cooling. Fusimotor activation by skin cooling was often accompanied by desynchronization of the frontal electroencephalogram (EEG), but was not a simple consequence of cortical arousal, in that warming the scrotum desynchronized the EEG without activating fusimotor fibres. Inhibition of neurons in the rostral medullary raphé by microinjections of glycine (0.5 m, 120-180 nl) reduced the fusimotor response to skin cooling by 95 +/- 3%, but did not prevent the EEG response. These results are interpreted as showing a novel thermoregulatory reflex that is triggered by cold exposure. It may underlie the increased muscle tone that precedes overt shivering, and could also serve to amplify shivering. Like several other cold-defence responses, this reflex depends upon neurons in the rostral medullary raphé.

In this study, we developed a heat and steam generating (HSG) sheet that generates steam for several hours, and analyzed its effects on thermoregulatory responses and thermal sensation. In seven healthy male subjects the lumbar region (lower back) was warmed for four hours in a cool environment of 20&deg;C and 40%RH. For each subject, three experiments were performed: 1) warming the lower back with a HSG sheet (12&times;20 cm), 2) warming with a heat generating (HG) sheet without steam, and 3) no warming (control). The skin and subcutaneous temperatures in and around the warmed area, as well as rectal temperature were measured. The subjects reported whole body thermal comfort, and local sensations in the warmed area. While the temperature under the sheet was similar between the HSG and HG sheets (approximately 38.5&deg;C), skin temperature at 2 cm from the sheet was about 0.9&deg;C higher (p<0.05) for the HSG sheet than the HG sheet. The subjects reported less whole body coldness during the warming by the HSG sheet than the HG sheet. They also reported stronger and more spreading warm sensation in the warmed region for the HSG sheet than the HG sheet. In a separate experiment using an apparatus with a heat flux sensor, higher heat flux was observed for the HSG sheet than the HG sheet, even though both sheets gave the same surface temperature. These results suggest that warming the skin with steam is more efficient than warming it with dry air.<br>

We investigated the effects of alcohol on thermoregulatory responses and thermal sensations during mild heat exposure in humans. Eight healthy men participated in this study. Experiments were conducted twice for each subject at a room temperature of 33 degrees C. After a 30-min resting period, the subject drank either 15% alcohol (alcohol session) at a dose of 0.36 g/kg body weight or equal volume of water (control session). Skin blood flow and chest sweat rate in the alcohol session significantly increased over those in controls 10 min after drinking. Deep body temperature in the alcohol session started to decrease 20 min after the onset of sweating and eventually fell 0.3 degrees C lower than in the controls. Whole body hot sensation transiently increased after alcohol drinking, whereas it changed little after water drinking. The increased "hot" sensation would presumably cause cool-seeking behavior, if permitted. Thus, alcohol influences thermoregulation so that body core temperature is lowered not only by automatic mechanisms (sweating and skin vasodilation) but also behaviorally. These results suggest that decreases in body temperature after alcohol drinking are not secondary to skin vasodilation, a well-known effect of alcohol, but rather result from a decrease in the regulated body temperature evidenced by the coordinated modulation of various effectors of thermoregulation and sensation.

Sensations evoked by innocuous thermal stimulation can be divided into two categories. One is "temperature sensation" in a narrow sense, which is directed towards an object outside the body. The other is the "thermal comfort/discomfort" of the body that is important for thermoregulation. We recently reported rCBF changes in the amygdala which correlated with thermal comfort during whole body cooling (Kanosue et al., 2000). In the present study we investigated the region of brain that is activated by local thermal stimulation of the hand. Eight healthy subjects were recruited and gave written informed consent to participate in the study. Warm (39 degrees C) or cold (25 degrees C) stimuli was applied to the right or left hand for 30 s by using a water circulating tube that covered the whole hand. Each subject reported the magnitude of the stimulus intensity of temperature sensation using a scale from 1 (very cold) to 9 (very hot). All subjects reported hot or cold sensations and not pain. We examined the correlation between the rating scores and regional activity over the entire brain with a 3 Tesla MR imagers (VP, General Electrics, Milwaukee, US). Activation was observed in the contralateral secondary somatosensory cortex in response to both warm and cold stimulation of the hand. No activation was observed in the amygdala. This suggests that temperature sensation and thermal comfort might be generated by completely different structures of the brain.

Sensations evoked by innocuous thermal stimulation can be divided into two categories. One is "temperature sensation" in a narrow sense, which is directed towards an object outside the body. The other is the "thermal comfort/discomfort" of the body that is important for thermoregulation. We recently reported rCBF changes in the amygdala which correlated with thermal comfort during whole body cooling (Kanosue et al., 2000). In the present study we investigated the region of brain that is activated by local thermal stimulation of the hand. Eight healthy subjects were recruited and gave written informed consent to participate in the study. Warm (39 degrees C) or cold (25 degrees C) stimuli was applied to the right or left hand for 30 s by using a water circulating tube that covered the whole hand. Each subject reported the magnitude of the stimulus intensity of temperature sensation using a scale from 1 (very cold) to 9 (very hot). All subjects reported hot or cold sensations and not pain. We examined the correlation between the rating scores and regional activity over the entire brain with a 3 Tesla MR imagers (VP, General Electrics, Milwaukee, US). Activation was observed in the contralateral secondary somatosensory cortex in response to both warm and cold stimulation of the hand. No activation was observed in the amygdala. This suggests that temperature sensation and thermal comfort might be generated by completely different structures of the brain.

The criptochrome genes (Cry1 and Cry2) are involved in the molecular mechanism that controls the circadian clock, and mice lacking these genes (Cry1(-/-)/Cry2(-/-)) are behaviorally arrhythmic. It has been speculated that the circadian clock modulates the characteristics of thermoregulation, resulting in body temperature (T(b)) rhythm. However, there is no direct evidence proving this speculation. We show here that T(b) and heat production in Cry1(-/-)/Cry2(-/-) mice are arrhythmic under constant darkness. In contrast, both rhythms occur under a light-dark cycle and/or periodical food restriction linked with spontaneous activity and/or eating, although they are not robust as those in wild-type mice. The relationship between heat production and T(b) in Cry1(-/-)/Cry2(-/-) mice is linear and identical under any conditions, indicating that their T(b) rhythm is determined by heat production rhythm associated with activity and eating. However, T(b) in wild-type mice is maintained at a relatively higher level in the active phase than the inactive phase regardless of the heat production level. These results indicate that the thermoregulatory responses are modulated according to the circadian phase, and the Cry genes are involved in this mechanism.

The hypothalamus, especially the preoptic area, plays a crucial role in thermoregulation, and our previous studies showed that the periaqueductal gray matter is important for transmitting efferent signals to thermoregulatory effectors in rats. Neurons responsible for skin vasodilation are located in the lateral portion of the rostral periaqueductal gray matter, and neurons that mediate non-shivering thermogenesis are located in the ventrolateral part of the caudal periaqueductal gray matter. We investigated the distribution of neurons in the rat hypothalamus that are activated by exposure to neutral (26 degrees C), warm (33 degrees C), or cold (10 degrees C) ambient temperature and project to the rostral periaqueductal gray matter or caudal periaqueductal gray matter, by using the immunohistochemical analysis of Fos and a retrograde tracer, cholera toxin-b. When cholera toxin-b was injected into the rostral periaqueductal gray matter, many double-labeled cells were observed in the median preoptic nucleus in warm-exposed rats, but few were seen in cold-exposed rats. On the other hand, when cholera toxin-b was injected into the caudal periaqueductal gray matter, many double-labeled cells were seen in a cell group extending from the dorsomedial nucleus through the dorsal hypothalamic area in cold-exposed rats but few were seen in warm-exposed rats. These results suggest that the rostral periaqueductal gray matter receives input from the median preoptic nucleus neurons activated by warm exposure, and the caudal periaqueductal gray matter receives input from neurons in the dorsomedial nucleus/dorsal hypothalamic area region activated by cold exposure. These efferent pathways provide a substrate for thermoregulatory skin vasomotor response and non-shivering thermogenes is, respectively. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

We surveyed the neural substrata for behavioral thermoregulation with immunohistochemical analysis of the expression of Fos protein in the rat brain. We used an operant system in which a rat exposed to heat (40 degrees C) could get cold air (0 degrees C) for 30 s when it moved into the reward area. Rats moved in and out of the reward area of the system periodically and thus maintained their body temperature at a normal level. In the rats performing heat escape behavior (active group), strong Fos immunoreactivity (Fos-IR) was found in the median preoptic nucleus (MnPO), parastrial nucleus (PS), and dorsomedial hypothalamus (DMH) compared with the controls. Another group of rats (passive group) were given the same temperature changes, regardless of the rat's movement, as those obtained by rats of the active group. Fos-IR in the MnPO was also seen in this group. The present results suggest that the PS and DMH play an important role in the genesis of thermoregulatory behavior, whereas the MnPO may be important for detecting changes in ambient and/or body temperatures.

The reduction of body core temperature (Tcore) after salt loading has been reported. In this study, we tested the hypothesis that, during a cold exposure in rats, (1) salt loading would decrease metabolic rate (MR), reducing Tcore, but (2) Tcore would be maintained when cold-escape/warm-seeking behaviour is available. In the first experiment (n = 7), MR and Tcore were measured by indirect calorimetry and telemetry, respectively, during 26, 20 and 10 degrees C exposure for 1 h each, in that order. In the second experiment (n = 7), each rat was placed in an operant system during the same exposure protocol as in the first experiment, where it could trigger a 40 degrees C air reward for 30 s at 20 and 10 degrees C by moving into specific areas (operant behaviour). In each experiment, rats repeated the same protocol twice with a subcutaneous injection (10 ml kg-1) of either isotonic saline (154 mM) or hypertonic saline (2500 mM). In the first experiment, MR in the isotonic-saline trial increased (P < 0.05) at 20 and 10 degrees C compared with that at 26 degrees C by 21 +/- 5 and 48 +/- 6 %, respectively (means +/- S.E.M.), with Tcore unchanged. However, values for MR and Tcore in the hypertonic-saline trial were lower (P < 0.05) than those in the isotonic-saline trial in any ambient temperature. In the second experiment, Tcore was also lower (P < 0.05) in the hypertonic-saline trial than in the isotonic-saline trial. The counts of the operant behaviour in the hypertonic-saline trial remained unchanged in each exposure period, but those in the isotonic-saline trial increased (P < 0.05) at 10 degrees C. These results may suggest that salt loading attenuates both metabolic and behavioural thermoregulatory responses to the cold.

To investigate the mechanism involved in the reduction of body core temperature (T(core)) during fasting in rats, which is selective in the light phase, we measured T(core), surface temperature, and oxygen consumption rate in fed control animals and in fasted animals on day 3 of fasting and day 4 of recovery at an ambient temperature (T(a)) of 23 degrees C by biotelemetry, infrared thermography, and indirect calorimetry, respectively. On the fasting day, 1) T(core) in the light phase decreased (P < 0.05) from the control; however, T(core) in the dark phase was unchanged, 2) tail temperature fell from the control (P < 0.05, from 30.7 +/- 0.1 to 23.9 +/- 0.1 degrees C in the dark phase and from 29.4 +/- 0.1 to 25.2 +/- 0.2 degrees C in the light phase), 3) oxygen consumption rate decreased from the control (P < 0.05, from 24.37 +/- 1.06 to 16.24 +/- 0.69 ml. min(-1). kg body wt(-0.75) in the dark phase and from 18.91 +/- 0.64 to 14.00 +/- 0.41 ml. min(-1). kg body wt(-0.75) in the light phase). All these values returned to the control levels on the recovery day. The results suggest that, in the fasting condition, T(core) in the dark phase was maintained by suppression of the heat loss mechanism, despite the reduction of metabolic heat production. In contrast, the response was weakened in the light phase, decreasing T(core) greatly. Moreover, the change in the regulation of tail blood flow was a likely mechanism to suppress heat loss.

To investigate the mechanism involved in the reduction of body core temperature (T-core) during fasting in rats, which is selective in the light phase, we measured T-core, surface temperature, and oxygen consumption rate in fed control animals and in fasted animals on day 3 of fasting and day 4 of recovery at an ambient temperature (T-a) of 23 degreesC by biotelemetry, infrared thermography, and indirect calorimetry, respectively. On the fasting day, 1) T-core in the light phase decreased (P &lt; 0.05) from the control; however, T-core in the dark phase was unchanged, 2) tail temperature fell from the control (P &lt; 0.05, from 30.7 +/- 0.1 to 23.9 +/- 0.1 degreesC in the dark phase and from 29.4 +/- 0.1 to 25.2 +/- 0.2 degreesC in the light phase), 3) oxygen consumption rate decreased from the control ( P &lt; 0.05, from 24.37 +/- 1.06 to 16.24 +/- 0.69 ml . min(-1) . kg body wt(-0.75) in the dark phase and from 18.91 +/- 0.64 to 14.00 +/- 0.41 ml . min(-1) . kg body wt(-0.75) in the light phase). All these values returned to the control levels on the recovery day. The results suggest that, in the fasting condition, T-core in the dark phase was maintained by suppression of the heat loss mechanism, despite the reduction of metabolic heat production. In contrast, the response was weakened in the light phase, decreasing T-core greatly. Moreover, the change in the regulation of tail blood flow was a likely mechanism to suppress heat loss.

Thermogenesis in the brown adipose tissue (BAT) is activated by the stimulation of the ventromedial hypothalamic nucleus (VMH). Local warming of the preoptic area (PO) suppresses this response. Injection of the GABA(A) receptor antagonist bicuculline into the caudal periaqueductal gray (cPAG), where excitatory neurons for BAT thermogenesis are located, did not influence the suppressive effect of PO warming. On the other hand, after bicuculline injection into the raphé pallidus, where excitatory neurons for BAT thermogenesis are also located, VMH stimulation produced BAT thermogenesis even during PO warming. The present results suggest that the inhibitory signal from the PO reaches the raphé pallidus and not the cPAG for the control of BAT thermogenesis.

Thermogenesis in the brown adipose tissue (BAT) is activated by the stimulation of the ventromedial hypothalamic nucleus (VMH). Local warming of the preoptic area (PO) suppresses this response. Injection of the GABA, receptor antagonist bicuculline into the caudal periaqueductal gray (cPAG), where excitatory neurons for BAT thermogenesis are located, did not influence the suppressive effect of PO warming. On the other hand, after bicuculline injection into the raphe pallidus, where excitatory neurons for BAT thermogenesis are also located, VMH stimulation produced BAT thermogenesis even during PO warming. The present results suggest that the inhibitory signal from the PO reaches the raphe pallidus and not the cPAG for the control of BAT thermogenesis. (C) 2002 Elsevier Science B.V. All rights reserved.

Salt loading decreases body core temperature (T(core)) at neutral ambient temperature (26 degrees C) and increases heat-escape/cold-seeking behaviour in desalivated rats. In this study, we tested the hypothesis that brain angiotensin II (AII) and arginine vasopressin (AVP) are associated with these responses. Surgically desalivated rats (n = 28) were administered an injection (S.C., 10 ml kg(-1)) of either normal saline (154 mM, NS) or hypertonic saline (2500 mM, HS) following an intracerebroventricular injection (10 microl kg(-1)) of an AII AT(1)-receptor antagonist (candesartan, 5 microg microl(-1)), an AVP V(1)-receptor antagonist ((beta-mercapto-beta, beta-cyclopenta-methylene propionyl(1), O-Me-Tyr(2), Arg(8))-vasopressin, 0.5 microg microl(-1)), or normal saline (154 mM). Each rat was placed in a behaviour box, first at 26 degrees C for 1 h to allow the measurement of baseline T(core) and movement. The ambient temperature was then elevated to 40 degrees C for the next 2 h, during which time the rat was able to trigger a 0 degrees C air reward for 30 s by moving into a specific area of the box (operant behaviour). The S.C. HS significantly decreased baseline T(core) at 26 degrees C (36.5 +/- 0.1 degrees C) and increased counts of operant behaviour at 40 degrees C (57 +/- 3) compared with results obtained following S.C. NS injection (37.4 +/- 0.1 degrees C and 42 +/- 1, respectively). These responses to s.c. HS were inhibited by the intracerebroventricular injection of AT(1) (37.3 +/- 0.1 degrees C and 43 +/- 2, respectively; P < 0.05) and V(1) antagonists (37.2 +/- 0.2 degrees C and 42 +/- 2, respectively; P < 0.05), although administration of both antagonists with S.C. NS had no effect. These results suggest that brain AII and AVP are involved in the decrease in T(core) observed at neutral ambient temperature and the increase in heat-escape/cold-seeking behaviour in response to osmotic stimulation, via the central AT(1) and V(1) receptors, respectively

Salt loading decreases body core temperature (T-core) at neutral ambient temperature (26degreesC) and increases heat-escape/cold-seeking behaviour in desalivated rats. In this study, we tested the hypothesis that brain angiotensin II (AII) and arginine vasopressin (AVP) are associated with these responses. Surgically desalivated rats (n = 28) were administered an injection (s.c., 10 ml kg(-1)) of either normal saline (154 mm, NS) or hypertonic saline (2500 mm, HS) following an intracerebroventricular injection (10 mul kg(-1)) of an AII AT(1)-receptor antagonist (candesartan, 5 mug mul(-1)), an AVP V-1-receptor antagonist ((beta-mercapto-beta, beta-cyclopenta-methylene propionyl(1), O-Me-Tyr(2), Arg(8))- vasopressin, 0.5 mug mul(-1)), or normal saline (154 mm). Each rat was placed in a behaviour box, first at 26degreesC for 1 h to allow the measurement of baseline T-core and movement. The ambient temperature was then elevated to 40 degreesC for the next 2 h, during which time the rat was able to trigger a 0 degreesC air reward for 30 s by moving into a specific area of the box (operant behaviour). The s.c. HS significantly decreased baseline T-core at 26 degreesC (36.5 +/- 0.1 degreesC) and increased counts of operant behaviour at 40degreesC (57 +/- 3) compared with results obtained following s.c. NS injection (37.4 +/- 0.1degreesC and 42 +/- 1, respectively). These responses to s.c. HS were inhibited by the intracerebroventricular injection of AT(1) (37.3 +/- 0.1 degreesC and 43 +/- 2, respectively; P &lt; 0.05) and V-1 antagonists (37.2 +/- 0.2&DEG;C and 42 +/- 2, respectively; P &lt; 0.05), although administration of both antagonists with s.c. NS had no effect. These results suggest that brain AII and AVP are involved in the decrease in T-core observed at neutral ambient temperature and the increase in heat-escape/cold-seeking behaviour in response to osmotic stimulation, via the central AT(1) and V-1 receptors, respectively.

To investigate the involvement of the periaqueductal gray (PAG) in the control of non-shivering thermogenesis, we tested the effects of electrical or chemical stimulation of the PAG on thermogenesis of brown adipose tissue (BAT) in urethane anesthetized rats. Electrical stimulation (0.1 mA, 33 Hz, 0.5 ms) or application of D,L-homocysteic acid (0.5 mM, 0.3 micro l) into the lateral region of the caudal PAG (cPAG) elicited BAT thermogenesis, measured as a rise in the local temperature of interscapular BAT. These results suggest that neurons in the cPAG send excitatory efferent signals for BAT thermogenesis.

To investigate the involvement of the periaqueductal gray (PAG) in the control of non-shivering thermogenesis, we tested the effects of electrical or chemical stimulation of the PAG on thermogenesis of brown adipose tissue (BAT) in urethane anesthetized rats. Electrical stimulation (0.1 mA, 33 Hz, 0.5 ms) or application of D,L-homocysteic acid (0.5 mM, 0.3 mul) into the lateral region of the caudal PAG (cPAG) elicited BAT thermogenesis, measured as a rise in the local temperature of interscapular BAT. These results suggest that neurons in the cPAG send excitatory efferent signals for BAT thermogenesis. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Regional activation of the brain was studied in humans using functional magnetic resonance imaging during whole body cooling that produced thermal comfort/discomfort. Eight normal male subjects lay in a sleeping bag through which air was blown, exposing subjects to cold air (8 degrees C) for 22 min. Each subject scored their degree of thermal comfort and discomfort every min. As the subjects reported more discomfort the blood oxygen level dependent response in the bilateral amygdala increased. There was no activation in the thalamus, somatosensory, cingulate, or insula cortices. This result suggests that the amygdala plays a role in the genesis of thermal discomfort due to cold.

Regional activation of the brain was studied in humans using functional magnetic resonance imaging during whole body cooling that produced thermal comfort/discomfort. Eight normal male subjects lay in a sleeping bag through which air was blown, exposing subjects to cold air (8degreesC) for 22 min. Each subject scored their degree of thermal comfort and discomfort every min. As the subjects reported more discomfort the blood oxygen level dependent response in the bilateral amygdala increased. There was no activation in the thalamus, somatosensory, cingulate, or insula cortices. This result suggests that the amygdala plays a role in the genesis of thermal discomfort due to cold. (C) 2002 Published by Elsevier Science Ireland Ltd.

The preoptic area (POA) occupies a crucial position among the structures participating in thermoregulation, but we know little about its efferent projections for controlling various effector responses. In this study, we used an immunohistochemical analysis of Fos expression during local warming of the preoptic area. To avoid the effects of anesthesia or stress, which are known to elicit Fos induction in various brain regions, we used a novel thermode specifically designed for chronic warming of discrete brain structures in freely moving rats. At an ambient temperature of 22 degrees C, local POA warming increased Fos immunoreactivity in the supraoptic nucleus (SON) and the periaqueductal gray matter (PAG). Exposure of animals to an ambient temperature of 5 degrees C induced Fos immunoreactivity in the magnocellular paraventricular nucleus (mPVN) and the dorsomedial region of the hypothalamus (DMH). Concurrent warming of the POA suppressed Fos expression in these areas. These findings suggest that thermal information from the preoptic area sends excitatory signals to the SON and the PAG, and inhibitory signals to the mPVN and the DMH.

To investigate the involvement of the medullary raphé in thermoregulatory vasomotor control, we chemically manipulated raphé neuronal activity while monitoring the tail vasomotor response to preoptic warming. For comparison, neuronal activity in the rostral ventrolateral medulla (RVLM) was manipulated in similar experiments. Injections of D,L-homocysteic acid (DLH; 0.5 mM, 0.3 microl) into a restricted region of the ventral medullary raphé suppressed the tail vasodilatation normally elicited by warming the preoptic area to 42 degrees C. DLH injection into the RVLM also suppressed the vasodilatation elicited by preoptic warming. Injection of bicuculline (0.5 mM, 0.3 microl) into the same raphé region suppressed the vasodilatation elicited by preoptic warming. Bicuculline injection into the RVLM did not suppress tail vasodilatation. These results suggest that neurones in both the medullary raphé and the RVLM are vasoconstrictor to the tail, but only those in the raphé receive inhibitory input from the preoptic area. That input might be direct and/or indirect (e.g. via the periaqueductal grey matter).

To investigate the involvement of the medullary raphe in thermoregulatory vasomotor control, we chemically manipulated raphe neuronal activity while monitoring the tail vasomotor response to preoptic warming. For comparison, neuronal activity in the rostral ventrolateral medulla (RVLM) was manipulated in similar experiments. Injections Of D,L-homocysteic acid (DLH; 0.5 mm, 0.3 mul) into a restricted region of the ventral medullary raphe suppressed the tail vasodilatation normally elicited by warming the preoptic area to 42degreesC. DLH injection into the RVLM also suppressed the vasodilatation elicited by preoptic warming. Injection of bicuculline (0.5 mm, 0.3 mul) into the same raphe region suppressed the vasodilatation elicited by preoptic warming. Bicuculline injection into the RVLM did not suppress tail vasodilatation. These results suggest that neurones in both the medullary raphe and the RVLM are vasoconstrictor to the tail, but only those in the raphe receive inhibitory input from the preoptic area. That input might be direct and/or indirect (e.g. via the periaqueductal grey matter).

The preoptic area (POA) occupies a crucial position among the structures participating in thermoregulation, but we know little about its efferent projections for controlling various effector responses. In this study, we used an immunohistochemical analysis of Fos expression during local warming of the preoptic area. To avoid the effects of anesthesia or stress, which are known to elicit Fos induction in various brain regions, we used a novel thermode specifically designed for chronic warming of discrete brain structures in freely moving rats. At an ambient temperature of 22 degreesC, local POA warming increased Fos immunoreactivity in the supraoptic nucleus (SON) and the periaqueductal gray matter (PAG). Exposure of animals to an ambient temperature of 5 degreesC induced Fos immunoreactivity in the magnocellular paraventricular nucleus (mPVN) and the dorsomedial region of the hypothalamus (DMH). Concurrent warming of the POA suppressed Fos expression in these areas. These findings suggest that thermal information from the preoptic area sends excitatory signals to the SON and the PAG, and inhibitory signals to the mPVN and the DMH. (C) 2002 Elsevier Science BV All rights reserved.

We examined body core and skin temperatures and thermal comfort in young Japanese women suffering from unusual coldness (C, n = 6). They were selected by interview asking whether they often felt severe coldness even in an air-conditioned environment (20-26 degrees C) and compared with women not suffering from coldness (N, n = 6). Experiments were conducted twice for each subject: 120-min exposure at 23.5 degrees C or 29.5 degrees C after a 40-min baseline at 29.5 degrees C. Mean skin temperature decreased (P < 0.05) from 33.6 +/- 0.1 degrees C (mean +/- SE) to 31.1 +/- 0.1 degrees C and from 33.5 +/- 0.1 degrees C to 31.1 +/- 0.1 degrees C in C and N during the 23.5 degrees C exposure. Fingertip temperature in C decreased more than in N (P < 0.05; from 35.2 +/- 0.1 degrees C to 23.6 +/- 0.2 degrees C and from 35.5 +/- 0.1 degrees C to 25.6 +/- 0.6 degrees C). Those temperatures during the 29.5 degrees C exposure remained at the baseline levels. Rectal temperature during the 23.5 degrees C exposure was maintained at the baseline level in both groups (from 36.9 +/- 0.2 degrees C to 36.8 +/- 0.1 degrees C and 37.1 +/- 0.1 degrees C to 37.0 +/- 0.1 degrees C in C and N). The rating scores of cold discomfort for both the body and extremities were greater (P < 0.05) in C than in N. Thus the augmented thermal sensitivity of the body to cold and activated vasoconstriction of the extremities during cold exposure could be the mechanism for the severe coldness felt in C.

Recently we found that food-deprived rats kept under a light-dark cycle showed a progressive reduction in body temperature during the light phase on each subsequent day while body temperature in the dark phase did not differ from baseline values. In this study, we investigated the effect of lesioning the hypothalamic suprachiasmatic nucleus (SCN) on body temperature modulation by food deprivation. In the SCN-lesioned rats in which daily rhythms of body temperature and activity were abolished, body temperature was unchanged by food deprivation. We also examined the effect of food deprivation on the daily changes in Fos expression in the SCN. Under normal fed conditions the number of SCN cells expressing Fos is high during the day and low at night. Food deprivation attenuated the amplitude of this daily change in Fos expression in the SCN. This tendency was prominent in the dorsal part of the SCN, while the ventral part showed no effect of food deprivation. These findings suggest that the SCN plays some role in body temperature modulation due to food deprivation.

We examined body core and skin temperatures and thermal comfort in young Japanese women suffering from unusual coldness (C, n=6). They were selected by interview asking whether they often felt severe coldness even in an air-conditioned environment (20-26degreesC) and compared with women not suffering from coldness (N, n=6). Experiments were conducted twice for each subject: 120-min exposure at 23.5degreesC or 29.5degreesC after a 40-min baseline at 29.5degreesC. Mean skin temperature decreased (P&lt;0.05) from 33.6&PLUSMN;0.1&DEG;C (mean &PLUSMN; SE) to 31.1&PLUSMN;0.1&DEG;C and from 33.5&PLUSMN;0.1&DEG;C to 31.1&PLUSMN;0.1&DEG;C in C and N during the 23.5&DEG;C exposure. Fingertip temperature in C decreased more than in N (P&lt;0.05; from 35.2+/-0.1degreesC to 23.6+/-0.2degreesC and from 35.5+/-0.1degreesC to 25.6+/-0.6degreesC). Those temperatures during the 29.5degreesC exposure remained at the baseline levels. Rectal temperature during the 23.5degreesC exposure was maintained at the baseline level in both groups (from 36.9+/-0.2degreesC to 36.8+/-0.1degreesC and 37.1+/-0.1degreesC to 37.0+/-0.1degreesC in C and N). The rating scores of cold discomfort for both the body and extremities were greater (P&lt;0.05) in C than in N. Thus the augmented thermal sensitivity of the body to cold and activated vasoconstriction of the extremities during cold exposure could be the mechanism for the severe coldness felt in C.

Recently we found that food-deprived rats kept under a light-dark cycle showed a progressive reduction in body temperature during the light phase on each subsequent day while body temperature in the dark phase did not differ from baseline values. In this study, we investigated the effect of lesioning the hypothalamic suprachiasmatic nucleus (SCN) on body temperature modulation by food deprivation. In the SCN-lesioned rats in which daily rhythms of body temperature and activity were abolished, body temperature was unchanged by food deprivation. We also examined the effect of food deprivation on the daily changes in Fos expression in the SCN. Under normal fed conditions the number of SCN cells expressing Fos is high during the day and low at night. Food deprivation attenuated the amplitude of this daily change in Fos expression in the SCN. This tendency was prominent in the dorsal part of the SCN. while the ventral part showed no effect of food deprivation. These findings suggest that the SCN plays some role in body temperature modulation due to food deprivation. (C) 2002 Elsevier Science B.V. All rights reserved.

Although the posterior part of the hypothalamus has long, been considered important for thermoregulatory shivering, it is unknown whether the neurons there or the passing fibers are implicated in the response. Exposure of urethane-anesthetized rats to cold (15-21 degreesC) elicits shivering. An injection of muscimol (0.5 mm), a GABA(A) receptor agonist, into the medial part of the hypothalamus, including the dorsomedial and posterior nuclei, suppressed the cold-induced shivering. This result suggests that neurons having an excitatory effect on shivering are in this region of the hypothalamus.

We tested the hypothesis that renal tubular Na+ reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O-2 uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P&lt; 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na+ in the proximal tubules was higher in Ex than in C (P&lt; 0.05). Saline loading decreased fractional tubular reabsorption of Na+ from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P&lt; 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P&lt; 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na+ reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na+ reabsorption during saline infusion 24 h after exercise.

We tested the hypothesis that renal tubular Na+ reabsorption increased during the first 24 h of exercise-induced plasma volume expansion. Renal function was assessed 1 day after no-exercise control (C) or intermittent cycle ergometer exercise (Ex, 85% of peak O-2 uptake) for 2 h before and 3 h after saline loading (12.5 ml/kg over 30 min) in seven subjects. Ex reduced renal blood flow (p-aminohippurate clearance) compared with C (0.83 +/- 0.12 vs. 1.49 +/- 0.24 l/min, P&lt; 0.05) but did not influence glomerular filtration rates (97 +/- 10 ml/min, inulin clearance). Fractional tubular reabsorption of Na+ in the proximal tubules was higher in Ex than in C (P&lt; 0.05). Saline loading decreased fractional tubular reabsorption of Na+ from 99.1 +/- 0.1 to 98.7 +/- 0.1% (P&lt; 0.05) in C but not in Ex (99.3 +/- 0.1 to 99.4 +/- 0.1%). Saline loading reduced plasma renin activity and plasma arginine vasopressin levels in C and Ex, although the magnitude of decrease was greater in C (P&lt; 0.05). These results indicate that, during the acute phase of exercise-induced plasma volume expansion, increased tubular Na+ reabsorption is directed primarily to the proximal tubules and is associated with a decrease in renal blood flow. In addition, saline infusion caused a smaller reduction in fluid-regulating hormones in Ex. The attenuated volume-regulatory response acts to preserve distal tubular Na+ reabsorption during saline infusion 24 h after exercise.

We examined the effect of hypertonic saline injection on heat-escape/cold-seeking behavior in desalivated rats. Rats were exposed to 40 degreesC heat after normal (154 mM NaCl, control) or hypertonic saline (2,500 mM NaCl) injection (1 ml/100 g body wt). The rats received a 0 degreesC air for 30 s when they entered a specific area in an experimental box. Core temperature (T(c)) surpassed 40 degreesC in both conditions when 0 degreesC air was not available. Hypertonic saline injection produced a lower baseline T(c) than control [36.9 +/- 0.2 and 37.9 +/- 0.2 degreesC (means +/- SE), P &lt; 0.05] and a greater number of 0&lt;degrees&gt;C air rewards during the 2-h heat with lower T(c) at the end (48 +/- 1 and 34 +/- 2, 37.6 +/- 0.1, and 37.3 +/- 0.1 degreesC in the control and hypertonic saline injection trial, respectively, P &lt; 0.05, n = 6). However, T(c) was similar (37.7 +/- 0.2 and 37.6 +/- 0.4&lt;degrees&gt;C in the control and hypertonic saline injection trial, n = 5) when 0 degreesC air was automatically and intermittently (35 times) given during the heat. Rats augment heat-defense mechanisms in response to osmotic stress by lowering the baseline T(c) and increasing heat-escape/cold-seeking behavior.

We examined the effect of hypertonic saline injection on heat-escape/cold-seeking behavior in desalivated rats. Rats were exposed to 40 degreesC heat after normal (154 mM NaCl, control) or hypertonic saline (2,500 mM NaCl) injection (1 ml/100 g body wt). The rats received a 0 degreesC air for 30 s when they entered a specific area in an experimental box. Core temperature (T(c)) surpassed 40 degreesC in both conditions when 0 degreesC air was not available. Hypertonic saline injection produced a lower baseline T(c) than control [36.9 +/- 0.2 and 37.9 +/- 0.2 degreesC (means +/- SE), P &lt; 0.05] and a greater number of 0&lt;degrees&gt;C air rewards during the 2-h heat with lower T(c) at the end (48 +/- 1 and 34 +/- 2, 37.6 +/- 0.1, and 37.3 +/- 0.1 degreesC in the control and hypertonic saline injection trial, respectively, P &lt; 0.05, n = 6). However, T(c) was similar (37.7 +/- 0.2 and 37.6 +/- 0.4&lt;degrees&gt;C in the control and hypertonic saline injection trial, n = 5) when 0 degreesC air was automatically and intermittently (35 times) given during the heat. Rats augment heat-defense mechanisms in response to osmotic stress by lowering the baseline T(c) and increasing heat-escape/cold-seeking behavior.

The body temperature of homeothermic animals is regulated by systems that utilize multiple behavioral and autonomic effector responses. In the last few years, new approaches have brought us new information and new ideas about neuronal interconnections in the thermoregulatory network. Studies utilizing chemical stimulation of the preoptic area revealed both heat loss and production responses are controlled by warm-sensitive neurons. These neurons send excitatory efferent signals for the heat loss and inhibitory efferent signals for the heat production. The warm-sensitive neurons are separated and work independently to control these two opposing responses. Recent electrophysiological analysis have identified some neurons sending axons directly to the spinal cord for thermoregulatory effector control. Included are midbrain reticulospinal neurons for shivering and premotor neurons in the medulla oblongata for skin vasomotor control. As for the afferent side of the thermoregulatory network, the vagus nerve is recently paid much attention, which would convey signals for peripheral infection to the brain and be responsible for the induction of fever. The vagus nerve may also participate in thermoregulation in afebrile conditions, because some substances such as cholecyctokinin and leptin activate the vagus nerve. Although the functional role for this response is still obscure, the vagus may transfer nutritional and/or metabolic signals to the brain, affecting metabolism and body temperature. (C) 2000 Elsevier Science B.V. All rights reserved.

We tested the hypothesis that an elevation in albumin synthetic rate contributes to increased plasma albumin content during exercise-induced hypervolemia. Albumin synthetic rate was measured in seven healthy subjects at 1-5 and 21-22 h after 72 min of intense (85% peak oxygen consumption rate) intermittent exercise and after 5 h recovery in either upright (Up) or supine (Sup) postures. Deuterated phenylalanine (d(5)-Phe) was administrated by a primed-constant infusion method, and fractional synthetic rate (FSR) and absolute synthetic rate (ASR) of albumin were calculated from the enrichment of dB-Phe in plasma albumin, determined by gas chromatography-mass spectrometry. FSR of albumin in Up increased significantly (P &lt; 0.05) from 4.9 +/- 0.9%/day at control to 7.3 +/- 0.9%/day at 22 h of recovery. ASR of albumin increased from 87.9 +/- 17.0 to 141.1 +/- 16.6 mg albumin . kg body wt(-1) . day(-1). In contrast, FSR and ASR of albumin were unchanged in Sup (3.9 +/- 0.4 to 4.0 +/- 1.4%/day and 74.2 +/- 8.9 to 85.3 +/- 23.9 mg albumin . kg body wt(-1) . day(-1) at control and 22 h of recovery, respectively). Increased albumin synthesis after upright intense exercise contributes to the expansion of greater albumin content and its maintenance. We conclude that stimuli related to posture are critical in modulating the drive for albumin synthesis after intense exercise.

We examined the hypothesis that activation of the muscle metaboreflex during dynamic exercise would augment influences tending to cause a rise in arginine vasopressin, plasma renin activity, and catecholamines during dynamic exercise in humans. Ten healthy adults performed 30 min of supine cycle ergometer exercise at similar to 50% of peak oxygen consumption with or without moderate muscle metaboreflex activation by application of 35 mmHg lower body positive pressure (LBPP). Application of LBPP during the first 15 or last 15 min of exercise increased mean arterial blood pressure, plasma lactate concentration, and minute ventilation, indicating an activation of the muscle metaboreflex. These changes were rapidly reversed when LBPP was removed. During exercise at this intensity, LBPP augmented the release of arginine vasopressin and catecholamines but not of plasma renin activity. These results suggest that, although in humans hormonal. responses are induced by moderate activation of the muscle metaboreflex during dynamic exercise, the thresholds for these responses may not be uniform among the various glands and hormones.

We tested the hypothesis that an elevation in albumin synthetic rate contributes to increased plasma albumin content during exercise-induced hypervolemia. Albumin synthetic rate was measured in seven healthy subjects at 1-5 and 21-22 h after 72 min of intense (85% peak oxygen consumption rate) intermittent exercise and after 5 h recovery in either upright (Up) or supine (Sup) postures. Deuterated phenylalanine (d(5)-Phe) was administrated by a primed-constant infusion method, and fractional synthetic rate (FSR) and absolute synthetic rate (ASR) of albumin were calculated from the enrichment of dB-Phe in plasma albumin, determined by gas chromatography-mass spectrometry. FSR of albumin in Up increased significantly (P &lt; 0.05) from 4.9 +/- 0.9%/day at control to 7.3 +/- 0.9%/day at 22 h of recovery. ASR of albumin increased from 87.9 +/- 17.0 to 141.1 +/- 16.6 mg albumin . kg body wt(-1) . day(-1). In contrast, FSR and ASR of albumin were unchanged in Sup (3.9 +/- 0.4 to 4.0 +/- 1.4%/day and 74.2 +/- 8.9 to 85.3 +/- 23.9 mg albumin . kg body wt(-1) . day(-1) at control and 22 h of recovery, respectively). Increased albumin synthesis after upright intense exercise contributes to the expansion of greater albumin content and its maintenance. We conclude that stimuli related to posture are critical in modulating the drive for albumin synthesis after intense exercise.

We examined the hypothesis that activation of the muscle metaboreflex during dynamic exercise would augment influences tending to cause a rise in arginine vasopressin, plasma renin activity, and catecholamines during dynamic exercise in humans. Ten healthy adults performed 30 min of supine cycle ergometer exercise at similar to 50% of peak oxygen consumption with or without moderate muscle metaboreflex activation by application of 35 mmHg lower body positive pressure (LBPP). Application of LBPP during the first 15 or last 15 min of exercise increased mean arterial blood pressure, plasma lactate concentration, and minute ventilation, indicating an activation of the muscle metaboreflex. These changes were rapidly reversed when LBPP was removed. During exercise at this intensity, LBPP augmented the release of arginine vasopressin and catecholamines but not of plasma renin activity. These results suggest that, although in humans hormonal. responses are induced by moderate activation of the muscle metaboreflex during dynamic exercise, the thresholds for these responses may not be uniform among the various glands and hormones.

To clarify whether an increase in urinary sodium (Na) excretion during cold-air exposure is attenuated in trained athletes, we analyzed the urinary and hormonal responses to cold-air exposure at 15 degrees C in trained (TR, n=9) and untrained men (UT, n=9), During 15 degrees C exposure in the UT group, the urinary Na excretion (UNaV), fractional excretion of Na and urinary Na to K ratio (U-Na/K) increased significantly (p&lt;0.01-0.05), but there were no variations in creatinine clearance or the filtered Na load. In the TR group, however, no significant changes were demonstrated in these parameters. The amount of increase in plasma noradrenaline and of decrease in plasma volume were greater, and the ADH and adrenaline responses were smaller in the TR group than those found in the UT group during 15 degrees C air exposure. A significant positive correlation was demonstrated between the increase of UNaV and both the relative changes of U-Na/K and mean blood pressure. These results indicated that natriuresis during cold-air exposure was induced by the decrease in tubular reabsorption of Na, and that natriuresis was attenuated in trained athletes.

To test the hypothesis that exercise-induced hypervolemia is a posture-dependent process, we measured plasma volume, plasma albumin content, and renal function in seven healthy subjects for 22 h after single upright (Up) or supine (Sup) intense (85% peak oxygen consumption rate) exercise. This posture was maintained for 5 h after exercise. Plasma volume decreased during exercise but returned to control levels by 5 h of recovery in both postures. By 22 h of recovery, plasma volume increased 2.4 +/- 0.8 ml/kg in Up but decreased 2.1 +/- 0.8 ml/kg in Sup. The plasma volume expansion in Up was accompanied by an increase in plasma albumin content (0.11 +/- 0.04 g/kg; P &lt; 0.05). Plasma albumin content was unchanged in Sup. Urine volume and sodium clearance were lower in Up than Sup (P &lt; 0.05) by 5 h of recovery. These data suggest that increased plasma albumin content contributes to the acute phase of exercise-induced hypervolemia. More importantly, the mechanism by which exercise influences the distribution of albumin between extra- and intravascular stores after exercise is altered by posture and is unknown. We speculate that factors associated with postural changes (e.g., central venous pressure) modify the increase in plasma albumin content and the plasma volume expansion after exercise.

To test the hypothesis that exercise-induced hypervolemia is a posture-dependent process, we measured plasma volume, plasma albumin content, and renal function in seven healthy subjects for 22 h after single upright (Up) or supine (Sup) intense (85% peak oxygen consumption rate) exercise. This posture was maintained for 5 h after exercise. Plasma volume decreased during exercise but returned to control levels by 5 h of recovery in both postures. By 22 h of recovery, plasma volume increased 2.4 +/- 0.8 ml/kg in Up but decreased 2.1 +/- 0.8 ml/kg in Sup. The plasma volume expansion in Up was accompanied by an increase in plasma albumin content (0.11 +/- 0.04 g/kg; P &lt; 0.05). Plasma albumin content was unchanged in Sup. Urine volume and sodium clearance were lower in Up than Sup (P &lt; 0.05) by 5 h of recovery. These data suggest that increased plasma albumin content contributes to the acute phase of exercise-induced hypervolemia. More importantly, the mechanism by which exercise influences the distribution of albumin between extra- and intravascular stores after exercise is altered by posture and is unknown. We speculate that factors associated with postural changes (e.g., central venous pressure) modify the increase in plasma albumin content and the plasma volume expansion after exercise.

The impact of posture on the immediate recovery of intravascular fluid and protein after intense exercise was determined in 14 volunteers. Forces which govern fluid and protein movement in muscle interstitial fluid pressure (P-ISF), interstitial colloid osmotic pressure (COPi), and plasma colloid osmotic pressure (COPi) were measured before and after exercise in the supine or upright position. During exercise, plasma volume (PV) decreased by 5.7 +/- 0.7 and 7.0 +/- 0.5 ml/kg body weight in the supine and upright posture, respectively. During recovery, PV returned to its baseline value within 30 min regardless of posture. PV fell below this level by 60 and 120 min in the supine and upright posture, respectively (P &lt; 0.05). Maintenance of PV in the upright position was associated with a decrease in systolic blood pressure, an increase in COPp (from 25 +/- 1 to 27 +/- 1 mmHg; P &lt; 0.05), and an increase in P-ISF (from 5 +/- 1 to 6 +/-: 2 mmHg), whereas COPi was unchanged. Increased PISF indicates that the hydrostatic pressure gradient favors fluid movement into the vascular space. However, retention of the recaptured fluid in the plasma is promoted only in the upright posture because of increased COPi.

The impact of posture on the immediate recovery of intravascular fluid and protein after intense exercise was determined in 14 volunteers. Forces which govern fluid and protein movement in muscle interstitial fluid pressure (P-ISF), interstitial colloid osmotic pressure (COPi), and plasma colloid osmotic pressure (COPi) were measured before and after exercise in the supine or upright position. During exercise, plasma volume (PV) decreased by 5.7 +/- 0.7 and 7.0 +/- 0.5 ml/kg body weight in the supine and upright posture, respectively. During recovery, PV returned to its baseline value within 30 min regardless of posture. PV fell below this level by 60 and 120 min in the supine and upright posture, respectively (P &lt; 0.05). Maintenance of PV in the upright position was associated with a decrease in systolic blood pressure, an increase in COPp (from 25 +/- 1 to 27 +/- 1 mmHg; P &lt; 0.05), and an increase in P-ISF (from 5 +/- 1 to 6 +/-: 2 mmHg), whereas COPi was unchanged. Increased PISF indicates that the hydrostatic pressure gradient favors fluid movement into the vascular space. However, retention of the recaptured fluid in the plasma is promoted only in the upright posture because of increased COPi.

We tested the hypothesis that cardiovascular responses to lower body positive pressure (LBPP) would be dependent on the posture of the subject and also on the background condition (rest or exercise). We measured heart rate (HR), mean arterial blood pressure (MAP), and cardiac stroke volume in eight subjects at rest and during cycle ergometer exercise (76 +/- 3 W) with and without LBPP (25, 50, and 75 mmHg) in the supine and upright positions. At rest, the increase in MAP was proportional to the increase in LBPP and was greater in the supine (6 +/- 2, 15 +/- 3, and 26 +/- 3 mmHg) than in the upright (2 +/- 3, 9 +/- 3, and 17 +/- 3 mmHg) position. During dynamic exercise, the increases in MAP evoked by 25, 50, and 75 mmHg LBPP were greater in the supine (13 +/- 2, 28 +/- 3, and 40 +/- 3 mmHg) than in the upright (7 +/- 3, 12 +/- 3, and 25 +/- 3 mmHg) position. We conclude that the systemic pressure response to LBPP is clearly dependent on the body position, with the larger pressure responses being associated with the supine position both at rest and during dynamic leg exercise.

To elucidate the role of increased plasma osmolality (P-osmol), which occurs during exercise in the regulation of cutaneous vasodilation (CVD) during exercise, we determined the relationship between the change in esophageal temperature (Delta T-es) required to elicit CVD (Delta T-es threshold for CVD) and P-osmol during light and moderate exercise (30 and 55% of peak oxygen consumption, respectively) and passive body heating. Then we compared the relationship with the data obtained in our previous study [A. Takamata, K. Nagashima, H. Nose, and T. Morimoto.Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R197-R204, 1997], in which we determined the relationships during passive body heating following isotonic (0.9% NaCl) or hypertonic (2 or 3% NaCl) saline infusions in the same subjects. P-osmol values at 5 min after the onset of exercise were 287.5 +/- 0.9 mosmol/kgH(2)O during light exercise and 293.0 +/- 1.2 mosmol/kgH(2)O during moderate exercise. P-osmol just before passive body heating was 289.9 +/- 1.4 mosmol/kgH(2)O. The Delta T-es threshold for CVD was 0.09 +/- 0.05 degrees C during light exercise, 0.31 +/- 0.09 degrees C during moderate exercise, and 0.10 +/- 0.05 degrees C during passive body heating. The relationship between the Delta T-es threshold for CVD and P-osmol was shown to be on the same regression line both during exercise and during passive body heating with or without infusions [A. Takamata, K. Nagashima, H. Nose, and T. Morimoto. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R197-R204, 1997]. Our data suggest that the elevated body core temperature threshold for CVD during exercise could be the result of increased P-osmol induced by exercise and is not due to reduced plasma volume or the intensity of the exercise itself.

To elucidate the role of increased plasma osmolality (P-osmol), which occurs during exercise in the regulation of cutaneous vasodilation (CVD) during exercise, we determined the relationship between the change in esophageal temperature (Delta T-es) required to elicit CVD (Delta T-es threshold for CVD) and P-osmol during light and moderate exercise (30 and 55% of peak oxygen consumption, respectively) and passive body heating. Then we compared the relationship with the data obtained in our previous study [A. Takamata, K. Nagashima, H. Nose, and T. Morimoto.Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R197-R204, 1997], in which we determined the relationships during passive body heating following isotonic (0.9% NaCl) or hypertonic (2 or 3% NaCl) saline infusions in the same subjects. P-osmol values at 5 min after the onset of exercise were 287.5 +/- 0.9 mosmol/kgH(2)O during light exercise and 293.0 +/- 1.2 mosmol/kgH(2)O during moderate exercise. P-osmol just before passive body heating was 289.9 +/- 1.4 mosmol/kgH(2)O. The Delta T-es threshold for CVD was 0.09 +/- 0.05 degrees C during light exercise, 0.31 +/- 0.09 degrees C during moderate exercise, and 0.10 +/- 0.05 degrees C during passive body heating. The relationship between the Delta T-es threshold for CVD and P-osmol was shown to be on the same regression line both during exercise and during passive body heating with or without infusions [A. Takamata, K. Nagashima, H. Nose, and T. Morimoto. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R197-R204, 1997]. Our data suggest that the elevated body core temperature threshold for CVD during exercise could be the result of increased P-osmol induced by exercise and is not due to reduced plasma volume or the intensity of the exercise itself.

We tested the hypothesis that cardiovascular responses to lower body positive pressure (LBPP) would be dependent on the posture of the subject and also on the background condition (rest or exercise). We measured heart rate (HR), mean arterial blood pressure (MAP), and cardiac stroke volume in eight subjects at rest and during cycle ergometer exercise (76 +/- 3 W) with and without LBPP (25, 50, and 75 mmHg) in the supine and upright positions. At rest, the increase in MAP was proportional to the increase in LBPP and was greater in the supine (6 +/- 2, 15 +/- 3, and 26 +/- 3 mmHg) than in the upright (2 +/- 3, 9 +/- 3, and 17 +/- 3 mmHg) position. During dynamic exercise, the increases in MAP evoked by 25, 50, and 75 mmHg LBPP were greater in the supine (13 +/- 2, 28 +/- 3, and 40 +/- 3 mmHg) than in the upright (7 +/- 3, 12 +/- 3, and 25 +/- 3 mmHg) position. We conclude that the systemic pressure response to LBPP is clearly dependent on the body position, with the larger pressure responses being associated with the supine position both at rest and during dynamic leg exercise.

To assess the impact of continuous negative-pressure breathing (CNPB) on the regulation of skin blood flow, we measured forearm blood flow (FBF) by venous-occlusion plethysmography and laser-Doppler flow (LDF) at the anterior chest during exercise in a hot environment (ambient temperature = 30 degrees C, relative humidity = similar to 30%). Seven male subjects exercised in the upright position at an intensity of 60% peak oxygen consumption rate for 40 min with and without CNPB after 20 min of exercise. The esophageal temperature (T-es) in both conditions increased to 38.1 degrees C by the end of exercise, without any significant differences between the two trials. Mean arterial pressure (MAP) increased by similar to 15 mmHg by 8 min of exercise, without any significant difference between the two trials before CNPB. However, CNPB reduced MAP by similar to 10 mmHg after 24 min of exercise (P &lt; 0.05). The increase in FBF and LDF in the control condition leveled off after 18 min of exercise above a T-es of 37.7 degrees C, whereas in the CNPB trial the increase continued, with a rise in T-es despite the decrease in MAP. These results suggest that CNPB enhances vasodilation of skin above a T-es of similar to 38 degrees C by stretching intrathoracic baroreceptors such as cardiopulmonary baroreceptors.

To assess the impact of continuous negative-pressure breathing (CNPB) on the regulation of skin blood flow, we measured forearm blood flow (FBF) by venous-occlusion plethysmography and laser-Doppler flow (LDF) at the anterior chest during exercise in a hot environment (ambient temperature = 30 degrees C, relative humidity = similar to 30%). Seven male subjects exercised in the upright position at an intensity of 60% peak oxygen consumption rate for 40 min with and without CNPB after 20 min of exercise. The esophageal temperature (T-es) in both conditions increased to 38.1 degrees C by the end of exercise, without any significant differences between the two trials. Mean arterial pressure (MAP) increased by similar to 15 mmHg by 8 min of exercise, without any significant difference between the two trials before CNPB. However, CNPB reduced MAP by similar to 10 mmHg after 24 min of exercise (P &lt; 0.05). The increase in FBF and LDF in the control condition leveled off after 18 min of exercise above a T-es of 37.7 degrees C, whereas in the CNPB trial the increase continued, with a rise in T-es despite the decrease in MAP. These results suggest that CNPB enhances vasodilation of skin above a T-es of similar to 38 degrees C by stretching intrathoracic baroreceptors such as cardiopulmonary baroreceptors.

We studied the difference of thermoregulatory responses between trained male athletes (TR, n = 9) and untrained men (UT, n = 7) during 60 min of cold exposure (15 degrees C) without shivering, and examined the effects of physical fitness and body fat on these responses. Mean skin temperature ((T) over bar(sk)), esophageal temperature (T-es), and skin conductance (K-b) were similar between TR and UT, and heat production ((M) over bar) for TR increased significantly during exposure at 15 degrees C. The (M) over bar at 15 degrees C correlated positively with maximal oxygen uptake and negatively with body fat (%BF), but not with T-es. The K-b correlated negatively with T-es and positively with (T) over bar(sk).The %BF also correlated negatively with K-b and (T) over bar(sk) during exposure at 15 degrees C, and the slope of %BF vs. (T) over bar(sk) relationship was significantly steeper in TR than in UT. These results suggest that (1) body temperature is maintained by the reduction of skin conductance, and (2) heat insulation independent of body fat is enhanced in trained athletes during cold exposure without shivering.

To test the hypotheses that plasma volume (PV) expansion 24 h after intense exercise is associated with reduced transcapillary escape rate of albumin (TERalb) and that local changes in transcapillary forces in the previously active tissues favor retention of protein in the vascular space, we measured PV, TERalb, plasma colloid osmotic pressure (COPp), interstitial fluid hydrostatic pressure (Pi), and colloid osmotic pressure in leg muscle and skin and capillary filtration coefficient (CFC) in the arm and leg in seven men and women before and 24 h after intense upright cycle ergometer exercise. Exercise expanded PV by 6.4% at 24 h (43.9 +/- 0.8 to 46.8 +/- 1.2 ml/kg, P &lt; 0.05) and decreased total protein concentration (6.5 +/- 0.1 to 6.3 +/- 0.1 g/dl, P &lt; 0.05) and COPp (26.1 +/- 0.8 to 24.3 +/- 0.9 mmHg, P &lt; 0.05), although plasma albumin concentration was unchanged. TERalb tended to decline (8.4 +/- 0.5 to 6.5 +/- 0.7%/h, P = 0.11) and was correlated with the increase in PV (r = -0.69, P &lt; 0.05). CFC increased in the leg (3.2 +/- 0.2 to 4.3 +/- 0.5 mu l.100 g(-1).min(-1).mmHg(-1), P &lt; 0.05), and Pi showed a trend to increase in the leg muscle (2.8 +/- 0.7 to 3.8 +/- 0.3 mmHg, P = 0.08). These data demonstrate that TERalb is associated with PV regulation and that local transcapillary forces in the leg muscle may favor retention of albumin in the vascular space after exercise.

To test the hypotheses that plasma volume (PV) expansion 24 h after intense exercise is associated with reduced transcapillary escape rate of albumin (TERalb) and that local changes in transcapillary forces in the previously active tissues favor retention of protein in the vascular space, we measured PV, TERalb, plasma colloid osmotic pressure (COPp), interstitial fluid hydrostatic pressure (Pi), and colloid osmotic pressure in leg muscle and skin and capillary filtration coefficient (CFC) in the arm and leg in seven men and women before and 24 h after intense upright cycle ergometer exercise. Exercise expanded PV by 6.4% at 24 h (43.9 +/- 0.8 to 46.8 +/- 1.2 ml/kg, P &lt; 0.05) and decreased total protein concentration (6.5 +/- 0.1 to 6.3 +/- 0.1 g/dl, P &lt; 0.05) and COPp (26.1 +/- 0.8 to 24.3 +/- 0.9 mmHg, P &lt; 0.05), although plasma albumin concentration was unchanged. TERalb tended to decline (8.4 +/- 0.5 to 6.5 +/- 0.7%/h, P = 0.11) and was correlated with the increase in PV (r = -0.69, P &lt; 0.05). CFC increased in the leg (3.2 +/- 0.2 to 4.3 +/- 0.5 mu l.100 g(-1).min(-1).mmHg(-1), P &lt; 0.05), and Pi showed a trend to increase in the leg muscle (2.8 +/- 0.7 to 3.8 +/- 0.3 mmHg, P = 0.08). These data demonstrate that TERalb is associated with PV regulation and that local transcapillary forces in the leg muscle may favor retention of albumin in the vascular space after exercise.

We examined the effect of increased plasma osmolality (P-osm) on cutaneous vasodilatory response to increased esophageal temperature (T-es) in passively heated human subjects (n = 6). To modify P-osm, subjects were infused with 0.9, 2, or 3% NaCl infusions (Inf) for 90 min on separate days. Infusion rates were 0.2, 0.15, and 0.125 ml . min(-1). kg body wt(-1) for 0.9, 2, and 3% Inf, respectively, which produced relatively similar plasma volume expansion. Thirty minutes after the end of infusion, subjects immersed their lower legs in a water bath at 42 degrees C (room temperature 28 degrees C) for 60 min after 10 min of preheating control measurements. Passive heating without infusion (NI) served as time control to account for the effect of volume expansion. P-osm (mosmol/kgH(2)O) values at the onset of passive heating were 289.9 +/- 1.4, 292.1 +/- 0.6, 298.7 +/- 0.7, and 305.6 +/- 0.6 after NI, 0.9% Inf, 2% Inf, and 3% Inf, respectively. The increases in T-es (Delta T-es) at equilibrium during passive heating (mean Delta T-es during 55-60 min) were 0.47 +/- 0.08, 0.59 +/- 0.08, 0.85 +/- 0.13, and 1.09 +/- 0.12 degrees C after NI, 0.9% Inf, 2% Inf, and 3% Inf, respectively, which indicates that T-es at equilibrium increased linearly as P-osm increased. Delta T-es required to elicit cutaneous vasodilation (Delta T-es threshold for cutaneous vasodilation) also increased linearly as P-osm increased as well as the Delta T-es threshold for sweating. The calculated increases in these thresholds per unit rise in P-osm from regression analysis were 0.044 degrees C for the cutaneous vasodilation and 0.034 degrees C for sweating. Thus the Delta T-es thresholds for cutaneous vasodilation and sweating are shifted to higher Delta T-es along with the increase in P-osm, and these shifts resulted in the higher increase in T-es during passive heating.

To clarify the relationship between aerobic power ((V) over dot O-2max), blood volume (BV), and thermoregulatory responses to exercise-heat stress, we analyzed the cross-sectional relationship between the resting BV, plasma volume (PV), erythrocyte volume (EV), (V) over dot O-2max, forearm blood flow (FBF), and sweating responses during exercise in a hot environment (31 degrees C, 50% relative humidity). Twelve college-aged male subjects with a mean maximal oxygen uptake of 48 (range 42-59) mL.kg(-1).min(-1), a mean PV of 54 (range 42-72) mL.kg(-1), a mean EV of 31 (range 23-43) mL.kg(-1), and a mean BV of 85 (range 67-115) mL.kg(-1) (measured by the Evans Blue dye dilution method) performed three sessions of 20-min cycle exercise at two levels of intensity (40% and 60% (V) over dot O-2max). The BV, PV, and EV correlated positively with peak FBF (r = 0.596-0.711, P &lt; 0.05), the increase of FBF in response to a unit rise in esophageal temperature (Tes; peak Delta FBF/peak Delta Tes) (r = 0.592-0.656, P &lt; 0.05) and with total sweat loss (TSL) (r = 0.599-0.634, P &lt; 0.05) during the exercise. The (V) over dot O-2max correlated with TSL during exercise at 40% (V) over dot O-2max (r = 0.578, P &lt; 0.05), but not with peak FBF and peak Delta FBF/peak Delta Tes. The (V) over dot O-2max per lean body mass also showed a significant positive correlation with BV (r = 0.769, P &lt; 0.01), PV (r = 0.706, P &lt; 0.05), and with EV (r = 0.841, P &lt; 0.001). The peak Delta FBF/peak Delta Tes was correlated positively with peak FBF (r = 0.597-0.830, P &lt; 0.05-0.01) and negatively with peak Tes (r = 0.641-0.769, P &lt; 0.05-0.01) during the exercise at the two levels. However, the chest sweat rate (CSR), TSL, and the increase of CSR in response to a unit rise in Tes (peak Delta CSR/peak Delta Tes) showed no correlation with peak Tes during the exercise at the two levels. These findings suggest that 1) heat dissipation responses during exercise were related more to blood volume than aerobic power and 2) skin blood flow was related more to body temperature than sweating responses during exercise under mild heat stress.

We examined the effect of increased plasma osmolality (P-osm) on cutaneous vasodilatory response to increased esophageal temperature (T-es) in passively heated human subjects (n = 6). To modify P-osm, subjects were infused with 0.9, 2, or 3% NaCl infusions (Inf) for 90 min on separate days. Infusion rates were 0.2, 0.15, and 0.125 ml . min(-1). kg body wt(-1) for 0.9, 2, and 3% Inf, respectively, which produced relatively similar plasma volume expansion. Thirty minutes after the end of infusion, subjects immersed their lower legs in a water bath at 42 degrees C (room temperature 28 degrees C) for 60 min after 10 min of preheating control measurements. Passive heating without infusion (NI) served as time control to account for the effect of volume expansion. P-osm (mosmol/kgH(2)O) values at the onset of passive heating were 289.9 +/- 1.4, 292.1 +/- 0.6, 298.7 +/- 0.7, and 305.6 +/- 0.6 after NI, 0.9% Inf, 2% Inf, and 3% Inf, respectively. The increases in T-es (Delta T-es) at equilibrium during passive heating (mean Delta T-es during 55-60 min) were 0.47 +/- 0.08, 0.59 +/- 0.08, 0.85 +/- 0.13, and 1.09 +/- 0.12 degrees C after NI, 0.9% Inf, 2% Inf, and 3% Inf, respectively, which indicates that T-es at equilibrium increased linearly as P-osm increased. Delta T-es required to elicit cutaneous vasodilation (Delta T-es threshold for cutaneous vasodilation) also increased linearly as P-osm increased as well as the Delta T-es threshold for sweating. The calculated increases in these thresholds per unit rise in P-osm from regression analysis were 0.044 degrees C for the cutaneous vasodilation and 0.034 degrees C for sweating. Thus the Delta T-es thresholds for cutaneous vasodilation and sweating are shifted to higher Delta T-es along with the increase in P-osm, and these shifts resulted in the higher increase in T-es during passive heating.

To assess the relationship between atrial natriuretic peptide (ANP) and the reduction in plasma volume (PV) during exercise, we measured changes in PV and ANP in seven male volunteers during treadmill exercise in air (AE) and with water immersion (WE) together with time control studies of rest in air and in water. Blood samples were collected from a catheter in the antecubital vein at exercise intensities of 32, 49, 65, and 78% of peak oxygen consumption (Vo(2)). Plasma ANP in AE increased significantly from the resting value [15 +/- 1 (SE) pg/ml] only at 78% of peak Vo(2) (29 +/- 5 pg/ml), whereas ANP in WE increased significantly at exercise levels of &gt;49% of peak Vo(2) and reached 68 +/- 9 pg/ml at 78% of peak Vo(2). Although PV in AE and WE decreased significantly with Vo(2) of &gt; 49% of peak Vo(2) (P &lt; 0.01), the decrease from the resting value in WE was significantly greater than that in AE of &gt;65% of peak Vo(2) (P &lt; 0.01) and the decreases at 78% of peak Vo(2) were -9.7 +/- 0.8 and -6.1 +/- 1.7%, respectively. The difference in the decrease in PV between AE and WE at corresponding Vo(2) correlated strongly with that in the increase in ANP (r = -0.97; P &lt; 0.01). These results are consistent with the hypothesis that ANP may be involved in the fluid shift from the intra- to extravascular space during exercise.

To assess the effects of alpha-adrenergic activation on hemorrhage-induced shifts of K+, Na+ and fluid between the intravascular and extravascular spaces, we continuously measured changes in plasma concentrations of K+ and Na+ (Delta[K+]p, Delta[Na+]p) and blood volume (Delta BV) over 60 min after hemorrhage in nephrectomized rats. Hemorrhage was conducted over 5 min at the level of 0.5, 1.0 and 1.5% of body weight (H-0.5, H-1.0, H-1.5), and the result was compared with hemorrhage of 1.0% body weight after administration of alpha(1)-adrenoreceptor antagonist prazosin (0.2 mg/kg, H-1.0P). Delta[K+]p increased significantly (p &lt; 0.05) after hemorrhage, and the peak value was proportional to the level of hemorrhage (0.18 +/- 0.08, 0.62 +/- 0.22 and 1.64 +/- 0.19 meq/l in H-0.5, H-1.0 and H-1.5, respectively). Delta[Na+]p decreased significantly (p &lt; 0.05) after hemorrhage, and the decrease was sustained until the end of the experiment (-0.8 +/- 0.6, -1.0 +/- 0.5 and -2.2 +/- 0.5 meq/l in H-0.5, H-1.0 and H-1.5, respectively). In H-1.0P, the increase in Delta[K+]p (0.25 +/- 0.09 meq/l at the peak) and the decrease in Delta[Na+]p (-0.2 +/- 0.1 meq/l at the bottom) were suppressed significantly (p &lt; 0.05) compared to H-1.0. Although Delta BV was greater in H-1.0P than H-1.0, plasma K+ content was not different between the groups. In H-1.0, the calculated concentrations of K+ and Na+ in the fluid which shifted into the intravascular space ([K+]sf, [Na+]sf) in the first 30 min after hemorrhage were higher in [K+]sf (6.25 +/- 0.70 meq/l) and lower in [Na+]sf (128.0 +/- 3.2 meq/l) than the pre-hemorrhage plasma level. With regard to H-1.0P, [K+]sf and [Na+]sf were not different from the pre-hemorrhage level of plasma. These results suggest that alpha-adrenergic activation after hemorrhage induces K+ movement into plasma to increase [K+]p, which might be related to the fluid shift from the intracellular to the extracellular space.

To assess the relationship between atrial natriuretic peptide (ANP) and the reduction in plasma volume (PV) during exercise, we measured changes in PV and ANP in seven male volunteers during treadmill exercise in air (AE) and with water immersion (WE) together with time control studies of rest in air and in water. Blood samples were collected from a catheter in the antecubital vein at exercise intensities of 32, 49, 65, and 78% of peak oxygen consumption (Vo(2)). Plasma ANP in AE increased significantly from the resting value [15 +/- 1 (SE) pg/ml] only at 78% of peak Vo(2) (29 +/- 5 pg/ml), whereas ANP in WE increased significantly at exercise levels of &gt;49% of peak Vo(2) and reached 68 +/- 9 pg/ml at 78% of peak Vo(2). Although PV in AE and WE decreased significantly with Vo(2) of &gt; 49% of peak Vo(2) (P &lt; 0.01), the decrease from the resting value in WE was significantly greater than that in AE of &gt;65% of peak Vo(2) (P &lt; 0.01) and the decreases at 78% of peak Vo(2) were -9.7 +/- 0.8 and -6.1 +/- 1.7%, respectively. The difference in the decrease in PV between AE and WE at corresponding Vo(2) correlated strongly with that in the increase in ANP (r = -0.97; P &lt; 0.01). These results are consistent with the hypothesis that ANP may be involved in the fluid shift from the intra- to extravascular space during exercise.