Modification of thermoregulatory response to heat stress by body fluid regulation

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1 J Phys Fitness Sports Med, 1(3): (212) JPFSM: Review Article Modification of thermoregulatory response to heat stress by body fluid regulation Akira Takamata Department of Environmental Health, Nara Women s University, Kitauoya Nishimachi, Nara , Japan Received: July 1, 212 / Accepted: September 5, 212 Abstract The thermoregulatory system interacts vitally with the body fluid regulatory system. Thermoregulatory response during heat stress, such as sweating and cutaneous vasodilation, stimulates body fluid regulatory response by elevating plasma osmolality and reducing central blood volume. Isotonic hypovolemia, or baroreceptor unloading, and plasma hyperosmolality, in turn, inhibit thermoregulatory response to heat stress, suggesting that body fluid regulation is given priority over thermoregulation. On the other hand, osmoregulatory vasopressin secretion and thirst are augmented by elevated body core temperature. Heat acclimation enhances thermoregulatory response to heat stress. Adaptation of the body fluid regulatory system, such as increased plasma volume and reduced osmotic inhibition of thermoregulatory response, is possibly involved in the mechanism for the enhancement of thermoregulatory response to heat stress by heat acclimation. In this review, we discuss the interaction between body fluid regulation, especially osmoregulation, and thermoregulation mainly in humans. Keywords : Osmoregulation, Volume Regulation, Sweating, Cutaneous Vasodilation, Heat Acclimation Introduction Preventing excessive heat accumulation, which causes hyperthermia, is critical for maintaining aerobic exercise performance, especially during high intensity exercise, because severe hyperthermia can be a critical factor of exhaustion during exercise 1). An increased body core temperature activates thermoregulatory response, such as sweating and cutaneous vasodilation 2), which stimulates body fluid regulatory and cardiovascular systems via hypovolemia, or baroreceptor unloading 3,4), and plasma hyperosmolality 4) ; activated body fluid regulatory and cardiovascular systems, in turn, inhibit thermoregulatory response to heat stress 4,5). Therefore, the thermoregulatory system vitally interacts with body fluid regulatory and cardiovascular systems, and maintenance of body fluid status possibly prevents progressive hyperthermia during exercise in a hot environment 4,5). The aim of this review is to discuss the interaction between body fluid regulatory and thermoregulatory systems, along with the effect of exercise training and heat acclimation on the interaction between these systems. Thermoregulation during heat stress In order to prevent excessive hyperthermia during heat stress, the thermoregulatory system increases heat Correspondence: takamata@cc.nara-wu.ac.jp loss from the body surface to the environment 2). Human autonomic thermoregulation during heat stress is accomplished by cutaneous vasodilation and sweating. Cutaneous vasodilation increases skin blood flow by reducing the vascular resistance of this region 3). Increased skin blood flow transfers heat from the body core to the surface, and increased skin temperature enhances heat dissipation from the body surface if skin temperature is higher than the atmospheric temperature. Evaporation of sweat enhances evaporative heat loss from the skin surface. Such thermoregulatory response is induced mainly by increased body core temperature, which is a signal for the negative feedback system, and by thermal input from the skin. The weight of thermal input for thermoregulatory response was estimated as for body core temperature and for mean skin temperature 6-8). Thermoregulatory response to increased body temperature can be quantified by the body temperature thresholds for the response, (represented as the body core temperature at the onset of thermoregulatory response), thermal responsiveness (represented as the increase in response per unit rise in body temperature above the threshold), and maximal response (represented as the leveling-off of a response resulting from increased body core temperature) 9). Thus, factors altering the body temperature thresholds, thermal responsiveness, and maximal response should have an impact on the regulated body core temperature during heat stress. There are several non-thermal factors which modify thermoregulatory response to heat

2 48 JPFSM: Takamata A stress 2,1,11). Among these factors, the body fluid regulatory system interacts most vitally with the thermoregulatory system 12-15). Body fluid change during heat stress and body fluid regulatory response Body fluid osmolality and volume are strictly controlled, within a very narrow range, by osmoregulatory and volume (ECF/plasma volume) regulatory systems 16). Plasma osmolality is one of the most tightly regulated homeostatic variables in mammals. A very small increase (3%) in plasma osmolality can elicit osmoregulatory vasopressin release and thirst 16-18). Vasopressin secretion and thirst are induced by increased plasma osmolality. Systemic vasopressin decreases urinary free water output by increasing free water reabsorption in the collecting duct; and water intake induced by thirst adds free water to the body. Extracellular fluid volume is regulated by the renin-angiotensin-aldosterone system (RAAS) and sodium appetite with a smaller contribution of vasopressin release and thirst 16). ECF volume is determined by sodium balance if the osmoregulatory system operates normally. RAAS decreases urinary sodium excretion by increasing sodium reabsorption, mainly in the distal tubule, and sodium appetite increases sodium content by increasing sodium intake. A relatively large decrease in plasma volume (~1 %) or blood pressure can stimulate vasopressin secretion and thirst 16). Sweating results in both hypovolemia and plasma hyperosmolality because of the hypotonic nature of sweat 19,2), and cutaneous vasodilation results in reduced central blood volume (baroreceptor unloading) by increasing blood pooling in the peripheral tissues 3,21). Therefore, the thermoregulatory response to heat stress, such as sweating and cutaneous vasodilation, stimulates both osmoregulatory and volume regulatory systems. This indicates there exists a strong interaction between thermoregulatory and body fluid regulatory systems. Effect of dehydration on thermoregulatory response to heat stress Since Adolph and associates reported that a water deficit, induced by profuse sweating during desert marching, increased the resting rectal temperature in the classic Man in the Desert in ), a number of studies have examined the effect of dehydration on thermoregulatory response. It is now well-established that dehydration attenuates thermoregulatory response, such as sweating and cutaneous vasodilation, to heat stress; and fluid replacement can reverse, at least partly, the dehydration-induced attenuation of thermoregulatory response to heat stress 4,5). However, Tokizawa et al. 23) recently reported that mild dehydration in humans attenuated autonomic thermoregulatory response and thermal sensation, but did not alter thermal pleasantness in a hot environment in human subjects, suggesting that behavioral thermoregulation will not be activated with mild dehydration. Further study is required to elucidate if hypohydration has no effect on thermal pleasantness or if severe hypohydration can attenuate thermal pleasantness. Dehydration induced by sweating, or thermal dehydration, results in extracellular fluid (ECF) sodium deficit, hypovolemia and ECF hyperosmolality. In this review, the effect of isotonic hypovolemia, or baroreceptor unloading, and plasma hyperosmolality on thermoregulatory response to heat stress are discussed separately. We also discuss the interactive effect of baroreceptor unloading and plasma hyperomolality on thermoregulatory response to heat stress. Hypovolemia and thermoregulation during heat stress To elucidate the effect of isotonic hypovolemia on thermoregulatory cutaneous vasodilation, Nadel et al. 24) examined forearm blood response to increased body temperature during exercise in diuretics-treated human subjects. They found that isotonic hypovolemia shifted the relationship between forearm blood flow/esophageal temperature response in a right/downward direction (Fig. 1), suggesting that isotonic hypovolemia inhibits thermoregulatory cutaneous vasodilation, while the effect of hyperhydration induced by antidiuretic hormon administration plus water ingestion (2 liters) was minimal. Although their data provided an insight into the inhibitory effect of isotonic hypovolemia on thermoregulatory cutaneous vasodilation, their data cannot provide us with enough information whether the inhibitory effect is caused by the increased body temperature threshold, reduced thermore Control Hypohydration Hyperhydration Fig. 1 The relationship between forearm blood flow and esophageal temperature during exercise in heat with 3 different hydration states: control, hypohydration and hyperhydration. Redrawn from Nadel, et al. (1981) 24).

3 JPFSM: Interaction between thermoregulation and body fluid regulation 481 sponsiveness, or both, because the number of data points is not enough to characterize the response. A recent study reported that isotonic hypohydration increased the body core temperature threshold for both cutaneous vasodilation during moderate exercise, but not for sweating; and isotonic hypohydration did not alter the thermal responsiveness for both cutaneous vasodilation and sweating 25). Baroreceptor unloading with use of lower body negative pressure (LBNP), which decreases central blood volume (CBV) without any change in total body fluid volume, also inhibited thermoregulatory cutaneous vasodilation during exercise 26-29) and passive body heating 28), indicating that the effect of hypovolemia is possibly mediated by the unloading of volume receptors in the cardiopulmonary region. However, Ryan and Proppe 3) reported that repletion of whole ECF volume, by isotonic saline, eliminated attenuation of the increase in iliac blood flow in dehydrated baboons; whereas the selective repletion of plasma volume by infusion of an isotonic 6% dextran solution only partly reversed attenuation. From the results, they concluded that the effect of dehydration on a thermally-induced increase in iliac vascular conductance was not due to reduced plasma volume, but rather to reduced interstitial volume 3). It is not clear if involvement of this mechanism in the hypovolemia-induced inhibition of cutaneous blood flow is specific for baboons. Although the mechanism of attenuated thermoregulatory cutaneous vasodilation by a reduced ECF volume remains controversial, involvement of cardiopulmonary baroreflex is likely involved in the inhibition of thermoregulatory cutaneous vasodilation. Kamijo et al. 31) recently examined the efferent mechanism for hypovolemia-induced inhibition of thermal cutaneous vasodilation, and they demonstrated that inhibition of cutaneous vasodilatation, induced by hypovolemia during hyperthermia, might be caused by a reduction in the skin sympathetic nerve activity component synchronized with the cardiac cycle. Their data further support the involvement of cardiopulmonary baroreflex in the hypovolemic inhibition of thermal cutaneous vasodilation. Baroreceptor unloading is likely to inhibit thermal cutaneous vasodilation, during exercise, by increasing the body core temperature threshold and decreasing both thermal responsiveness and maximal response 27). The hypovolemic effect on thermal sweating is controversial. Studies show changes in blood volume do not influence thermoregulatory sweating in exercising humans 25,32). Although Mack et al. 27) reported that baroreceptor unloading with use of LBNP inhibits thermal sweating during exercise, isotonic hypovolemia seems to inhibit thermoregulatory cutaneous vasodilation more selectively than sweating. Plasma hyperosmolality and thermoregulatory response to heat stress The effect of plasma hyperosmolality, without hypo- volemia, on thermoregulatory evaporative heat loss, including sweating and panting, has been intensively studied 12,15). Increased ECF/plasma osmolality (cell dehydration) attenuates thermal sweating in exercising humans 33,34), and goats 35), as well as respiratory evaporative heat loss in other animal species in response to passive heating 36,37). Fortney et al. 33) compared the effect of dehydration and plasma hyperosmolality on forearm blood flow, and sweating response to an increased esophageal temperature induced by moderate exercise. They found that dehydration increased the body temperature threshold for sweating and cutaneous vasodilation, and also reduced thermoresponsiveness above the threshold; whereas hyperosmolality, without hypovolemia, elevated the body temperature threshold with unchanged thermoresponsiveness. From these observations, they concluded that plasma hyperosmolality increases the body temperature threshold for thermoregulatory responses, such as sweating and cutaneous vasodilation; and hypovolemia reduces thermoresponsiveness above the threshold. Takamata et al. 38,39) reported that increased plasma osmolality elevates the esophageal temperature thresholds for both sweating and cutaneous vasodilation with thermoresponsiveness above the threshold unchanged in passively heated humans (Fig. 2). Thus, plasma hyperosmolality increases the body temperature threshold for sweating, but does not alter thermoresponsiveness during heat stress. The delayed onset of sweating and cutaneous vasodilation during heat stress, i.e. the increased esophageal temperature threshold for sweating, was the major factor resulting in greater heat storage during passive heating in a condition of cell dehydration 38,39). Animal studies have demonstrated that intracerebroventricular (ICV) 4,41) or intra-arterial 42) infusion of hypertonic solution inhibits thermoregulatory evaporative heat loss without any changes in systemic osmolality. In addition, the activity of the hypothalamic thermosensitive neurons, of slice preparations, was inhibited with a hypertonic medium 43). Thus, the mechanism of ECF/plasma hyperosmolality-induced inhibition of thermoregulatory evaporative heat loss has been considered a central effect. Cell dehydration, induced by increased ECF/plasma osmolality, stimulates thirst and vasopressin secretion 16,18). Drinking causes a rapid reduction of osmoregulatory response, such as thirst and plasma vasopressin release, before any changes in plasma osmolality or plasma volume occur. This response has been demonstrated in dogs 44), and also in humans following 24 h water deprivation 45) and hypertonic saline infusion 46). It has been hypothesized that the rapid effect of drinking is mainly mediated by mechanical stimulation of the oropharyngeal receptors; and this reflex has been called the oropharyngeal reflex. Takamata, et al. 38) examined the effect of drinking on osmotically-inhibited sweating in passively heated humans, and found that osmotic inhibition of thermal sweating was reversed immediately after drinking a small amount

4 482 JPFSM: Takamata A Fig. 2 The chenges in local chest sweating rate ( SR ch; left) and cutaneous vascular conductance ( CVC; right) as a function of the change in esophageal temperature ( T es) during passive body heating after hypertonic or isotonic saline infusion. Values are the means ± SE of 11 subjects. Modified from Takamata et al. (21) 39). because an inhibitory effect of plasma hyperosmolality on thermoregulation occurred without a reduction in plasma osmolality. While the effect of hyperosmolality on thermoregulatory evaporative heat loss has been intensively studied 12,15), the effect of increased plasma osmolality on thermoregulatory cutaneous vasodilatory response to increased body temperature has received much less attention than the effect of hypovolemia or baroreceptor unloading 21). Fortney et al. 33) compared the effects of dehydration and hyperosmolality on thermoregulatory response, such as forearm blood flow and sweating, to increased body core temperature during exercise. They reported that the esophageal temperature threshold for the increase in forearm blood flow, presumably cutaneous blood flow, was elevated in exercising human subjects by plasma hyperosmolality induced by hypertonic saline infusion following water deprivation. In contrast, Proppe 53) reported that hypovolemia, induced by diuretics treatment, attenuated the increase in iliac blood flow (iliac vascular conductance) as much as dehydration, during passive body heating in baboons; but hyperosmolality did not have such an effect. From these results, he concluded that the dehydrationinduced reduction in limb blood flow, presumably skin blood flow, is mainly caused by hypovolemia or reduced interstitial fluid volume; and that the effect of hyperosmolality is negligible. Takamata et al. 39,54) examined the effect of plasma hyperosmolality on thermoregulatory cutaneous vascular and sweating responses in humans during passive body heating. They found that the increase in esophageal temperature, required to elicit both cutaneous vasodilation and sweating ( Tes threshold for cutaneous vasodilation and sweating), increased linearly with the increase in plasma osmolality. Thus, a larger increase in Tes was required to elicit a response with the increase in plasma osmolality; and the equilibrated temperature during pasof water (Fig. 3). Several studies in humans 47,48), goats 35) and sheep 49) showed similar results, although plasma osmolality or osmoregulatory response before and after drinking were not measured in most of the studies. The recovery of sweating occurred immediately after drinking, without any change in plasma osmolality or plasma volume (Fig. 3), suggesting that this response is mediated by the receptors in the early alimentary tract, probably the oropharyngeal receptor 38,49). Because plasma osmolality remained high after drinking in a hyperosmotic condition, and drinking reversed the osmotic inhibition of thermal sweating to almost the level seen in the euhydrated condition, the local or direct effect of hyperosmolality on the sweat glands was not the main cause of the osmotic inhibition of thermal sweating in humans. Further, drinking did not have a direct effect on thermal sweating, because the sweating rate did not increase in response to drinking in the euhydrated condition. Taken together, these results suggest that the osmotic inhibitory effect on thermal sweating in humans is mainly a central effect, and drinking itself can remove this osmotic inhibition of the thermoregulatory center. The acute recovery of thermal sweating by drinking water was associated with reduced thirst ratings and reduced AVP secretion; and oropharyngeal stimulation is known to suppress osmoregulatory response, such as thirst and AVP secretion. It is postulated that drinking eliminates the osmotic inhibitory input to the thermoregulatory center 38). It hase been reported that drinking may well attenuate osmosensitive neuron activity 5,51). It is unlikely that changes in plasma AVP have a direct influence on the thermoregulatory center 52) and/or the sweat glands 19). These data allow us to speculate that the osmoreceptors or central osmoregulatory pathways, which induce both thirst and AVP secretion, are involved in the osmotic inhibition of thermoregulatory sweating. It is unlikely that thermosensitive neurons are directly inhibited by osmotic stimulus,

5 JPFSM: Interaction between thermoregulation and body fluid regulation Fig. 4 Tes thresholds for cutaneous vasodilation ( Tes for CVD), for sweating ( Tes for sweating), and Tes during thermal equilibrium as functions of plasma osmolality (Posm) during passive body heating after isotonic or hypertonic saline infusion. All data points determined for each subject, in each condition, are shown as small gray circles, and mean and SE (n=6) in each condition, as black circles. Modified from Takamata et al. (1997) 54). Fig. 3 Effect of drinking water on local chest sweating (SR ch), esophageal temperature (T es), plasma osmolality (P osm), change in plasma volume ( PV), plasma arginine vasopressin concentration ([AVP] p), and subjective thirst rating. Subjects were infused with either hypertonic saline (3 % NaCl; black circles) or isotonic saline (.9 % NaCl; gray circles) before passive body heating. Subjects drank 2-ml water at 6 min after the onset of heating (indicated by shaded column). Data are shown as mean and SE of 7 subjects. Values significantly different from values of the predrinking period are indicated by an. Modified from Takamata et al. (1995) 38). sive body heating also increased linearly with the increase in plasma osmolality. They proposed that the rise in the Tes threshold per unit increase in plasma osmolality was.44 C for cutaneous vasodilation,.34 C for sweating, and.35 C for equilibrated body core temperature increase during passive body heating (Fig. 4). The thermoresponsiveness (defined by the slope of the Tes-response relationship above the threshold) of cutaneous vasodilation was likely to be unchanged. Thus, in humans, the inhibitory effect of plasma hyperosmolality is not specific for sweating, but also for cutaneous vasodilation, and plasma hyperosmolality increases the body core temperature thresholds for both sweating and cutaneous vasodilation without a change in thermal responsiveness of these responses above the threshold. In contrast, hyperosmolality did not influence the thermally-induced increase in iliac blood flow 53). The thermally-induced increase in hind limb vascular conductance in baboons was nearly completely mimicked by an a-adrenergic receptor blockade, suggesting that there is no human-like active vasodilatory system, and that skin blood flow is controlled mainly by the reduction in vasoconstrictor tone in baboons 55). To elucidate the efferent mechanism for osmotic inhibition of thermal cutaneous vasodilation, Shibasaki et al. 56) examined the effect of plasma hyperosmolality on the cutaneous vascular response to increased body core temperature on the sites with or without treatment of bretylium, which inhibits the vasoconstrictor system. They found that bretylium treatment did not alter the osmoti-

6 484 JPFSM: Takamata A cally-inhibited cutaneous vascular response to heat stress. Thus, the osmotically-induced elevation of the internal temperature threshold for cutaneous vasodilation is due primarily to an elevation in the body core temperature threshold for the onset of active vasodilation, and not to enhancement of vasoconstrictor activity. Plasma hyperosmolality attenuates the active vasodilatory system, as well as sweating, by elevation of the body core temperature thresholds 21,56,57). Kamijo et al. 58) reported that oropharyngeal stimulation can reverse dehydration-induced inhibition of thermoregulatory cutaneous vasodilation in exercising humans, suggesting that the mechanism for osmotic inhibition of cutaneous vasodilation is the same as the mechanism for osmotic inhibition of sweating. The central osmoreceptor or osmoregluratory pathway, involved in thirst and vasopressin secretion, might be involved in the osmotic inhibition of thermal cutaneous vasodilation 38,58). In contrast to the effect on autonomic thermoregulatory response, plasma hyperosmolality augmented heatescape and cold-seeking behavior in rats 59,6), suggesting that behavioral thermoregulation is enhanced by plasma hyperosmolality. It was also reported that dehydrated sheep, exposed to heat, exhibit selective brain cooling up to threefold greater than when euhydrated 61). These responses might contribute to preventing excessive water loss and hyperthermia by compensating osmotic inhibition of an autonomic thermoregulatory response. Interactive effect of plasma hyperosmolality and baroreceptor unloading on thermoregulatory response to heat stress There are a few studies examining the interactive effect of hypovolemia, or baroreceptor unloading, and plasma hyperosmolality on thermoregulatory response. Nakajima, et al. 62) examined the effect of isotonic hypovolemia, induced by diuretic treatment, and hyperosmolality induced by subcutaneous injection of hypertonic saline in rats, and they found that hypovolemia attenuated a maximal tail vasodilatory response to hyperthermia; and plasma hyperosmolality, with hypovolemia, increased the body core temperature threshold for tail vasodilation without further reduction in tail vascular conductance. The effect of hypovolemia and plasma hyperosmolality seemed to have an additive effect in their study. However, the mode of interactive action of hypovolemia and hyperosmolality remains unknown from their study, because the effect of hyperosmolality without hypovolemia was not examined. Further, regulation of tail vascular response to increased temperature is different from human cutaneous vascular response because the tail is rich in arteriovenous anastomoses (AVAs) 63). It is hard to compare the regulation of cutaneous blood flow in rats with such regulation in humans. In humans, Ito, et al. 64) found that the decrease in peripheral vascular conductance, in response to baroreceptor unloading, became larger during hyperthermia. They concluded that an interactive effect exists of plasma osmolality and central hypovolemia on peripheral vascular response during heat stress, but not in normothermia. Thus, plasma osmolality and baroreceptor unloading have a synergistic effect on thermoregulatory active vasodilation. On the other hand, Lynn et al. 65) reported an additive effect of hyperosmolality and baroreceptor unloading on the onset threshold for increases in CVC during whole body heat stress, while the onset threshold for sweating during heat stress was only elevated by hyperosmolality, with no effect of the baroreflex. Further study is required to fully elucidate the interactive effect of plasma osmolality and baroreceptor unloading on thermoregulatory response to heat stress. Thermal modification of osmoregulation Body fluid volume and its osmolality are controlled within a very narrow range by the osmoregulatory and volume (ECF volume) regulatory systems 16). Fluid regulatory hormone vasopressin secretion and thirst are stimulated by extracellular fluid hyperosmolality, i.e., cell dehydration, and are also stimulated, to a lesser extent, by hypovolemia including reduced atrial or arterial blood pressure 18). There are several factors, other than plasma hyperosmolality and/or hypovolemia, which stimulate vasopressin secretion, such as nausea, pain, hypoxia, and hypoglycemia, etc. 18,66). In addition to these influences, several studies have revealed that heat exposure elevates plasma vasopressin concentration and reduces the urinary excretion rate 67-69), suggesting that an increased body temperature is a potential factor for vasopressin secretion. Thermal dehydration induces both ECF hyperosmolality (cell dehydration) and ECF sodium deficit (hypovolemia), and thermoregulatory cutaneous vasodilation reduces central blood volume (central hypovolemia). Forsling et al. 67) reported that whole body passive heating increased plasma vasopressin concentration in pigs, and hypothalamic cooling reduced this response; but they found inconsistent changes in plasma vasopressin concentration with hypothalamic or spinal cord heating and cooling in cold, thermoneutral and warm conditions. Szczepanska-Sadowska 7) reported that hypothalamic heating augmented AVP secretion in dogs. Takamata et al. 71) examined the effect of passive body heating on osmoregulatory responses in humans, such as vasopressin secretion and subjective thirst. They reported that passive body heating, without changing plasma osmolality, did not increase plasma vasopressin concentration. They also reported thatwhile the hypertonic saline infusion increased vasopressin secretion in both hyperthermic and normothermic conditions, the increase in plasma vasopressin concentration was much higher during hyperthermia than normothermia, and fluid intake following infusion was

7 JPFSM: Interaction between thermoregulation and body fluid regulation 485 also larger under hyperthermia; although the increase in plasma osmolality during and after infusion was similar (Fig. 5). Thus, the effect of hyperthermia was dependent on the level of plasma osmolality. From these results, Takamata et al. 71) concluded that the effect of the increase in body temperature on vasopressin secretion is plasma osmolality dependent; and the contradictory literature concerning the effects of increased body temperature may be due to a lack of strict control of plasma osmolality. The augmented osmosensitivity for vasopressin secretion and thirst, caused by increased body temperature, would contribute to body fluid restoration and conservation during progressive thermal dehydration. A recent study demonstrated that the trpv1 gene is required in the AVP neurons Lower leg immersion 3 % NaCl infusion Thermoneutral Passive heating Cutaneous circulation is controlled primarily by thermal drive or body temperature, and a couple of nonthermal factors are known to modify this thermoregulatory cutaneous vascular response 21,29). It has been reported that exercise inhibits thermoregulatory cutaneous vasodilation in an exercise intensity-dependent manner. Light exercise does not alter thermoregulatory cutaneous vasodilation, while moderate to heavy exercise inhibits cutaneous vascular response by elevating the body temperature threshold 74-76). An increase in plasma osmolality occurs in response to exercise intensity in a fashion similar to the elevation of the body core temperature threshold for cutaneous vasodilation 77-79). Takamata et al. 8) examined the relationship between the increase in body temperature, required to elicit cutaneous vasodilation ( Tes threshold for cutaneous vasodilation), and plasma osmolality during light/moderate exercise (~3 and 55 % of peak V O 2 ) and passive body heating. Then they compared that relationship with data obtained in their previous study, of the same subjects, in which they determined the relationships during passive body heating following isotonic (.9% NaCl) or hypertonic (2 to 3% NaCl) saline infusion 54). The results showed that the relationship between the Tes threshold for cutaneous vasodilation and plasma osmolality was shown to be on the same regression line, both during exercise and during passive body heating, with or without infusions (Fig. 6). Those data suggest that the elevation of the body core temperature threshold for cutaneous vasodilation could be the result of increased plasma osmolality induced by exercise, and not due to reduced plasma volume or the intensity of exercise itself. Mitono et al. 81) examined further to elucidate the involvement of increased plasma osmolality during exercise in the elevation of the body core temperature threshold for cutaneous vasodilation. They infused hypotonic saline to prevent exercise-induced hyperosmolality, and determined the body core temperature threshold for cutaneous vasodilation. They found that elevation of the body core temperature threshold, for forearm vascular conductance, was attenuated by an acute hypotonic saline infusion, suggesting that the exercise-induced increase in the body core temperature threshold for forearm vascular conductance is at least partially attributed to the increased plasma osmolality induced by exercise 8,81). Both exercise-induced inhibition and osmotic inhibi- Rehydration Fig. 5 Plasma osmolality, subjective thirst rating, plasma arginine vasopressin concentration ([AVP]p), and cumulative water intake (CWI), before, during, and after hypertonic saline infusion. Values are mean and SE of seven subjects. Significant differences between thermoneutral and passive heating are indicated by an. Modified from Takamata et al. (1995) 71). for thermally-induced vaspressin secretion. Thus, the AVP neurons are likely to be thermosensitive 72). The interactive effect of body temperature and osmolality on AVP secretion remains unkinown. However, a similar interaction has been provided by the demonstration that TRPV4- expressing cells show a noticeably greater response to hypotonicity at 37 C than at room temperature 73). Thermoregulatory cutaneous vasodilation during exercise: Involvement of osmoregulation

8 486 JPFSM: Takamata A tion of cutaneous vasodilation, by the increased body core temperature threshold, are not due to increased sympathetic vasoconstrictor tone, but rather to attenuated active vasodilator outflow 56,82). Therefore, the mechanism for exercise-induced elevation of the core temperature threshold for cutaneous vasodilation can be mediated by increased plasma osmolality; and, thus, the hypothesis can be supported that hyperosmolality, induced by exercise, is involved in the elevation of the body core temperature threshold for cutaneous vasodilation during intense exercise. Fig. 6 Relationship between Tes threshold for cutaneous vasodilation ( T es for CVD) and plasma osmolality (P osm) during light (black circles) and moderate exercise (black triangles) and passive heating (white circle), and passive body heating with isotonic or hypertonic saline infusion (gray circles). Mean and SE values for each condition are shown as large symbols. Modified from Takamata et al. (1998) 8). Heat acclimation and osmoregulatory adaptation Due to the hypotonic nature of sweat 19), profuse sweating during prolonged heat exposure and/or exercise results in hyperosmotic hypovolemia. Heat acclimation reduces sweat sodium concentration 83-85), and therefore, the increase in plasma osmolality at a given sweat output should be larger in heat-acclimated people, which would be beneficial to maintain ECF/plasma volume during prolonged sweating because a larger increase in ECF/plasma osmolality draws more free water from the intracellular to the extracellular space 86). Thus, hypovolemic inhibition of thermoregulatory response, mainly cutaneous vascular response, is expected to become smaller with heat acclimation, by preventing excessive ECF loss 87). Heat acclimation improves thermal endurance 1,83), and shifts the body temperature threshold for sweating and cutaneous vasodilation to a lower body core temperature 88), although the sweat sodium concentration is decreased. Takamata et al. 39) determined the relationship between osmotic inhibition of thermoregulatory response and sweat sodium concentration in 11 subjects. The osmotic inhibition was quantified as an increase in Tes threshold for sweating and cutaneous vasodilation per unit rise in plasma osmolality. As shown in Fig. 7, osmotic inhibition of thermoregulatory sweating and cutaneous vasodilation were linearly correlated with sweat sodium concentration. These results suggest that heat acclimation could attenuate the osmotic inhibitory effect on thermoregulation. The effect of heat acclimation is likely to be specific to the osmotic inhibition of thermoregulation, but not to osmoregulation in general, because osmosensitivity for vasopressin secretion is not related to sweat sodium concentration. Ichinose et al. 89) examined the effect of heat acclimation on osmotic inhibition of thermoregulatory response (longitudinal study). They found that osmotic elevation of the body core temperature threshold for cu- Fig. 7 Relationship between the shift in Tes threshold for sweating per unit rise in plasma osmolality (Osmotic shift in Tes for sweating) and sweat sodium concentration (left), and between osmotic shift in Tes for cutaneous vasodiltion (CVD) and sweat sodium concentration. Modified from Takamata et al. (21) 39).

9 JPFSM: Interaction between thermoregulation and body fluid regulation 487 taneous vasodilation was attenuated by ten-day exercise training, but not for sweating. They also found that attenuation of osmotic elevation of the body core temperature threshold for cutaneous vasodilation was correlated with plasma volume expansion by exercise training. Taken together, osmoregulatory adaptation is possibly involved in the mechanism of heat acclimation, in addition to the involvement of plasma volume expansion 4,9). This osmoregulatory adaptation contributes to maintaining a lower body temperature during progressive heat exposure or during exercise accompanied by profuse sweating. Conclusions The maintenance of body fluid volume and osmolality, as an internal environment, is essential to maintaining the physiological functions of organisms. In this review, the authorrs have shown that thermoregulatory function was inhibited by plasma hyperosmolality, and that hyperthermia augments osmoregulatory vasopressin secretion and thirst. It was also demonstrated that osmoregulatory adaptation is possibly involved in the mechanism of heat acclimation. Although accumulated data suggest that the interaction between osmoregulation and thermoregulation occurs in the central nervous system, the central mechanism of this interaction still remains unknown. It is expected that future studies will investigate the mechanisms for the interaction between body fluid regulation and thermoregulation. References 1) Nielsen B, Hales JR, Strange S, Christensen NJ, Warberg J, Saltin B Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment. J Physiol (Lond). 46: ) Nadel ER Recent advances in temperature regulation during exercise in humans. 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