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J Appl Physiol 105: 1509-1518, 2008. First published September 11, 2008; doi:10.1152/japplphysiol.01206.2007
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Effect of hypohydration on hyperthermic hyperpnea and cutaneous vasodilation during exercise in men

Naoto Fujii,1 Yasushi Honda,1 Keiji Hayashi,1 Narihiko Kondo,2 and Takeshi Nishiyasu1

1Institute of Health and Sports Science, University of Tsukuba, Tsukuba City; and 2Faculty of Human Development, Kobe University, Kobe, Japan

Submitted 12 November 2007 ; accepted in final form 10 September 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We tested the hypothesis that, in humans, hypohydration attenuates hyperthermic hyperpnea during exercise in the heat. On two separate occasions, thirteen male subjects performed a fluid replacement (FR) and a no-fluid replacement (NFR) trial in random order. The subjects performed two bouts of cycle exercise (Ex1 and Ex2, 30–60 min) at 50% peak oxygen uptake (VO2 peak) in 35°C separated by a 70- to 80-min rest period, during which they drank water containing 25 mosmol/l sodium in the FR trial but not the NFR trial. The drinking in the FR trial nearly restored the body fluid to the euhydrated condition, so that the body fluid status differed between the trials before Ex2 (the difference in plasma osmolality before Ex2 was 9.4 mosmol/kgH2O; plasma volume was 7.6%, and body weight was 2.5%). The slopes of the linear relationships between ventilatory variables (minute ventilation, ventilatory equivalents for oxygen uptake and carbon dioxide output, tidal volume, respiratory frequency, and end-tidal CO2 pressure) and esophageal temperature (Tes) did not significantly differ between Ex1 and Ex2, or between the FR and NFR trials. On the other hand, during Ex2 in the NFR trial, the Tes threshold for the onset of increased forearm vascular conductance (FVC) was higher, and the slope and peak values of the relationship between FVC and Tes were lower than during Ex1 in the NFR trial and during Ex2 in the FR trial. These findings suggest that hypohydration does not affect the hyperthermic hyperpnea during exercise, although it markedly attenuates the cutaneous vasodilatory response.

thermoregulation; respiration; ventilation; skin circulation

IN MANY SPECIES of mammals and birds, an elevation in body temperature stimulates ventilation and increases evaporative heat loss for thermoregulation (the so-called panting response) (42). In 1905, Haldane (25) was the first to report that hyperthermia also increases ventilation in humans, and the recent review by White (53) suggested that the hyperthermic hyperventilatory response provides countercurrent cooling of blood perfusing the brain (selective brain cooling). However, the mechanism and the physiological significance of this response in humans are not fully understood.

Hayashi et al. (26) and Nybo and Nielsen (37) recently reported that during prolonged submaximal exercise [50–57% peak oxygen uptake (VO2 peak)] in the heat in humans, minute ventilation (VE) increases linearly with increasing esophageal temperature (Tes), but this ventilatory response appears independent of skin temperature (Tsk) and the rate of increase in core temperature (26). Such prolonged exercise in the heat usually leads to profuse sweating, which can lead to hypohydration. Indeed, body weight was reduced by 1.5% in Hayashi's study (unpublished data), and by 0.7% in Nybo and Nielsen's study (37). Thus hypohydration might have affected the relationship between VE and Tes during exercise in both of those studies. Consistent with that idea, Senay and Christensen (43) showed that hypohydration affects the ventilatory response in the heat, but their results did not show the relationship between the ventilatory response and core temperature, and the result was obtained under resting conditions, not during exercise. It therefore remains unclear whether body fluid status affects the hyperthermic hyperpnea during exercise in humans.

Although human studies on the relationship between hydration status and hyperthermic hyperpnea are limited, this is not the case with animal studies. It has been shown, for example, that hypohydration attenuates the ventilatory response to an increase in core temperature in exercising dogs (3), resting fowl (2), resting cats (5, 12, 13), and resting rabbits (46). On the other hand, hypohydration reportedly leads to an increase in ventilation in resting rabbits (7) but little or no change in ventilation in exercising goats (6, 35). Thus the effect of hypohydration on the ventilatory response to an increase in core temperature is still not completely understood in animals and could differ among species.

It has been speculated that when body temperature increases under conditions of dehydration, homeostatic conflict between thermoregulation and body fluid regulation occurs. The attenuated ventilatory response to an increase in core temperature under conditions of dehydration could indicate that fluid homeostasis overrides thermoregulatory responses in the aforementioned animals (2, 3, 5, 12, 13, 46). Consistent with this idea, in exercising humans, hypohydration reportedly attenuates thermoregulatory responses (e.g., cutaneous vasodilation and sweating) to increases in core temperature (15, 16, 17, 34, 44). Although the physiological significance of hyperthermic hyperpnea remains unclear, since respiratory heat loss induced by increases in ventilation may contribute to heat dissipation in exercising humans, as do cutaneous vasodilation and sweating (32), hyperthermic hyperpnea may also be a thermoregulatory response, and, if so, it is plausible that this response is also attenuated by hypohydration.

Accordingly, we hypothesized that hypohydration attenuates both hyperthermic hyperpnea and the cutaneous vasodilatory response during exercise in humans. To test that idea, we compared these parameters during exercise under conditions designed to produce either euhydration or hypohydration.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   Thirteen healthy male subjects [age = 24.0 ± 2.3 (SD) yr; height = 170.2 ± 2.4 cm; body weight (BW) = 66.6 ± 7.7 kg; VO2 peak = 48.9 ± 6.0 ml·kg–1·min–1] participated in this study, which was approved by the Human Subjects Committee of the University of Tsukuba. All participants provided written informed consent. None of the subjects were smokers, and none were taking medication. Before any data were collected, the subjects were allowed to practice on the cycle ergometer until accustomed to its style.

VO2 peak test.   Several days before beginning the experiments, the subjects came to the laboratory (in the morning or afternoon) and performed an incremental cycling exercise to volitional exhaustion to determine VO2 peak (818E, Monark; customized for semi-recumbent cycling). The subjects initially performed a light warm-up (30 W, 60 rpm) for 3 min and then 1 min later performed an incremental cycling exercise. The exercise was started at 60 W, after which the load was increased at a rate of 15 W/min throughout the entire exercise period. The subjects pedaled at 60 rpm, and volitional fatigue was defined as an inability to pedal at more than 50 rpm. The subjects breathed from a mask that covered the mouth and nose (the inside volume of the mask was 80 ml). A mass-flow sensor (hot-wire type) and a gas-sampling tube (the sampling volume rate was below 0.2 l/min) were connected to the mask, and the expired volume and gases were analyzed using an electric gas flow meter (RM300i, Minato Medical Science). The dead space, resistance of the respiratory apparatus, and the loss of volume caused by the gas sampling were all sufficiently small that we considered their effects on the data to be negligible. The flowmeter was calibrated with the aid of an appurtenant calibration instrument able to blow a fixed volume (2 liters) of reference gases of known concentration. VE, VO2, and carbon dioxide output (VCO2) were calculated at 60-s intervals. VO2 peak was taken as the highest value of VO2 achieved by a given subject, as some subjects did not achieve a plateau (even though the respiratory exchange rate exceeded 1.1 when VO2 reached its peak value). The VO2 peak test was performed in an environmental chamber (Fujiika, Chiba, Japan) maintained at 25°C and 50% relative humidity. The room air was ventilated to prevent any increase in the CO2 concentration. Wind speed in the room was below 0.2 m/s.

Experimental design.   Beginning at least 2 days after the VO2 peak test, two trials were carried out during which the subjects performed two bouts of exercise (Ex 1 and Ex 2) in the heat separated by a rest period. In the fluid replacement (FR) trial, the subject drank sodium water (described in detail below) during the rest period; in the no-fluid replacement (NFR) trial, the subject drank no fluid during the rest period so that the body fluid statuses differed between the trials during Ex 2. The trials were carried out in random order separated by at least 6 days. Subjects were asked to abstain from strenuous exercise, alcohol, and caffeine for 24 h before the two experiments. To standardize the subject's hydration status, they were all asked to consume the same meal and to drink 500 ml water on the night before the experiment. In addition, the subjects consumed only a light breakfast and 300 ml of water 2 h before each trial.

For both trials, each subject came to the laboratory at 8:30 AM and rested for 30 min sitting in a chair (ambient temperature = 25°C). During this time, a thermocouple was inserted into the esophagus via the nasal passage to a distance equivalent to one-fourth of the subject's height to measure Tes. Thereafter, the subject voided urine, and BW was recorded, after which he moved to the environmental chamber (ambient temperature = 35°C), where he sat in a chair behind the ergometer to rest for 30 min. During this time, a heart rate (HR) monitor, thermocouples for measuring Tsk, a cuff (on the upper right arm) and electrodes for measuring arterial blood pressure, and a mask for measuring respiratory gases and volume were attached. In addition, for measuring forearm blood flow (FBF), a mercury-Silastic strain gage (at the left forearm), a cuff to occlude venous blood flow (in upper left arm), and a cuff to exclude hand blood flow (in the left wrist) were also attached. Before the start of any measurements, a blood sample was collected from a warmed fingertip, and after all measurements were started, the subject rested for another 5 min. The subject then exercised on a cycle ergometer continuously at 50% VO2 peak in a hot environment (ambient temperature = 35°C, relative humidity = 50%, wind speed below 0.2 m/s). We previously confirmed that the blood lactate concentration was <2 mmol/l during the exercise (45 min) with heat stress (Tes increased above 39.0°C) (26).

When Tes reached 39.0°C or the subject could not cycle at 60 rpm, the load was reduced and the exercise was continued to reduce their body weight to a given level (the elapsed exercise time ranged from 50 to 60 min). At this point, the load and the revolution speed were specific for each subject, although all subjects exercised for at least 40 min at 50% VO2 peak. The data collected before the load was reduced were analyzed. Immediately after Ex1, a blood sample was collected from a warmed fingertip, and the HR monitor, thermocouples for measuring Tsk, cuffs, and a rubber strain gage were taken off the subject's body; the thermocouple for measuring Tes was left in place. The subject was then toweled off, and urine volume (UV) and postexercise BW were measured. Thereafter, the subject moved to a comfortable environmental room (ambient temperature = 25°C, relative humidity = 50%) and drank sodium water in the FR trial but not in the NFR trial. Except for this period during the FR trial, the subjects received no fluid during the experiment in either trial. After the rest period (70–80 min), a urine sample was collected and BW was measured. The subject then moved to the hot environment (the same environmental conditions as in Ex1) and sat in a chair behind the ergometer to rest for 30 min. During this time, the instruments that were taken off after Ex1 were reattached. Before making any measurements, a blood sample was collected from a warmed fingertip, and after all measurements were started, the subject rested for another 5 min. The subject then exercised on the cycle ergometer continuously for 30–50 min at 50% VO2 peak. Each subject exercised until Tes reached the same Tes recorded at the end of Ex1 or until volitional fatigue was reached. Immediately after the exercise, a blood sample was collected from a warmed fingertip, and all the instruments were taken off. The subject was then toweled off, and UV and postexercise BW were measured.

Fluid replacement.   The drink ingested by the subjects during the recovery period consisted of water containing NaCl (Na+ = 25 mosmol/l, Cl– = 25 mosmol/l, osmolality = 54.2 ± 1.1 mosmol/kgH2O); no carbohydrate was present. The amount of drink consumed during the FR corresponded to 150% of the BW lost between the pre-Ex1 and post-Ex1 measurements (the average volume consumed was 1.8 ± 0.4 liters). The temperature of the sodium water was set to ~38.0°C to minimize fluctuations in Tes, and the subjects drank the water as quickly as possible during the 70- to 80-min rest period (the average time required to drink was 37.2 ± 11.9 min).

Measurements.   Tes and Tsk data were collected via copper-constantan thermocouples, sampled and recorded on a computer (ThinkPad A21p, IBM) every 1 s via a data logger system (WE7000, Yokogawa, Japan), and averaged over 30-s periods. Tsk was measured at six sites (chest, upper back, lower back, abdomen, thigh, and calf), and mean Tsk (Tsk) was calculated using the method of Taylor et al. (45). HR was recorded every 5 s using a HR monitor (Vantage NV, Polar) and averaged over 30-s periods. The right arm was placed on a table at heart level, and arterial blood pressure was measured every 1 min using an automated sphygmomanometer (STBP-780, Nippon Colin). Mean arterial blood pressure (MAP) was calculated as the diastolic blood pressure plus one-third of the pulse pressure. FBF in the left forearm was estimated using venous occlusion plethysmography with the aid of a mercury-Silastic strain gauge (55). To facilitate venous return, the left arm was elevated 10 cm above the heart level. Pressure in the venous occlusion cuff was set at ~45 mmHg, and the circulation to the hand was excluded using a wrist cuff inflated to 220–230 mmHg. The wrist cuff was released periodically so as not to cause discomfort. FBF was measured twice a minute for a minimum of 10–20 s after the upper arm cuff was inflated. This routine was repeated until FBF measurement was ended. The strain gauge was calibrated before Ex1 and Ex2 using a cylinder and 20-g weight; during the measurement of FBF, the tension on the rubber strain gauge was maintained at ~20 g. The venous occlusion plethysmography technique is sensitive to body movements and to the initial distending pressure in the veins. Therefore, to minimize artifacts caused by body movements, the forearm was loosely supported by slings at the wrist, with the forearm extended in front of the subject, and shoulder and upper body were held to the seat of the chair. Moreover, we did not use the first two blood flows after venous occlusion to calculate FBF. Because there is little or no change in forearm muscle blood flow during whole body heating (10) and prolonged exercise (30), we were able to estimate increases in skin blood flow from increases in FBF during heat stress. Forearm vascular conductance (FVC) was calculated as FBF divided by MAP and expressed in milliliters per 100 ml tissue per minute per 100 mmHg.

BW was measured before Ex1 (Pre1), immediately after Ex1 (Post1), before Ex2 (Pre2), and immediately after Ex2 (Post2). UV was measured at Pre2 and Post2. BW was measured at Pre2 and Post2, after urine collection. BW was determined using a platform scale with a minimum calibration of 10 g (accuracy is ±5 g). The volume of the collected urine was measured using a measuring cylinder with a minimum calibration of 5 ml. Expired gas was measured using the same analyzers used in the VO2 peak test (see above). From the analyzers, VE, tidal volume (VT), respiratory frequency (fR), VO2, VCO2, ventilatory equivalents for VO2 (VE/VO2) and VCO2 (VE/VCO2), and end-tidal CO2 pressure (PETCO2) were recorded over 30-s periods. Blood samples from a warmed fingertip were taken at Pre1, Post1, Pre2, and Post2. From the blood samples, hemoglobin (Hb) concentrations, hematocrits (Hct), and plasma osmolality (Posm) were measured. Hb was measured using the azidemethemoglobin method (B-Hemoglobin, Hemocue); Hct was measured by microhematocrit centrifugation. Blood samples used for measurement of Posm were transferred to heparin-treated tubes and centrifuged at 4°C, after which the osmolality of the separated plasma was immediately measured based on freezing point depression (One-Ten osmometer, Fiske). The percent change of plasma volume ({Delta}PV) was calculated from the Hb and Hct measurements using the equations of Dill and Costill (11). During the exercise, ratings of perceived exertion (RPEs) were recorded every 5 min.

All data except Tsk (n = 12) and FBF (n = 12) were successfully measured in all subjects.

Data analysis.   Because it has been suggested that VE increases with increases in core temperature, and the effect of skin temperature on the relationship between VE and Tes is small (26), we considered Tes to be the dominant variable affecting VE, rather than mean body temperature. To assess the relationship between ventilatory variables (VE, VE/VO2, VE/VCO2, VT, fR, and PETCO2) and Tes, we plotted the variables as a function of Tes and conducted linear regression analysis (26). Because it takes ~4 min from the start of the exercise for VE to reach a steady state (51), only data obtained after the first 5 min of the exercise were used for the regression analysis. The slope of the regression line relating VE and Tes (VE slope) was considered to be an index of the ventilatory response to the increase in core temperature. VE/VO2 slope, VE/VCO2 slope, VT slope, fR slope, and PETCO2 slope were similarly evaluated. We compared VE slopes obtained during Ex1 in the two trials and found reproducibility to be highly significant (r = 0.93, P < 0.05, n = 13).

After plotting FBF as a function of Tes, we determined one horizontal line and one regression line relating FBF and Tes. The horizontal line was determined by averaging resting FBFs (baseline level of FBF), and the regression line was determined from the plots of FBF above the baseline level by fitting the data with a linear function using the method of least squares. We defined the regression line as FBF slope. Using a computer algorithm, the Tes threshold for increases in FBF was determined as the point where the horizontal and regression lines crossed (TFBF-threshold). We also defined the change in Tes from the resting value to TFBF-threshold as {Delta}TFBF-threshold. Above a certain core temperature, FBF did not increase with increases in core temperature, suggesting that a plateau in FBF had been reached. The averaged FBF value at the plateau level was defined as FBFpeak. FVC slope, TFVC-threshold, {Delta}TFVC-threshold, and FVCpeak were also determined similarly. As with VE slope, we compared FBF slopes obtained during Ex1 in the two trials and found reproducibility to be highly significant (r = 0.93, P < 0.05, n = 12).

Data were analyzed using two-factor repeated-measures ANOVA. We set one factor as time (within FR or NFR) and the other as trial type (FR or NFR) for analyzing hydration status and the slopes of regression lines relating Tes to ventilatory variables and relating forearm blood flow or vascular responses to Tes. Moreover, to analyze the time courses of changes in variables within each bout of exercise, we set one factor as time (preexercise and exercise time at 5-min intervals) and the other as each bout of exercise (FR-Ex1, FR-Ex2, NFR-Ex1, and NFR-Ex2). The time courses of the changes were analyzed for data obtained during the period when all of the subjects were still participating (up to 30 min during Ex2 in the NFR trial, 35 min during Ex2 in the FR trial, and 40 min during Ex1 in the FR and NFR trials). After determining the main effects, pairwise differences were identified post hoc using Tukey's highly significant difference procedure. All values are reported as means ± SD. Values of P < 0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Hydration status and fluid loss.   The hydration status of the subjects before heating was nearly identical in both the FR and NFR trials, as indicated by the similar values for Hb, Hct, Posm, and BW (Table 1). After Ex1, subjects were hypohydrated in both trials, and the degree of hypohydration did not differ between trials (Table 1). After Ex1 in the FR trial (Ex1-FR), drinking returned BW, PV, and Posm nearly to the euhydrated values, whereas in the NFR trial, the subjects remained hypohydrated (Table 1). After Ex2, subjects were hypohydrated after both trials, but the degree of hypohydration was greater after the NFR trial than after the FR trial (Table 1).


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  		Table 1. Hematologic status and fluid loss over the course of the experiments

 
Body temperature.   Tsk and Tes increased steadily during each trial (Fig. 1, A and B). Tes increased by 2.0 ± 0.4°C during Ex1-FR, by 2.1 ± 0.3°C during Ex1-NFR, by 1.8 ± 0.3°C during Ex2-FR, and by 1.8 ± 0.2°C during Ex2-NFR. The rates of increase in Tes during Ex2-FR (2.7 ± 0.5°C/h) and Ex2-NFR (3.0 ± 0.6°C/h) were both significantly greater than during Ex1-NR and Ex1-NFR (2.4 ± 0.5°C/h). During Ex2, moreover, the rate of increase in Tes was significantly greater in the NFR trial than in the FR trial. Tsk and Tes were significantly higher during Ex2-NFR than during Ex1-NFR or Ex2-FR (Fig. 1, A and B).


Figure 1
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  		Fig. 1. Time-dependent changes in mean skin temperature (Tsk; A), esophageal temperature (Tes; B), heart rate (HR; C), and mean arterial blood pressure (MAP; D) during two bouts of cycle exercise (Ex1 and Ex2) in the fluid replacement (FR; {circ} and {triangleup}, respectively) and no-fluid replacement (NFR; bullet and {blacktriangleup}, respectively) trials. Pre, preexercise. $ Significant difference between Ex1 and Ex2 at the same time point during the FR trial. {dagger}Significant difference between Ex1 and Ex2 at the same time point during the NFR trial. *Significant difference between Ex2 at the same time point during the FR and NFR trials.

 
VE, VT, fR, and PETCO2.   During each exercise, VE and fR increased, while PETCO2 decreased steadily and VT remained unchanged (Fig. 2, A--D). VE, VT, and fR were significantly higher and PETCO2 was significantly lower during Ex2 than during Ex1 in both trials (Fig. 2, A--D). During Ex2, moreover, PETCO2 was significantly lower in the FR than in the NFR trial (Fig. 2, A--D).


Figure 2
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  		Fig. 2. Time-dependent changes in minute ventilation (VE; A), tidal volume (VT; B), respiratory frequency (fR; C), and end-tidal CO2 pressure (PETCO2; D) during Ex1-FR ({circ}), Ex2-FR ({triangleup}), Ex1-NFR (bullet), and Ex2-NFR ({blacktriangleup}). $ Significant difference between Ex1 and Ex2 at the same time point during the FR trial; {dagger}Significant difference between Ex1 and Ex2 at the same time point during the NFR trial. *Significant difference between Ex2 at the same time points in the FR and NFR trials.

 
VO2 and VCO2.   VO2 and VCO2 were nearly unchanged during each exercise, although they were significantly higher during Ex2-FR than during Ex1-FR and were significantly higher during Ex2-NFR than during Ex1-NFR or Ex2-FR (Fig. 3, A and B).


Figure 3
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  		Fig. 3. Time-dependent changes in oxygen uptake (VO2; A) and carbon dioxide output (VCO2; B) during Ex1-FR ({circ}), Ex2-FR ({triangleup}), Ex1-NFR (bullet), and Ex2-NFR ({blacktriangleup}). $ Significant difference between Ex1 and Ex2 at the same time point during the FR trial. {dagger}Significant difference between Ex1 and Ex2 at the same time point during the NFR trial. *Significant difference between Ex2 at the same time points in the FR and NFR trials.

 
Tes-dependent changes in VE, VE/VO2, VE/VCO2, VT, fR, and PETCO2.   Ventilatory variables plotted against Tes from rest to the end of the heating session are shown in Fig. 4, A--F. During Ex1 and Ex2 in both trials, the VT and PETCO2 were increased during the first few minutes of the exercise, with only a small change in Tes. Thereafter, VT and PETCO2 gradually declined, while VE, VE/VO2, VE/VCO2, and fR increased linearly with increases in Tes. The slopes of the regression lines relating Tes to VE, VE/VO2, VE/VCO2, VT, fR, and PETCO2 were evaluated in each subject and are shown in Tables 2. There were no significant differences between the values obtained in Ex1 and Ex2, or between FR and NFR.


Figure 4
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  		Fig. 4. Tes-dependent changes in VE (A), ventilatory equivalent for VO2 (VE/VO2; B), ventilatory equivalent for VCO2 (VE/VCO2; C), VT (D), fR (E), and PETCO2 (F) during Ex1-FR ({circ}), Ex2-FR ({triangleup}), Ex1-NFR (bullet), and Ex2-NFR ({blacktriangleup}). Each symbol is the 30-s averaged value for all subjects.

 

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  		Table 2. Slopes of regression lines calculated after plotting VE, VE/VO2, VE/VCO2, VT, fR, and PETCO2 against Tes

 
Tes-dependent changes in FBF and FVC.   FBF and FVC increased gradually during each exercise. TFBF-threshold and TFVC-threshold were nearly the same, so that TFVC-threshold and {Delta}TFVC-threshold could be used to evaluate the points at which FBF and FVC abruptly increased from their resting values. As depicted in Fig. 5, A and B, and Table 3, skin blood flow and the cutaneous vasodilatory response to an increase in core temperature during Ex2-NFR were significantly attenuated (higher threshold temperature and lower values for the slope and peak), compared with those seen during Ex1-NFR and Ex2-FR.


Figure 5
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  		Fig. 5. Tes-dependent changes in forearm vascular conductance (FVC) during Ex1-FR ({circ}) and Ex2-FR ({triangleup}) (A) and during Ex1-NFR (bullet) and Ex2-NFR ({blacktriangleup}) (B) in one representative subject.

 
HR and MAP.   HR increased steadily, while MAP was unchanged during Ex1 and Ex2 in both the FR and NFR trials (Fig. 1, C and D). HR was significantly higher during Ex2-FR than during Ex1-FR and was significantly higher during Ex2-NFR than during Ex1-NFR or Ex2-FR (Fig. 1C).

RPE.   RPE increased steadily during Ex1 and Ex2 in both trials. RPE during Ex1 increased from 11.8 ± 1.3 (FR) and 11.9 ± 1.3 (NFR) at 5 min to 16.5 ± 1.8 (FR) and 16.5 ± 1.6 (NFR) at 40 min; moreover, RPE during Ex2 increased from 13.2 ± 1.5 (FR) and 13.2 ± 1.6 (NFR) at 5 min to 17.4 ± 1.2 at 30 min (NFR) and 17.5 ± 1.8 at 35 min (FR). RPE during Ex2 was significantly higher than during Ex1 in both trials.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We compared the ventilatory and cutaneous vasodilatory responses to increases in core temperature during two bouts of exercise (Ex1 and Ex2) in FR and NFR trials. Before Ex2-FR, both Posm and PV were restored almost to their pre-Ex1 levels, indicating that the intermediate drinking nearly restored the body fluid to the euhydrated condition. By contrast, subjects remained hypohydrated in the NFR trial. Consequently, the body fluid status differed between the trials before Ex2 (the difference in plasma osmolality before Ex2 was 9.4 mosmol/kgH2O, while the relative differences in plasma volume and body weight were 7.6% and 2.5%, respectively). Our main findings are 1) the slopes of the regression lines relating the various ventilatory variables (VE, VE/VO2, VE/VCO2, VT, fR, and PETCO2) to Tes did not significantly differ between Ex1 and Ex2, or between the FR and NFR trials; and 2) during Ex2-NFR, the Tes threshold for the onset of the increase in FVC was higher, while the slope and peak values of the relationship between FVC and Tes were markedly lower than those during Ex1-NFR or Ex2-FR.

Hypohydration and the hyperthermic ventilatory response.   In the present study, VE slope during Ex2 did not significantly differ in the FR and NFR trials (8.8 and 9.9 l·min–1°·C–1, respectively; Fig. 4A, Table 2), even though the body fluid statuses before Ex2 were quite different ({Delta}BW, {Delta}PV, and Posm in the FR vs. the NFR trial were –0.0 vs. –2.5%, –0.6 vs. –8.2%, and 285.3 vs. 294.7 mosmol/kgH2O, respectively; Table 1). Similarly, VE/VO2 slope, VE/VCO2 slope, VT slope, fR slope, and PETCO2 slope did not significantly differ in the FR and NFR trials (Fig. 4, B–F, Table 2). There have been no previous studies in humans aimed at determining whether hypohydration affects the hyperthermic hyperpnea during exercise, but Senay and Christensen (43) investigated the effect of hypohydration on the ventilator response in resting heated humans. In that study, five male subjects were exposed to 43°C for 12 h during rehydration (loss of BW was replenished hourly with 0.1% saline) and dehydration trials (BW was progressively reduced by 5%). It was observed that both VE and Posm were increased in the dehydration trial, but neither VE nor Posm was increased in the rehydration trial. These results suggest that increases in Posm can lead to increases in VE in resting heated humans. In that study, however, core temperature (oral temperature) was substantially higher in the dehydration trial than rehydration trials (37.69 vs. 37.07°C at 12 h after entering the hot environment). Because elevations in core temperature increase VE at rest (18, 19), as it does during exercise, the increased VE seen in the dehydration trial could have been caused by the greater increase in core temperature rather than the increased Posm. Consistent with that idea, before Ex2 in the present study, VE did not significantly differ between the FR and NFR trials (Fig. 2A), even though Posm was significantly higher in the latter than the former (Table 1). Importantly, before Ex2, there was not a significant difference in Tes between the NFR and FR trials (Fig. 1B).

When hypohydration occurs, there are several possible factors that could affect the ventilatory response to an increase in core temperature during exercise in humans: factor 1) increases in plasma K+, lactate production (it is accompanied by H+ production and a decrease in pH), and plasma catecholamines (22, 23, 24), which are considered ventilatory stimulants (27, 39, 40, 51, 52); factor 2) chemosensory discharge induced by increases in osmolality (31, 49) may stimulate ventilatory drive; and factor 3) detection of hyperosmolality by brain osmoreceptors may attenuate the ventilatory response to the increase in body temperature (4, 47). If factor 1 and/or 2 occurred, ventilation would increase, but if factor 3 occurred, ventilation would be attenuated. In our study, there are several possible reasons why the ventilatory response to an increase in core temperature was unaffected by hypohydration. 1) The effects of these factors may be too small to change ventilation. Indeed, changes in plasma K+, pH, and catecholamines under conditions of dehydration (22, 23, 24) were smaller than those at high-intensity exercise (9, 24, 33). Further, increased chemosensory discharge was previously seen with a 10% increase in Posm (31, 49), which is higher than that in the present study (~2.5%); 2) factors 1 and 2 might balance factor 3, so that ventilation is not changed; 3) these factors have little or no effect on the ventilatory response. Indeed, plasma K+, pH, and catecholamine levels are not closely related to the increase in ventilation during exercise (9, 33). When plasma K+ increases, peripheral chemoreceptors are excited and ventilation increases, and ventilatory responses to elevations in lactate acid and norepinephrine are enhanced (39). We would speculate that when multiple ventilatory stimuli are excited simultaneously (e.g., increases in plasma K+, lactate acid, catecholamines, and core temperature, as well as secondary stimuli reflecting the increase in plasma K+), the effects of some stimuli may be offset and so do not cause an excessive increase in ventilation, as was suggested previously (50).

Furthermore, there may be little or no involvement of brain osmoreceptors in the observed ventilatory response. However, if during exercise more severe hypohydration occurs, like observed in Senay and Christensen's study (43) (BW was reduced by 5%, Posm was increased by 11 mosmol/kgH2O), the ventilatory response might be changed.

Our results suggest that ventilation increases along with increases in core temperature, irrespective of hydration status. Consistent with that idea, Holmberg and Calbet (28) recently reported that VE increases with increases in right atrial temperature at a rate of 12.6 l·min–1·°C–1 when dehydration was prevented by infusion of 0.9% saline. We therefore suggest that hypohydration is not a factor for hyperthermic hyperpnea and that other factor(s) could be involved. Although it has been proposed that hyperthermic hyperpnea may be associated with increased sensitivity of peripheral chemoreceptors induced by hyperthermia (53), Fujii et al. (18) suggested that the increased sensitivity of peripheral chemoreceptors is not the dominant factor for hyperthermic hyperpnea. Another possible factor that could contribute to hyperthermic hyperpnea is the increase in core temperature, itself (53). Animal studies have shown that local heating of the isolated medulla, which contains central chemoreceptors, increases neural activity in the ventral respiratory group, which in turn increases ventilation (48), although the importance of an increase in core temperature in humans remains unclear.

It is known that in a hot environment panting species such as dogs and birds can increase dead space ventilation to dissipate heat (8) and that this panting response is attenuated under conditions of hypohydration in exercising dogs (BW was reduced by 9.5%, PV was reduced by 17%, Posm was increased by 27 mosmol/kgH2O) (3), resting fowl (BW was reduced by 15.1%) (2), resting cats (BW was reduced by 10%, Posm was increased by 22 mosmol/kgH2O) (5), resting cats (BW was reduced by 8–9.8%, Posm was increased by 21–55 mosmol/kgH2O) (12), and resting rabbits (BW was reduced by 11.4%, PV was reduced by 30–33%, Posm was increased by 18 mosmol/kgH2O) (47). By contrast, hypohydration reportedly leads to increases in ventilation in resting rabbits (PV was reduced by 16.1%) (7). Similarly, goats pant and are able to sweat (although they cannot sweat for long), and the regulation of cutaneous blood flow also contributes to their thermoregulation (6), as is seen in humans. Nijland and Baker (35) reported that although hypohydration (BW was reduced by 8.6%, and Posm was increased by 21 mosmol/kgH2O) reportedly shifts the core temperature threshold for an increase in sweating upward in exercising goats, as has been seen in exercising humans (17, 44), hypohydration does not change the slope of the regression line relating blood temperature (at right atrium) to respiratory evaporative water loss (Eres, index of panting response). Moreover, Baker and Nijland (6) reported that although the regression line relating blood temperature (at right atrium) to Eres was shifted downward by hypohydration (BW was reduced by 9.2%) in the exercising goat, the shift was small. We therefore suggest that in goats (and humans), which show increases in both sweating and ventilation with increases in core temperature, hypohydration has little effect on the ventilatory response to an increase in core temperature during exercise. We further suggest that when hypohydration progresses farther than in our experiment, such as occurred in the aforementioned animal studies, hyperthermic hyperpnea might be changed.

Hypohydration and thermoregulatory responses.   In the present study, TFVC-threshold and TFVC-{Delta}threshold were significantly higher during Ex2-NFR than during Ex1-NFR or Ex2-FR (Table 3), and Posm was significantly higher before Ex2-NFR than before Ex1-NFR or Ex2-FR (Table 1). Earlier studies have shown that the Tes threshold for cutaneous vasodilation is shifted upward with an increase in Posm during exercise in male subjects (17, 44), suggesting upward shifts in the Tes threshold for cutaneous vasodilation could mainly reflect increases in Posm. In the present study, FBF slope, FVC slope, FBFpeak, and FVCpeak were all significantly lower during Ex2-NFR than during Ex1-NFR or Ex2-FR (Table 3). In addition, {Delta}PV before Ex2-NFR was significantly lower than before Ex1-NFR and Ex2-FR (Table 1). Earlier studies also showed that a reduction in PV reduced the slope of the relation between cutaneous blood flow and Tes (15, 17, 34), as well as the maximal cutaneous blood flow in exercising male subjects (17, 34). Thus the lower FBF slope, FVC slope, FBFpeak, and FVCpeak during Ex2-NFR could reflect the reduction in PV.


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  		Table 3. Forearm blood and vascular responses to Tes

 
Like the cutaneous vascular response to increases in core temperature, hypohydration reportedly attenuates the sweating response to an increase in core temperature; that is, an increase in Posm shifts the Tes threshold leading to an increase in the sweating rate, reduction in PV, reduction in the slope of the line relating sweating rate to Tes, and reduction in the maximal sweating rate in exercising male subjects (15, 16). Tsk during Ex2-NFR was higher than during Ex1-NFR and Ex2-FR (Fig. 1A), which was probably caused by a lower sweat rate, resulting in diminished evaporative heat loss. We therefore suggest that, in the present study, the cutaneous vascular response, and perhaps the sweating response, to increases in core temperature were attenuated by hypohydration, as was seen in earlier studies.

With respect to the effect of rehydration on thermoregulation, it has been reported that during prolonged submaximal exercise in the heat, forearm vascular resistance in a euhydration trial, in which male subjects received fluid, was lower than in a dehydration trial, in which they received no fluid (21). Furthermore, Nose et al. (36) reported that FBF during prolonged submaximal exercise in a warm environment with isotonic saline infusion was higher than without infusion in male subjects. In the FR trial in the present study, increased Posm and decreased {Delta}PV following Ex1 were nearly restored to those seen before Ex1 (Table 1). Thus, drinking would have prevented the attenuation of the FBF and FVC responses to the increase in Tes during Ex2-FR.

Homeostatic prioritization.   Our results suggest that in hyperthermic exercising humans, fluid homeostasis overrides thermoregulation (cutaneous vasodilation and probably also sweating). Since cutaneous vessels can receive blood at a rate of as high as 7–8 l/min over the entire body surface during hyperthermia (29), we suggest that reducing cutaneous blood flow could effectively increase central blood volume so that circulatory homeostasis is maintained. Gonzalez et al. (21) showed that dehydration reduces cardiac output (which can reduce MAP) and increases cutaneous vascular resistance (which can increase MAP). We therefore suggest that a further decline in MAP caused by hypohydration is prevented by increases in cutaneous vascular resistance during exercise in the heat. Consistent with this idea, we observed that hypohydration significantly attenuated FVC elicited by an increase in Tes (Fig. 5, Table 3) with unchanging MAP (Fig. 1D). Furthermore, HR during Ex2 was higher than that during Ex1 in both the FR and NFR trials (Fig. 1C). If the higher HR during Ex2 contributed to preventing the declines in cardiac output and MAP, the higher HR during Ex2 could also be interpreted as circulatory homeostasis. As with cutaneous vasodilation, we suggest that attenuation of sweating (which can help sustain blood volume) also makes an important contribution to protecting fluid and circulatory homeostasis during exercise in the heat. As a result of the concession to fluid and circulatory homeostasis (diminished thermoregulatory drives), however, body temperature should be regulated at a higher level, as is seen in the present study (higher Tes and Tsk during Ex2 in NFR, Fig. 1, A and B), and in resting sheep (20), exercising dogs (3), and exercising goats (6).

Our results suggest that even though cutaneous vasodilation (and probably also sweating) is suppressed by hypohydration, hyperthermic hyperpnea is unaffected. Since hyperthermic hyperpnea is thought to be an important factor for selective brain cooling (53), we suggest it might be maintained to prevent an increase in brain temperature even under hypohydrated conditions; that is, brain thermoregulation overrides fluid homeostasis. On the other hand, we suggest that water loss through respiration is much lower than the loss caused by sweating during exercise in the heat (32). Consequently, attenuation of respiration might not be an effective means of protecting fluid and circulatory homeostasis.

In the present study, PETCO2 declined with increases in exercise time (Fig. 2D), which suggests that hyperthermic hyperpnea occurs with increases in alveolar ventilation, leading to respiratory alkalosis. The same observation was made in earlier human (1, 19, 26) and animal (14) studies. If hyperthermic hyperpnea is induced by thermoregulatory drive in exercising humans, we suggest that thermoregulatory drive (increase in ventilation) overrides chemoregulation (e.g., arterial CO2 pressure) in hyperthermic exercising humans. On the other hand, evidence suggests that reducing arterial CO2 pressure through hyperthemic hyperpnea reduces blood flow to the brain (18, 41), so that the overridden chemoregulation could threaten brain circulatory homeostasis. Clearly, hierarchical ordering of homeostasis in hyperthermic exercising humans is complex, and additional studies will be required to conclusively determine whether hyperthermic hyperpnea is a thermoregulatory response.

Limitations.   Although the rates of increase in Tes (2.4 and 3.0°C/h) and Tsk (35–37°C) were different between the trials in the present study, the differences were relatively small and well within the range seen in the study by Hayashi et al. (26), in which the rate of increase in Tes (1.9–3.6°C/h) and difference in Tsk (35–39°C) during cycling exercises at 50% VO2 peak (same as the present study) did not affect hyperthermic hyperpnea. Although White and Cabanac (54) reported that the higher rate of increase in core temperature affected hyperthermic hyperpnea, in their study the difference in the rates (3.8 and 6.3°C/h) was much greater than in our study. In addition, to change the rate of increase in core temperature, they changed the rate of increase in workload. Consequently, the augmented increase in VE they observed could reflect the increase in workload and not simply the increase in core temperature.

Given that a higher Tsk augments the cutaneous vasodilatory response to an increase in core temperature (29), the higher Tsk during Ex2-NFR could have augmented the cutaneous vasodilatory response compared with that during Ex1-NFR and Ex2-FR. Considering the effect of Tsk, it is possible that the attenuated cutaneous vasodilatory response during Ex2-NFR was modulated, and thus the actual attenuation caused by the hypohydration was greater than that evaluated in the present study.

As mentioned above, it is possible that the extent of the hypohydration induced in the present study was too small to induce a change in the ventilatory response. However, the 2.5% {Delta}BW, 8.2% {Delta}PV, and 4.5 mosmol/kgH2O change in Posm seen in the present study were physiologically significant and markedly attenuated the cutaneous vasodilatory response. We therefore conclude that hypohydration within the physiological range does not affect hyperthermic hyperpnea during exercise.

In the present experiment, moreover, we did not rehydrate during the exercise, so that the subjects were not euhydrated throughout any trial, particularly toward the end of each trial, when core temperature was elevated. And it was true that the subjects were more hypohydrated in the NFR trial (particularly due to the cutaneous changes). It is thus possible that hyperthermic hyperpnea during exercise could be affected by the gradual increase in Posm and/or decrease in PV that occurs during exercise. Furthermore, we did not separate the impact of decrease in PV independent of increase in Posm. Therefore, if decrease in PV and increase in Posm have opposite effects on VE, then the outcome will be difficult to interpret. Additional studies will be needed to examine these issues, including a trial that manipulates both Posm and PV independently of changes in core temperature. In addition, we did not evaluate the extent to which fluid absorption had occurred before Ex2, and we did not evaluate the effects of ventilatory stimulants such as plasma K+, the acid-base status, and plasma catecholamines. Consequently, the extent to which these factors affected our results is unclear.

In summary, we investigated whether hypohydration attenuates the ventilatory response to increases in core temperature during exercise. Subjects performed two bouts of exercise separated by a rest period, during which they drank sodium water in the FR trial but not in the NFR trial. The intermediate drinking nearly restored the lost body fluid, so that body fluid status before Ex2 differed between the two trials. The results suggest that hypohydration does not affect hyperthermic hyperpnea during exercise, although it attenuates the cutaneous vasodilatory response.


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This study was supported by grants from the Center of Excellence (COE) projects, and Ministry of Education, Science, and Culture of Japan.


   ACKNOWLEDGMENTS
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We sincerely thank the volunteer subjects in the present study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. Nishiyasu, Institute of Health and Sports Science, Univ. of Tsukuba, Tsukuba City, Ibaraki 305-8574, Japan (e-mail: nisiyasu{at}taiiku.tsukuba.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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