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1Department of Sports Medical Sciences, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine; 2Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto; and 3Department of Environmental Health, Life Science and Human Technology, Nara Women’s University, Nara, Japan
Submitted 7 February 2005 ; accepted in final form 18 April 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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O2 peak) under isoosmotic conditions (C), and at 65% O2 peak under isoosmotic (HEXIOS) and hypoosmotic (HEXLOS) conditions. In HEXLOS, hypoosmolality was attained by hypotonic saline infusion with DDAVP, a V2 agonist, before exercise. Posmol (mosmol/kgH2O) increased after the start of exercise in both HEX trials (P < 0.01) but not in C. The average Posmol at 5 and 10 min in HEXIOS was higher than in C (P < 0.01), whereas that in HEXLOS was lower than in HEXIOS (P < 0.01). The change in THFVC was proportional to that in Posmol in every subject for three trials. The change in THFVC per unit change in Posmol (
THFVC/Posmol, °C·mosmol–1·kgH2O–1) was 0.064 ± 0.012 when exercise intensity increased from C to HEXIOS, similar to 0.086 ± 0.020 when Posmol decreased from HEXIOS to HEXLOS (P > 0.1). Moreover, there were no significant differences in plasma volume, heart rate, mean arterial pressure, and plasma lactate concentration around THFVC between HEXIOS and HEXLOS (P > 0.1). Thus the increase in THFVC due to increased exercise intensity was at least partially explained by the concomitantly increased Posmol. esophageal temperature; threshold; plasma osmolality
O2 peak). On the other hand, Taylor et al. (29) suggested a graded increase of THFVC with exercise intensity above 125 W. This was confirmed by Smolander et al. (23), suggesting that THFVC above 80% of O2 peak was higher than at 30% O2 peak. The threshold therefore increased curvilinearly with exercise intensity, but the mechanism remains unknown. Because plasma osmolality (Posmol) is known to increase with increased exercise intensity in the same way as THFVC (17), we postulated that increased Posmol would be associated with increased THFVC with exercise intensity. Experimentally, Takamata et al. (25) reported that the upward shift of THFVC with exercise intensity was well correlated with the increase in Posmol during light and moderate exercise intensity and that this relationship was similar to that determined in passively heated subjects with graded increases in Posmol by hypertonic saline infusion (24). They concluded that increased Posmol is a primary contributor to the upward shift of THFVC during exercise, because the relationship between THFVC and Posmol was not influenced by exercise intensity.
However, because plasma volume (PV) decreases with exercise intensity (17), and acute hypovolemia by the administration of a diuretic (14) and/or reduced venous return to the heart by lower body negative pressure increases THFVC (11), baroreceptor unloading with increased exercise intensity likely contributes to increased THFVC. Moreover, because the plasma lactate concentration ([Lac–]p) reportedly increased with Posmol during graded exercise (17), the accumulation of lactic acid in contracting muscles would suppress cutaneous vasodilation via metaboreceptors in the muscles (2). However, to our knowledge, there have been no attempts to investigate the effects of increased Posmol alone on the upward shift of THFVC with exercise intensity by excluding other possible factors: decreased PV and increased [Lac–]p.
In this study, we selectively reduced the increased Posmol at high exercise intensity by hypotonic saline infusion before exercise to investigate the effects on THFVC while maintaining PV. The purpose of this study was to examine whether increased Posmol with exercise intensity is a primary contributor to the upward shift of THFVC. Our hypotheses were that increased THFVC at high exercise intensity would be suppressed by reducing Posmol alone and that the suppression per unit reduction in Posmol would be similar to the increase in THFVC per unit increase in Posmol with increased exercise intensity.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This study was approved by the Review Board on Human Experiments, Shinshu University School of Medicine; eight male subjects gave written, informed consent before participating in this study. The physical characteristics of the subjects were 21 ± 1 (SD) yr old, 172 ± 5 cm tall, 65.8 ± 6.6 kg in body weight, and 50.9 ± 6.2 ml·kg–1·min–1 in O2 peak. They were healthy and nonsmoking with no overt history of cardiovascular or pulmonary diseases.
Trials
Subjects underwent three exercise trials according to exercise intensity and Posmol: a low-exercise-intensity trial at 30% of O2 peak after isoosmotic saline infusion (0.9%) (C), and two high-exercise-intensity trials at 65% O2 peak after isoosmotic (HEXIOS) or hypotonic (0.45%) saline infusion (HEXLOS). Each trial was conducted at the same time of day with at least 5 days between trials to avoid any effects of circadian rhythm and thermal adaptation by exercise. The order of the trials was randomized.
Protocols
O2 peak was determined with graded cycle-ergometer exercise in a semirecumbent position more than 1 wk before the start of the study as described below. For the thermoregulatory response test in all trials, subjects were asked to fast, except for water, for at least 12 h before the experiments and to drink a glass of tap water (200 ml) 1 h before the experiments.
In the C and HEXIOS trials, subjects reported to the laboratory at 8:00 AM normally hydrated but without breakfast. Clad in shorts and shoes, the subjects emptied their bladders, entered a chamber with a controlled ambient temperature of 28 ± 0.5°C (mean ± ranges) and relative humidity of 50 ± 1%, and then put on a thermal suit and sat in the contoured chair of the cycle ergometer in a semirecumbent position. The sleeves of the suit were cut off at the elbows, and the right and left forearms and hands were open to the air for catheterization and the measurement of FBF, respectively. The remaining parts of the body were covered, except for the feet. The suit was perfused with water warmed to 36°C to maintain the mean skin temperature (Tskin) at 33–35°C during exercise. A Teflon catheter was inserted into the large antecubital vein of the right forearm for blood sampling and saline infusion. After a wait of more than 10 min at rest, baseline blood was taken at 9:00 AM and then subjects in the C and HEXIOS trials were infused with 0.9% saline solution warmed to 36.5°C at 0.05 and 0.2 ml·kg–1·min–1, respectively, for 90 min. The volume of 0.9% saline infusion in the C and HEXIOS trials was determined by preliminary studies to maintain PV at a similar level to that in the HEXLOS trial at 5–10 min after the start of exercise, around which time THFVC was observed.
In the HEXLOS trial, subjects came to the laboratory at 7:30 AM and entered the chamber at 8:00 AM. A Teflon catheter was inserted and a blood sample was taken after a 10-min rest, and then subjects were infused with 0.2 µg/ml of 1-deamino-8-D-arginine-vasopressin (DDAVP), a V2 agonist (Desmopressin, Kyowa-Hakko, Tokyo) at 1.0 ml/min for 20 min. They put on a thermal suit at 9:00 AM and were infused with 0.45% saline solution at 0.15 ml·kg–1·min–1 for 90 min. Because the urine volume before entering the artificial climate chamber was minimal, all the infused volume of 0.45% saline was confirmed as retained in the body.
After a wait of 30 min for the body fluid to stabilize after infusion, the measurements were started at 
11:00 AM for all trials. Baseline measurements were taken for 10 min, and then subjects exercised for 20 min during which time FBF, heart rate (HR), systolic (SAP) and diastolic (DAP) arterial pressures, Tes, and Tskin were measured as described below.
Measurements
O2 peak.
O2 peak was measured by using graded exercise with a cycle ergometer in a semirecumbent position at 25°C of ambient temperature and 50% of relative humidity. After electrocardiogram electrodes were applied, a mouthpiece was connected for respiratory gas measurement, and the subjects started pedaling at 60 cycles/min without loading. The intensity was increased by 60 W every 3 min until 180 W, and above this intensity it was increased by 30 W every 2 min until 240 W and then by 15 W every 2 min until subjects were not able to maintain the rhythm because of exhaustion. The oxygen consumption rate was calculated every 15 s from the oxygen and carbon dioxide fractions in expired gas and the expired ventilatory volume (Aeromonitor AE260, Minato Tokyo, Japan). O2 peak was determined by averaging the three largest consecutive values at the end of exercise.
Tes and Tskin. Tes was monitored every 5 s using a thermocouple in polyethylene tubing (PE-90). The tip of the tube was advanced to one-fourth of the subject’s standing height from the external nares. Skin temperature was also monitored every 5 s using a thermocouple attached to three sites: right forearm (Tfa), chest (Tch), and right thigh (Tth). Tskin was calculated as Tskin = 0.25 Tfa + 0.43 Tch + 0.32 Tth from the body surface area distribution and the thermal sensitivity of each skin area (18).
HR and Arterial Blood Pressures
HR was recorded every 1 min by using an electrocardiogram trace (Life Scope 8, Nihon Kohden, Tokyo, Japan). SAP and DAP were measured every 1 min from the right upper arm at the heart level by inflating the cuff with sonometric pickup of Korotokoff’s sound (STBP-780 Colin, Komaki, Japan). The mean arterial pressure (MAP) was calculated as (SAP-DAP)/3+DAP.
FBF and forearm skin vascular conductance. FBF was measured every 1 min by venous occlusion plethysmography using a Whitney mercury-in-Silastic strain gauge placed around the left forearm (32). The venous occlusion cuff was inflated to 60 mmHg while the hand was eliminated from the circulation with a wrist cuff inflated to 280 mmHg. Forearm skin vascular conductance (FVC) was calculated as FBF/MAP.
Blood chemicals.
Blood samples were obtained preinfusion and postinfusion before the onset of exercise (0 min), and after 5, 10, and 20 min of exercise. The percent change in plasma volume from the preinfusion levels (PV) was determined from hematocrit (%: microcentrifuge method) and hemoglobin concentration (g/dl: cyanomethohemoglobin method) (4). After the remaining blood was centrifuged, aliquots of plasma were used to determine the plasma protein concentration (g/dl: refractometry), plasma sodium concentration ([Na+]p, mmol/kgH2O; flame photometry, Flamephotometer 480, Corning, Medfield, MA), [Lac–]p (mmol/kgH2O, YSI 2300 STAT PLUS, Yellow Springs, OH), and Posmol (mosmol/kgH2O, freezing point depression method; one-ten osmometer, Fiske, Norwood, MA). The electrolyte concentrations in plasma were presented in millimoles per kilogram H2O after correction for plasma protein concentration (16).
Analyses of the Tes-vs.-FVC relationship.
As shown in Fig. 1, the Tes-vs.-FVC relationship was fitted with two regression equations for the C trial or three for the HEX trials for mean values using standard Y-minimized regression analysis as described by Takeno et al. (28). The first was determined from the first sharp increase in Tes for 10 min before rapid FVC increase, the second was determined from rapid FVC increase, and the third was determined from measurements after the second component. The THFVC was determined from the crossing of the first and second regression lines. Any increase in FVC (FVC) at a given increase in Tes (Tes) (FVC/Tes) was determined from the second slope in each subject, and the results by statistical analyses are summarized in Table 1. The THFVC and the slope were determined by three separate investigators who were familiar with the method, and the three values measured were averaged. The investigators were blinded to the experimental designs of the determinations.
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Three-way ANOVA (exercise intensity x Posmol x time) for repeated measures was used to test the differences in HR, MAP, Tes, Tskin, and blood chemicals among the trials. Two-way ANOVA (exercise intensity x Posmol) for repeated measures was used to test the differences in THFVC and FVC/Tes. Subsequent post hoc tests to determine significant differences in the various pairwise comparisons were performed using Fisher’s least significant difference test. The slope of FVC/Tes was determined by standard Y-minimized regression analyses. All values in each trial were reported as the means ± SE for eight subjects. The null hypothesis was rejected at P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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PV were similar in the HEX trials. Posmol and [Na+]p are presented pre- and postinfusion, at 5, 10, and 20 min of exercise, with changes from the levels of preinfusion as Posmol and [Na+]p. Posmol and [Na+]p in the HEX trials increased after the start of exercise but remained unchanged in the C trial. Posmol and [Na+]p were all significantly lower in the HEXLOS trial than in the HEXIOS trial at rest and during exercise (P < 0.05) except for [Na+]p at 10 min.
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PV were identical between the HEX trials (Table 1 and Fig. 2). The slope of FVC/Tes calculated from the second regression equation was not significantly different between the HEX trials and was significantly lower in the HEXIOS trial than in the C trial (Table 1). The THFVC time after the start of exercise (Time) was not significantly different among the trials.
Figure 3 shows the relationship between THFVC and Posmol, where Posmol was determined by averaging the values at 5 and 10 min, around which time (Time) THFVC was observed (Table 1). In each subject, THFVC increased in proportion to Posmol with increased exercise intensity from the C to the HEXIOS trial and, inversely, THFVC decreased with reduced Posmol from the HEXIOS to HEXLOS trial. Posmol (mosmol/kgH2O) at THFVC for eight subjects was 293 ± 1 in the C trial, 301 ± 1 in the HEXIOS trial, and 298 ± 1 in the HEXLOS trial with significant differences between every pair (P < 0.05). Moreover, the reduction in THFVC per unit decrease in Posmol determined from differences between the HEXIOS and HEXLOS trials (THFVC/Posmol,°C·mosmol–1·kgH2O–1) was 0.086 ± 0.02, similar to 0.064 ± 0.01 between the C and HEXLOS trials.
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PV and [Lac–]p in each subject, where PV and [Lac–]p were determined by averaging the values at 5 and 10 min of exercise, around which time THFVC (Time) was observed (Table 1). The PV at THFVC for 8 subjects was –2.2 ± 1.5% in the C trial, –4.4 ± 1.1% in the HEXIOS trial, and –4.8 ± 1.1% in the HEXLOS trial with no significant differences among them. [Lac–]p (mmol/kgH2O) at THFVC was 1.4 ± 0.1 in the C trial, 5.7 ± 0.4 in the HEXIOS trial, and 6.0 ± 0.3 in the HEXLOS trial with no significant differences between the HEX trials.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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O2 peak of exercise was decreased when Posmol was reduced by hypotonic saline infusion whereas PV, [Lac–]p, MAP, and HR remained unchanged, and that the reduction in THFVC per unit decrease in Posmol was similar to the increase in THFVC per unit increase in Posmol when exercise intensity was increased (Fig. 3). Exercise Intensity, PV, Posmol, and [Lac–]p
As shown in Table 2 and Fig. 2, Posmol, [Na+]p, and [Lac–]p in the HEX trials increased and PV decreased after the start of exercise whereas they remained unchanged in the C trial. Regarding the mechanisms for increased Posmol and/or decreased PV with exercise intensity, Sjøgaard et al. (22), analyzing muscle biopsies, suggested that, during dynamic leg extension, plasma water moved into the interstitial space of the contracting muscles below 50–70% of O2 peak, and above this intensity, plasma water moved into the intracellular fluid space. It is probable that changes in PV and Posmol with exercise intensity result from movement of the plasma water not only into the interstitial but also into the intracellular space because of increased capillary pressure resulting from increased MAP (12). Alternatively, this fluid shift may be the result of increased osmotic gradient induced by the accumulation of osmoles, i.e., lactate, between the inter- and intracellular spaces (22). Moreover, Nose et al. (17) found that the increase in [Na+]p was highly correlated with that in [Lac–]p during exercise, suggesting that the increased negative charge of the Lac– ion restricts Na+ ion movement from the vascular space during exercise at relatively high intensity, resulting in increased Posmol. Thus, because the exercise intensity-dependent increase in Posmol or [Na+]p is closely associated with increased [Lac–]p and decreased PV, it is unclear which of them is mainly associated with increased THFVC with exercise intensity. In this study, we selectively reduced [Na+]p and Posmol in the HEXLOS trial compared with the HEXIOS trial while maintaining PV, [Lac–]p, HR, MAP, and relative exercise intensity at similar levels.
Posmol and THFVC
As shown in Fig. 3, THFVC increased in proportion to the increased Posmol in each subject, and the sensitivity of the increased THFVC per unit increase in Posmol (THFVC/Posmol) was similar to the sensitivity of the reduced THFVC per unit decrease in Posmol. There have been several studies suggesting that hyperosmolality increased the Tes thresholds for cutaneous vasodilation (24, 25) or sweating (6, 19). Fortney et al. (6) suggested that the THFVC and Tes thresholds for sweating both increased by 0.5°C during bicycle exercise at 65–75% of O2 peak when Posmol increased by 10 mosmol/kgH2O by hypertonic saline infusion before exercise while maintaining PV at the same level as the control trial. However, in their study, because Posmol increased above the level induced by exercise itself, it was unclear whether the upward shift of THFVC with increased exercise intensity (23, 29) was caused by the increased Posmol. In this study, THFVC and Posmol levels in the HEXLOS trial were between those in the C and HEXIOS trials.
Sawka et al. (19) studied the effects of acute hypervolemia and acute hypovolemia on the Tes threshold for sweating at a given intensity of treadmill running, and analyzed the results in relation to the resultant change in Posmol. They suggested that the Tes threshold in the hypervolemic trial was lower than in the control trial with an attenuated increase in Posmol. On the other hand, the threshold was higher in the hypovolemic trial than that in the control trial with an enhanced increase in Posmol. However, because they did not separate the effects of Posmol from those of blood volume, it is unclear whether the lower Posmol decreases the threshold. Thus ours is the first study to isolate the Posmol effects on THFVC within the physiological range. We found that THFVC at 65% O2 peak of exercise was decreased with reduced Posmol and that the sensitivity (THFVC/Posmol) was similar to that with increased exercise intensity from 30 to 65% O2 peak, demonstrating that Posmol plays an important role in the upward shift of THFVC with increased exercise intensity.
Regarding the afferent pathway of the effect of hyperosmolality on skin blood flow and sweating, Nielsen et al. (15) suggested the involvement of brain osmoreceptors acting on hypothalamic thermoregulatory neurons. This idea has been tested in panting and sweating animals by intravascular or intracerebroventricular hypertonic infusions (1). The addition of hypertonic artificial cerebrospinal fluid to the cerebrospinal fluid was reported to inhibit thermal panting and produce vasoconstriction in the ear skin of hyperthermic rabbits (30). Moreover, an intraventricular infusion of water into dehydrated cats exposed to heat stress was reported to recover panting toward the hydrated level (3). Thus osmosensitive mechanisms in the brain may be involved in the upward shift of THFVC with increased exercise intensity.
However, it remains unknown whether this is a direct influence of extracellular fluid osmolality on thermosensitive cells (21) or by thermosensitive neurons receiving a projection from osmosensitive structures in the circumventricular organs, which are involved in regulating body fluid and arterial pressure homeostasis (5). Ichinose et al. (8) recently examined whether Posmol was involved in the downward shift of THFVC after heat acclimation and endurance training at a given intensity of exercise and found that the sensitivity of the upward shift of THFVC per unit increase in Posmol, by pretreatment with a hypertonic infusion, was reduced by 50% after 10-day endurance training, concluding that reduced osmotic sensitivity was closely associated with improved thermoregulatory response. Regarding the mechanisms, because the sensitivity of ADH secretion to altered Posmol was reported to be enhanced in fit subjects (7) and even remained unchanged in heat-acclimatized subjects (27), they suggested that reduced osmotic sensitivity after 10-day endurance training was limited to thermoregulation through a different path from that for ADH secretion (8). Because the plasma ADH level at 65% O2 peak, the same relative exercise intensity as in this study, was reported to remain the same as at rest despite a 5 mosmol/kgH2O increase of Posmol (26), the upward shift of THFVC with increased exercise intensity may be caused by a different osmosensitive mechanism from that for ADH secretion.
[Lac–]p and THFVC
The upward shift of THFVC at a given increase in Posmol (THFVC/Posmol) from the C to the HEXIOS trial was 0.064°C·mosmol–1·kgH2O–1, slightly higher than the 0.040°C·mosmol–1· kgH2O previously reported by Takamata et al. (25), whereas PV at THFVC was similar between the two studies. They suggested that THFVC/Posmol, determined by increasing exercise intensity from 30% to 55% O2 peak, was similar to that determined in passively heated subjects with a graded increase in Posmol by hypertonic saline infusion. However, because [Lac–]p at 55% O2 peak of exercise in their study likely remained unchanged relative to 30% O2 peak (17) and [Lac–]p in this study increased to 7 mmol/kgH2O (Fig. 2), we surmised that the enhanced sensitivity of THFVC/Posmol with increased exercise from the C to HEXIOS trial could be associated with reduced pH in the contracting muscles owing to enhanced lactate production (20). Experimentally, Crandall et al. (2) reported in passively hyperthermic subjects that forearm cutaneous vasodilation was suppressed by isometric handgrip exercise as well as after postexercise ischemia in the contralateral forearm, suggesting that muscle metaboreceptors may also be involved in the exercise intensity-associated increase in THFVC.
Limitations
In this study, desmopressin (DDAVP) was administered in the HEXLOS trial to retain hypotonic saline in the body. Although the effects of DDAVP on THFVC were not completely excluded, the expression of V2 receptors is limited to the ascending limb of Henle’s loop or the collecting duct in the kidney (10). Moreover, there were no significant differences in MAP and HR at rest between HEXLOS and other trials. These results suggest that the effects of DDAVP on the Posmol-THFVC relationship are minimal.
The volume of 0.45% saline infusion in the HEXLOS trial was designed to negate the presumed increase in Posmol at THFVC by free water loss into the contracting muscles (17). However, because the infusion rate was restricted to avoid hemolysis in the peripheral vein into which hypotonic saline was infused, Posmol at THFVC remained slightly but significantly higher than in the C trial. However, Posmol in the HEXLOS trial was successfully reduced to a significantly lower level than in the HEXIOS trial.
THFVC is known to increase by 0.2°C with a 1°C decrease in Tskin (13). In addition, Tskin is decreased by sweating, which removes heat from the skin surface for evaporation. To avoid differences in Tskin among the trials, a thermal suit was used to maintain constant Tskin and to minimize evaporative heat loss by maintaining vapor pressure saturated in the microenvironment under the suit. As a result, Tskin for all trials was controlled within the range of 34 ± 1°C. Although Tfa in all trials transiently decreased at 5 min of exercise compared with at rest (not shown), this decrease was too small to decrease Tskin (Table 4), and it was not significantly different among the trials. These results suggest no significant differences in thermal input from the skin surface of the entire body to the thermoregulatory center among the trials.
In conclusion, we examined the role of Posmol in the exercise intensity-associated increase in THFVC, and the results suggested that Posmol is at least partially involved in the elevation of THFVC above moderate exercise intensity.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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