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J Appl Physiol 98: 2011-2018, 2005. First published January 20, 2005; doi:10.1152/japplphysiol.00888.2004
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Cutaneous vascular responses to isometric handgrip exercise during local heating and hyperthermia

Gregg R. McCord and Christopher T. Minson

Department of Human Physiology, University of Oregon, Eugene, Oregon

Submitted 17 August 2004 ; accepted in final form 15 January 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The dramatic increase in skin blood flow and sweating observed during heat stress is mediated by poorly understood sympathetic cholinergic mechanisms. One theory suggests that a single sympathetic cholinergic nerve mediates cutaneous active vasodilation (AVD) and sweating via cotransmission of separate neurotransmitters, because AVD and sweating track temporally and directionally when activated during passive whole body heat stress. It has also been suggested that these responses are regulated independently, because cutaneous vascular conductance (CVC) has been shown to decrease, whereas sweat rate increases, during combined hyperthermia and isometric handgrip exercise. We tested the hypothesis that CVC decreases during isometric handgrip exercise if skin blood flow is elevated using local heating to levels similar to that induced by pronounced hyperthermia but that this does not occur at lower levels of skin blood flow. Subjects performed isometric handgrip exercise as CVC was elevated at selected sites to varying levels by local heating (which is independent of AVD) in thermoneutral and hyperthermic conditions. During thermoneutral isometric handgrip exercise, CVC decreased at sites in which blood flow was significantly elevated before exercise (–6.5 ± 1.8% of maximal CVC at 41°C and –10.5 ± 2.0% of maximal CVC at 43°C; P < 0.05 vs. preexercise). During isometric handgrip exercise in the hyperthermic condition, an observed decrease in CVC was associated with the level of CVC before exercise. Taken together, these findings argue against withdrawal of AVD to explain the decrease in CVC observed during isometric handgrip exercise in hyperthermic conditions.

skin; human; thermoregulation; sudomotor

BLOOD FLOW IN NONGLABROUS skin is regulated by two branches of the sympathetic nervous system: a noradrenergic branch responsible for vasoconstriction and a cholinergic branch responsible for cutaneous active vasodilation (5, 7, 8, 11). Sympathetic noradrenergic nerves are known to exert tonic control over skin blood flow at rest in normothermic environments. The nerves maintain this constricted tone through release of norepinephrine, which binds to {alpha}1- and {alpha}2-receptors located on cutaneous blood vessels. When core body temperature is challenged in cold environmental conditions, sympathetic noradrenergic nerve activity is increased to promote further vasoconstriction. In contrast, when a human is heated so as to increase core body temperature, tonic vasoconstriction is released and blood flow increases. The initial 5–15% rise in blood flow is due to withdrawal of the sympathetic noradrenergic vasoconstriction of the blood vessel. The remaining 85–95% increase in skin blood flow is due to active vasodilation via a poorly understood neurotransmitter mechanism. In recent years, a role for nitric oxide and vasoactive intestinal peptide in cutaneous active vasodilation has been established (1, 7, 19, 20, 25), although the exact interactions between these and potentially other substances remain to be elucidated. At approximately the same internal core body temperature threshold for active vasodilation during heat stress, the sudomotor system is also activated. The sudomotor system is known to be controlled by sympathetic cholinergic nerves that release acetylcholine, which binds to muscarinic receptors on sweat glands resulting in increased humidity of the skin so as to cool the skin through evaporative heat loss. It has been shown that muscarinic-receptor activation by acetylcholine may contribute to cutaneous active vasodilation through nitric oxide at the onset of active vasodilation (10, 22), although this has not been observed during more prolonged heat stress (20).

Because sweating and active vasodilation are known to increase in parallel during heat stress, it has been suggested that cutaneous active vasodilation and sweating may be controlled through a single sympathetic cholinergic nerve by means of cotransmission (8, 24). Evidence for this theory was provided in an elegant study by Kellogg et al. (9) in which they presynaptically blocked cholinergic nerves with botulinum toxin A during heat stress, effectively abolishing the sweating and active vasodilation responses (9). It was also demonstrated during this experiment that atropine administration abolished the sweating response but that it only partially attenuated active vasodilation.

In a study by Crandall and colleagues (3), cutaneous vascular conductance (CVC) was found to decrease, whereas sweat rate increased, when isometric handgrip exercise was performed during hyperthermia, although this has not been observed during mild hyperthermia (13). These investigators proposed that the mechanism responsible for the decrease in CVC was withdrawal of active vasodilation, because superimposed adrenergic vasoconstriction was eliminated as a possibility by presynaptically blocking adrenergic nerves by iontophoresis of bretylium tosylate. This finding is contrary to observations by Kellogg et al. (8) showing that dynamic exercise during hyperthermia produces decreases in CVC via sympathetic vasoconstriction. In a follow-up study, Crandall and colleagues (4) further examined this phenomenon and determined that the withdrawal of active vasodilation was most likely mediated by a metaboreflex, because the decrease in CVC persisted when blood flow to the exercising arm was occluded to trap metabolites at the cessation of exercise. These data, taken together with the study of Kellogg et al. (9), suggested the possibility of independent cholinergic nerve control of sweating and active vasodilation.

Although withdrawal of active vasodilation is one logical explanation for the drop in CVC observed during bouts of isometric handgrip exercise in hyperthermic conditions, other interpretations of the data of Crandall et al. (3) are possible. For example, the large rise in arterial pressure that occurs in response to isometric handgrip exercise may cause the local release of vascular vasoconstrictor substances. Furthermore, it is possible that decreases in CVC could be explained by myogenic vessel autoregulation responding to the large increase in perfusion pressure attending isometric handgrip exercise. While taking these possibilities into consideration, our goal in the present study was to determine whether the decrease in CVC observed during hyperthermic isometric handgrip exercise could be explained by a mechanism other than withdrawal of active vasodilation. The fact that Crandall and colleagues (3) only observed a decrease in CVC during the second bout of hyperthermic isometric handgrip exercise but not in the first trial when active vasodilation was clearly present raises the question of why CVC failed to decrease during the first hyperthermic handgrip. Thus we conducted two separate protocols to test the hypothesis that CVC will decrease during isometric handgrip exercise when skin blood flow has been raised to levels similar to that induced by hyperthermia using local heating. The protocols designed for this experiment were aimed at identifying whether the response observed by Crandall and colleagues (3) could be repeated when levels of skin blood flow are elevated but in the absence of active vasodilation. To accomplish this, the first protocol investigated the effects of isometric handgrip exercise on CVC by using varying levels of local heating to progressively raise the level of skin blood flow before exercise. This protocol was used to emulate the substantial rise in skin blood flow observed during hyperthermia without engaging the active vasodilator response. In the second protocol, we used both local heating and whole body heating to establish whether the response observed during the first protocol would be altered in the presence of active vasodilation or whether the response was more dependent on the level of blood flow before onset of exercise. A follow-up protocol was also carried out in which bretylium tosylate was perfused via microdialysis to presynaptically block the release of norepinephrine to further demonstrate that the observed responses were not due to adrenergic vasoconstriction.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   A total of 10 subjects (8 men and 2 women, aged 21–25 yr old) participated in the experiments. Some subjects participated in both of the protocols. The two women were taking oral contraceptives, and they were studied during menstruation because the phase of oral contraceptive use is known to alter the skin blood flow response to whole body heating (2). All subjects were healthy, normotensive, and nonsmokers. Institutional Review Board of the University of Oregon approval was obtained, and each subject gave both written and oral informed consent before participation.

Protocol 1: Isometric handgrip exercise during normothermic conditions.   The subject reported to the laboratory at least 2 h before the experimental protocol to give written consent, to have their height and weight measured, and to become familiarized with the laboratory. At this time, the subject also performed a maximal voluntary contraction on a handgrip dynamometer with their dominant arm. The subject was asked to not hold his or her breath or tense other body parts while performing the handgrip exercise.

The subject then returned to the laboratory at least 2 h later for the experimental protocol. Heart rate (HR) and respiration were continuously monitored on a computer screen by equipping the subjects with a five-lead electrocardiogram (Cardiocap 5, Datex Ohmeda, Andover, MA). An automated blood pressure cuff was placed over the brachial artery of the dominant arm. Infrared photoplethysmograpahy of the contralateral finger was used to continuously measure arterial pressure throughout the experimental protocol (Portapres, TNO Biomedical Instrumentation, Amsterdam, The Netherlands). Four sites on the nondominant forearm were equipped for measurement of skin blood flow by using laser-Doppler flowmetry (moorLAB, Moor Instruments, Devon, UK) with integrated local heaters. CVC was calculated as red blood cell flux (mV)/mean arterial pressure (MAP; mmHg). Sweat rate was measured by passing dry nitrogen gas across 1 cm2 of skin at 250 ml/min into a capacitance hygrometer to measure relative humidity (Viasala, Woburn, MA).

Before baseline measurements were taken, the subject was supine for 30–45 min for instrumentation. After 5 min of baseline measurements, multiple blood pressure measurements were taken via brachial auscultation to verify pressure from the Portapres. The subject then performed isometric handgrip exercise at 30% of his or her previously determined maximal voluntary contraction for 3 min. Visual feedback to the subject and the investigators using a computer monitor ensured that 30% maximum was maintained for the full 3 min. Breathing was monitored by the investigator on a monitor (Cardiocap 5, Datex Ohmeda, Andover, MA), and the subject was encouraged to breathe normally throughout the experiment. After the first bout of isometric handgrip exercise, MAP was allowed to return to baseline levels before proceeding with the next portion of the protocol. The temperature of the local heaters at three of the four sites was then raised to 39, 41, and 43°C, with one local heater remaining at 33°C to act as a control site. The temperature of local heaters was increased in increments of 0.5°C over 5-s intervals to the desired temperatures (15). Skin blood flow at the locally heated sites was allowed to plateau (at least 30 min from the start of local heating), and blood pressure via brachial auscultation was periodically measured from the dominant arm to verify the Portapres measurement. Once a stable plateau in skin blood flow was observed in all the sites, the second bout of isometric handgrip was performed. The subject was then allowed to recover for 7–12 min before the final isometric handgrip trial. The temperature of the local heaters was then raised to 44°C to elicit maximal cutaneous vasodilation, and another blood pressure via brachial auscultation was taken.

Follow-up for protocol 1.   Two additional subjects participated in a follow-up protocol. Instrumentation was exactly the same as the first protocol except for the modifications listed below. Before lying on the table, the subject was dressed in a tube-lined water-perfused suit. The suit covered the entire body except the face, hands, feet, and forearm where measurements were taken. During baseline measurements and isometric handgrip measurements, thermoneutral water (32.5°C) was perfused through the suit. Two microdialysis fibers (model MD 2000, Bioanalytical Systems, West Lafayette, IN) with a membrane length of 10 mm and a molecular mass cutoff of 20 kDa were placed in the skin of the ventral aspect of the nondominant forearm. The microdialysis probe was placed with a 25-gauge needle inserted through the dermis of the skin by using sterile techniques in the absence of anesthesia. The probe was then threaded through the internal lumen of the needle and the needle was withdrawn, leaving the membrane. The fibers were then taped in place and continuously perfused with 20 mM bretylium tosylate at a rate of 2 µl/min with a microinfusion pump (Harvard Apparatus, Holliston, MA; and model CMA/102, CMA Microdialysis, Stockholm, Sweden). Sites were at least 5 cm apart. Bretylium tosylate was used to presynaptically block the release of norepinephrine from sympathetic noradrenergic nerves. If the absence of noradrenergic vasoconstrictor influence does not alter the decrease in the CVC to isometric handgrip exercise in the presence of local heating, then it can be concluded that noradrenergic neural activity does not contribute to the CVC response observed during isometric handgrip exercise and local heating. Skin blood flow was indexed at four sites: two sites infused with bretylium tosylate and two other sites independent of drug influence.

To test the effectiveness of bretylium tosylate at blocking the sympathetic vasoconstrictor response, a 10-min cold stress was administered by perfusion of 5°C water through the water-perfused suit. Adrenergic nerve blockade was determined to be adequate when skin blood flow was observed to decrease only at control sites independent of bretylium tosylate. Skin blood flow was then allowed to return to pre-cold stress levels at the two skin sites not perfused with bretylium tosylate, and a 5-min baseline was taken. The temperature of the local heaters was then increased to 39 and 43°C at the bretylium tosylate sites and to 39 and 43°C at the sites independent of drug influence. Once skin blood flow had reached a plateau at all four sites, the subject performed an isometric handgrip for 3-min at 30% of their maximum. Skin blood flow was then allowed to return to preexercise levels at all four sites, and a second cold stress was administered to ensure the effectiveness of bretylium tosylate. The temperature of the local heaters was then increased to 44°C at all four laser-Doppler flowmetry sites to elicit maximum cutaneous vasodilation. CVC values were then converted to percentages of their relative maximum for each site (i.e., %CVCmax).

Protocol 2: Isometric handgrip exercise during hyperthermic conditions.   Six male subjects participated in the hyperthermic protocol. In the four subjects who participated in both protocols, experiments were conducted between 2 and 7 days apart. The two subjects who did not participate in the first protocol came to the laboratory for orientation and to perform the maximal handgrip test the day before the hyperthermic protocol. Instrumentation was exactly the same as with the first protocol except for modifications listed below. Before lying on the bed, the subject was dressed in a tube-lined water perfused suit, which was used to raise core body temperature, and an impermeable vinyl garment to prevent evaporative heat loss once sweating commenced. The suit covered the entire body except the face, hands, feet, and forearm where measurements were taken. During baseline measurements, thermoneutral water (32.5°C) was perfused through the suit. A sublingual thermistor was used to measure oral temperature (Tor), and this was used as an index of core body temperature. After instrumentation, 5 min of baseline data were collected. The temperature of the local heaters was then increased to 39, 41, and 43°C with one control site remaining at 33°C. Skin blood flow at the locally heated sites was allowed to plateau. After the plateau, 50°C water was perfused through the tube-lined suit to increase Tor and to induce cutaneous active vasodilation and sweating. As with the thermoneutral day, blood pressure was measured continuously using the Portapres while periodic blood pressures were taken via brachial auscultation to verify the accuracy of the Portapres. The first hyperthermic isometric handgrip was performed after red blood cell flux had approximately doubled from baseline values at the control site and the subject had begun to sweat. The second bout of exercise was performed after sublingual temperature increased to ≥0.5°C above baseline. After the second handgrip trial, water perfusing through the suit was lowered to 32.5°C to allow the subject to cool. The temperature of the local heaters was then increased to 44°C at all four laser-Doppler flowmetry sites to elicit maximum cutaneous vasodilation. CVC values were then converted to percentages of their relative maximum for each site (i.e., %CVCmax).

Data and statistical analyses.   Data were digitized and stored on a computer at 40 Hz. Data were analyzed offline with signal-processing software (Windaq, Dataq Instruments, Akron, OH). CVC was averaged over stable 20-s periods at each time point. Comparisons of HR and MAP responses to isometric handgrip exercise among the three trials for the thermoneutral condition were made via repeated-measures ANOVA, and between the two trials in the hyperthermic condition by paired t-tests. Baseline CVC values and the CVC values during local heating were compared by using ANOVA. For the repeated-measures ANOVA and ANOVA, Tukey's post hoc analysis was chosen. In both the thermoneutral and hyperthermic protocols, paired t-tests were used to analyze significant differences between preexercise and end-exercise CVC values within a given site. All data are presented as average ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Thermoneutral protocol.   Sweat rate and core body temperature did not change during any of the thermoneutral isometric handgrip trials. Baseline values for CVC were taken before local heating of any of the forearm sites. There were no differences between baseline CVC values among the four sites. Baseline HR averaged 65 ± 3 beats/min and MAP averaged 87 ± 1 mmHg. The rise in HR and MAP was similar in all the trials.

During the first isometric handgrip trial, before local heating of any of the sites, CVC did not change significantly from preexercise to end-exercise values at any site (P > 0.05). HR increased significantly from 65 ± 3 to 79 ± 3 beats/min (P < 0.05), and MAP increased from 87 ± 1 to 118 ± 3 mmHg.

Before the second handgrip trial, skin blood flow was increased at three of the four sites via local heating. Local heating to 39°C (34 ± 6% CVCmax), 41°C (72 ± 4% CVCmax), and 43°C (95 ± 3% CVCmax) resulted in progressive increases in CVC that were all significantly different from baseline and the other sites (all P < 0.01). Figure 1 displays the changes in CVC of individual subjects and the mean CVC ± SE from preexercise to end exercise during the second bout of isometric handgrip exercise. CVC did not change significantly at the control site or the 39°C site from preexercise to end exercise. However, when the individual data are examined, a tendency toward vasodilation at 39°C site can be observed (4 of 6 subjects vasodilated). CVC decreased significantly from preexercise to end exercise at the 41 and the 43°C sites (both P < 0.05). HR increased from 61 ± 3 to 81 ± 3 beats/min (P < 0.05), and MAP increased from 88 ± 1 to 124 ± 3 mmHg (P < 0.05). Red blood cell flux increased by an average of 18 ± 11 laser-Doppler flux units [arbitrary units (AU)] at the control site (P > 0.05), 101 ± 20 AU at the 39°C site, 70 ± 9 AU at the 41°C site, and 69 ± 14 AU at the 43°C site (P < 0.05) during the second bout of isometric handgrip exercise.



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  		Fig. 1. Cutaneous vascular conductance (CVC) of individual subjects before (Pre) exercise (Ex) and at the end (End) of exercise during the second thermoneutral isometric handgrip (IHG) exercise in 4 skin sites: control, locally heated to 39°C (39-site), locally heated to 41°C (41-site), and locally heated to 43°C (43-site). Bar graphs represent average CVC values ± SE for subjects before (Pre) and at the end (End) of isometric exercise. %Max, percentage of maximum. *Significant difference from values before exercise within a skin site, P < 0.05.

 
Much like the second trial, the third handgrip produced no significant change in CVC at the control site or 39°C site. However, CVC significantly decreased from preexercise to end exercise at the 41 and 43°C sites (both P < 0.05). HR increased from 63 ± 3 to 78 ± 2 beats/min (P < 0.05), and MAP increased from 89 ± 1 to 126 ± 3 mmHg (P < 0.05). Red blood cell flux increased by an average of 12 ± 8 AU at the control site (P > 0.05), 76 ± 23 AU at the 39°C site, 55 ± 13 AU at the 41°C site, and 74 ± 12 AU at the 43°C site (P < 0.05) during the third bout of isometric handgrip exercise.

Follow-up protocol 1.   Isometric handgrip was performed when skin blood flow had reached a plateau after local heating. CVC decreased from 86 ± 4% preexercise to 79 ± 5% end-exercise at the bretylium tosylate-infused 43°C site. A similar decrease was also observed at sites locally heated to 43°C with normal sympathetic vasoconstrictor influence (86 ± 3% preexercise to 79 ± 2% end exercise). CVC did not change at the 39°C sites of either condition substantially. CVC decreased by an average of 4% CVCmax during cold stress at sites where bretylium tosylate was not present, whereas CVC showed no decrease at sites where bretylium tosylate had been infused, indicating bretylium tosylate provided an adequate blockade of sympathetic vasoconstrictor influence.

Hyperthermic protocol.   The rise in HR and MAP was similar in both trials. The first handgrip trial was performed when skin blood flow had approximately doubled at the control site and Tor had increased 0.32 ± 0.07°C (P < 0.05 from baseline). Figure 2 displays changes in CVC of individual subjects during the first bout of isometric handgrip exercise during hyperthermia. CVC increased from 15 ± 3% preexercise to 25 ± 4% CVCmax end exercise at the control site (P < 0.05), whereas no significant change was observed at the 39°C site, although there was a trend toward a decrease in CVC because CVC decreased in five of the six subjects (P = 0.08). CVC in the 41 and 43°C sites decreased significantly from preexercise to end exercise (both P < 0.05). HR increased from 65 ± 1 to 81 ± 2 beats/min (P < 0.05), and MAP rose from 87 ± 1 to 121 ± 2 mmHg (P < 0.05). Relative humidity of the skin increased by 4 ± 1% during the first bout of exercise (P < 0.05 from preexercise to end exercise). Red blood cell flux increased by an average of 75 ± 21 AU at the control site (P < 0.05), 84 ± 20 AU at the 39°C site, 42 ± 11 AU at the 41°C site, and 27 ± 5 AU at the 43°C site (P < 0.05) during the first bout of hyperthermic isometric handgrip exercise.



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  		Fig. 2. CVC of individual subjects before exercise and at the end of exercise during the first hyperthermic handgrip exercise trial in 4 skin sites: control, locally heated to 39°C, locally heated to 41°C, and locally heated to 43°C. Bar graphs represent average CVC values ± SE for subjects before and at the end of isometric exercise. *Significant difference from values before exercise within a skin site, P < 0.05.

 
Skin blood flow was significantly higher in the control site during the second bout of isometric handgrip exercise compared with that of the first handgrip (P < 0.05). Figure 3 displays CVC from preexercise to end exercise for the second bout of isometric handgrip during hyperthermia. Tor was increased an average of 0.50 ± 0.03°C from baseline (P < 0.05). The average CVC at all sites significantly decreased from preexercise to end exercise (all P < 0.05). HR increased from 90 ± 4 to 107 ± 4 beats/min, and MAP increased from 88 ± 1 to 123 ± 2 mmHg (both P < 0.05). Relative humidity increased by an average of 2.0 ± 0.2% during the second bout of exercise (P < 0.05 from preexercise to end exercise). Skin blood flow increased by an average of 47 ± 17 laser-Doppler flux units (LDF) at the control site (P < 0.05), 61 ± 18 LDF at the 39°C site, 38 ± 5 LDF at the 41°C site, and 48 ± 8 LDF at the 43°C site (P < 0.05) during the second bout of hyperthermic isometric handgrip exercise.



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  		Fig. 3. CVC of individual subjects before exercise and at the end of exercise during the second hyperthermic handgrip exercise trial in 4 skin sites: control, locally heated to 39°C, locally heated to 41°C, and locally heated to 43°C. The bar graphs represent average CVC values ± SE for subjects before and at the end of isometric handgrip exercise. *Significant difference from values before exercise within a skin site, P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The goal of this study was to determine whether the decrease in CVC previously observed during isometric handgrip exercise in a hyperthermic state could be explained by a mechanism other than withdrawal of active vasodilation (3). Our approach was to investigate the changes in CVC when skin blood flow was elevated to varying levels before performing isometric handgrip exercise during both normothermic and hyperthermic conditions. The primary finding of this study was that the decrease in CVC observed during isometric handgrip is not likely explained by withdrawal of active vasodilation. These conclusions are based on three important observations. First, in the normothermic condition, decreases in CVC were observed during isometric handgrip exercise when skin blood flow was significantly elevated to levels equal to or above ~40–50% CVCmax before the onset of isometric exercise. In the follow-up study, we demonstrated that this is not due to increased adrenergic vasoconstriction. Second, CVC decreased in most subjects during mild hyperthermia at skin sites in which local heating was used to raise CVC before handgrip exercise but not at the control site. Third, CVC did not decrease significantly during hyperthermia in the control site until CVC was significantly elevated to >40% CVCmax, consistent with our findings in the normothermic condition.

Crandall and colleagues (3) were the first to observe a decrease in CVC and a concomitant increase in sweat rate with isometric handgrip exercise during hyperthermia. Because the authors observed this decrease in CVC in skin sites in which they had clearly inhibited the adrenergic vasoconstrictor system with bretylium tosylate, it was concluded that the decline in CVC was due to withdrawal of active vasodilation and could not be explained by a superimposed adrenergic vasoconstriction. The observed separation of CVC and sweating was used to suggest that active vasodilation and sweating may be controlled by separate cholinergic nerves. In a follow-up study, Crandall and colleagues (4) extended these findings to suggest that the withdrawal of active vasodilation was a reflex response arising from metaboreceptor stimulation. This conclusion was based on the observation that the decline in CVC persisted when blood flow to the exercising arm was occluded at the cessation of exercise. Our findings extend their original observations to suggest that a mechanism other than withdrawal of active vasodilation is responsible for the decrease in CVC observed during isometric handgrip exercise.

In an earlier report, Taylor et al. (23) investigated the cutaneous vascular responses to isometric handgrip exercise during local heating to 39°C, and they observed an increase in CVC to isometric exercise, similar to our findings in most subjects at this temperature. These findings were taken by Crandall et al. (3) to suggest the decrease in CVC during isometric handgrip exercise in the hyperthermic state could not be explained as an autoregulatory response. However, locally heating the skin to 39°C does not raise skin blood flow to the level at which decreases in CVC have been observed during isometric exercise in hyperthermia. In fact, CVC was only observed to decrease during hyperthermia in both studies by Crandall and colleagues (3, 4) when CVC was at least 50% CVCmax before isometric exercise. Thus our goal in the normothermic study was to simulate the experiment by Taylor et al. (23) by locally heating skin to 39°C before isometric exercise and to 41 and 43°C to raise CVC to higher values in which a decrease in CVC with isometric handgrip exercise had been observed during hyperthermia in the studies by Crandall and colleagues (3).

Our goal in the hyperthermic protocol was to examine effects of elevated skin blood flow during both mild and more pronounced hyperthermia on the CVC response to isometric handgrip exercise and to determine whether the presence of active vasodilation caused the CVC response to differ substantially from the normothermic protocol. In the first hyperthermic handgrip trial, in which skin blood flow at the control site had doubled from baseline, we did not observe a significant decrease in CVC in the control site. In fact, similar to the responses of several subjects in the 39°C site during normothermia, we observed an increase in CVC in some subjects. However, we observed significant decreases during this trial in the 41 and 43°C sites and in five of six subjects in the 39°C site (P = 0.08). The tendency for an increase in CVC at the control site is most likely due to withdrawal of adrenergic vasoconstrictor tone. In the following handgrip trial in the hyperthermic condition, subjects performed isometric handgrip exercise during more pronounced hyperthermia as core body temperature was ≥0.5°C above baseline temperature and CVC was >40% CVCmax in the control site prior to handgrip exercise. During this trial, CVC decreased significantly during isometric handgrip exercise in all sites.

Taking into consideration the findings from our two protocols and data from Crandall and colleagues (3, 4), it appears there is a threshold value of skin blood flow that must be achieved before isometric handgrip exercise to observe a decrease in CVC. That is, a decrease in CVC in response to isometric handgrip exercise was most consistently observed when skin blood flow was elevated to at least 40–50% CVCmax before exercise, but it was not consistently observed at lower levels of skin blood flow, even in the same individual during the same handgrip trial. In fact, we observed a vasodilation in most subjects when CVC was elevated above baseline levels but below 40% CVCmax. When skin blood flow was elevated above ~50% CVCmax before isometric handgrip exercise, a decrease in CVC was observed in nearly every subject in our study and in the studies by Crandall and colleagues, irrespective of whether skin blood flow was raised before isometric handgrip exercise via local heating or whole body heating. The discordant CVC responses observed at skin sites raised to different levels of CVCmax during the same handgrip trial within an individual further argue against the decrease in CVC during isometric handgrip being a neurally mediated response. A neural response of central nervous system origin, without competing local influences, would be expected to be directionally similar and observed at all sites simultaneously for a given subject. A more likely explanation for these responses is blood vessel autoregulation. Although a number of potential mechanisms for autoregulation have been hypothesized, the most likely to explain the findings in our study is myogenic autoregulation. According to this hypothesis, the arterioles respond to intravascular pressure as a stimulus, with pressure elevation causing constriction (6).

Our finding that CVC in nonglabrous skin does not change during isometric handgrip exercise in the absence of local heating or hyperthermia was also observed by others (3, 13, 17, 23). However, we and others observed an increase in CVC in most subjects when skin was locally heated to 39°C (23) as well as during mild hyperthermia (13). Basing their discussion on prior work by Folkow and Löfving (5), Taylor and colleagues (23) expertly suggested that at relatively high levels of constriction (i.e., normothermia) the resistance vessels would not be particularly distensible and elevations in arterial pressure would not cause a large enough increase in the vessel radius to yield a measurable reduction in vascular resistance. However, when vascular smooth muscle relaxes, vessel distensibility is increased. With greater distensibility, increases in arterial pressure cause more marked increases in vessel radius and measurable increases in vascular conductance. Our data during local heating to the higher temperatures in the thermoneutral protocol, and during pronounced hyperthermia, extend this concept to suggest there is a level of distensibility of the blood vessel that must be achieved to stimulate an increase in cutaneous vascular tone possibly via myogenic autoregulation, which is not observed if the blood vessel is not sufficiently predilated. Because the cutaneous vascular bed is highly compliant, this mechanism could serve to protect the blood vessel and distal capillary from potential damage due to high perfusion pressures, and yet it would allow for a high skin blood flow for thermoregulatory purposes.

Although myogenic autoregulation seems the most likely explanation for our findings, it is currently not possible to experimentally test this hypothesis in humans, and thus other possible mechanisms must also be considered. Skin sympathetic nerve activity (SSNA) has been shown to increase during isometric handgrip exercise in normothermia, suggesting that noradrenergic vasoconstriction is also a potential mechanism that could account for the decrease in CVC observed during isometric handgrip exercise (14, 16, 18, 24). The investigations of SSNA, however, have failed to clearly demonstrate a relationship between increased SSNA and increased cutaneous vascular resistance in nonglabrous skin during isometric exercise in normothermic conditions. Furthermore, when bretylium tosylate was used to presynaptically block noradrenergic nerves during either local heating or pronounced hyperthermia (3), CVC was still observed to decrease during isometric handgrip exercise. Taken together, these data provide strong evidence against increased adrenergic vasoconstriction explaining the CVC response observed.

Because CVC is a calculated value from red blood cell flux and MAP, it is also possible that the rise in pressure at the blood vessel was not as great as it was in the larger blood vessels of the finger in which blood pressure was measured. This would be problematic, because it would suggest there is a fundamental problem in the procedure by which cutaneous vascular tone is determined when accounting for changes in arterial pressure. However, there is little support for this technical limitation because the responses within a given individual were variable; such that CVC was observed to increase in modestly vasodilated skin sites while simultaneously decrease in skin sites in which red blood cell flux was significantly higher before isometric exercise. The possibility that the responses could be attributed to a venoarteriolar reflex also seems unlikely, because it is doubtful that venous pressure rose significantly in the experimental arm during isometric exercise with the contralateral arm. The possibility still exists that redundant mechanisms may participate in the reduced CVC during isometric handgrip exercise during hyperthermia, because we were not able to block active vasodilation during hyperthermia. However, on the basis of the data presented, this possibility seems unlikely as the discordant CVC responses within an individual during a given handgrip trial argue against the response being a central nervous system response.

Similar to the findings in previous studies in nonglabrous skin (3, 4, 11–13, 21), we observed an increase in sweat rate during combined whole body heating and isometric handgrip exercise. It has been suggested that the increase in sweat rate during isometric handgrip exercise is a metaboreflex response, because it has been observed in nonglabrous skin during postisometric exercise ischemia (4, 12, 13, 21). On the basis of the concept that those changes in active vasodilation and sweating are directionally similar, this would suggest that a slight vasodilation should occur in response to isometric exercise. However, the present study suggests that a local increase in cutaneous vascular tone may compete with the increase in active vasodilator nerve activity when skin blood flow is significantly elevated before isometric handgrip exercise, leading to an observed increase in sweat rate and concomitant decrease in CVC.

In conclusion, we found that the observed separation between CVC and sweating during hyperthermic isometric handgrip exercise is most likely not due to withdrawal of active vasodilation. We observed that a decrease in CVC during isometric handgrip exercise was associated with the level of skin blood flow before the onset of exercise during both normothermic and hyperthermic conditions. These findings support the possibility of local control of cutaneous vascular tone during isometric handgrip exercise.


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These studies were funded by National Heart, Lung, and Blood Institute Grant HL-70928.


   ACKNOWLEDGMENTS
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The authors greatly appreciate the willingness of the subjects to participate in these studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. T. Minson, 122 C Esslinger Hall, 1240 Univ. of Oregon, Eugene, OR 97403-1240 (E-mail: minson{at}uoregon.edu)

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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