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When one is exposed to a stressful situation in their daily life, a common response is hyperventilation. Although the physiological significance of stress-induced hyperventilation remains uncertain, this response may blunt perception of the stress-inducing stimulus. This study examined the effects of voluntary hyperventilation and resultant hypocapnia on the local skin thermal detection threshold in normothermic resting humans. Local skin thermal detection thresholds were measured in 15 young adults (three females) under three breathing conditions: 1) spontaneous breathing (Control trial), 2) voluntary hypocapnic hyperventilation (HH trial), and 3) voluntary normocapnic hyperventilation (NH trial). Local skin thermal detection thresholds were measured using thermostimulators containing a Peltier element that were attached to the forearm and forehead. The temperature of the probe was initially equilibrated to the skin temperature, then gradually increased or decreased at a constant rate (±0.1 °C/s) until the participants felt warmth or coolness. The difference between the initial skin temperature and the local skin temperature at which the participant noticed warmth/coolness was assessed as an index of the local skin warm/cool detection threshold. Local detection of warm and cool stimuli did not differ between the Control and NH trials, but it was blunted in the HH trial as compared with the Control and NH trials, except for detection of warm stimuli on the forearm. These findings suggest that hyperventilation-induced hypocapnia, not hyperventilation per se, attenuates local skin thermal perception, though changes in responses to warm stimuli may not be clearly perceived at some skin areas (e.g., forearm).

Purpose Women remain underrepresented in the exercise thermoregulation literature despite their participation in leisure-time and occupational physical activity in heat-stressful environments continuing to increase. Here, we determined the relative contribution of the primary ovarian hormones (estrogen [E2] and progesterone [P4]) alongside other morphological (e.g., body mass), physiological (e.g., sweat rates), functional (e.g., aerobic fitness) and environmental (e.g., vapor pressure) factors in explaining the individual variation in core temperature responses for trained women working at very high metabolic rates, specifically peak core temperature (Tpeak) and work output (mean power output). Methods Thirty-six trained women (32 ± 9 year, 53 ± 9 ml·kg−1·min−1), distinguished by intra-participant (early follicular and mid-luteal phases) or inter-participant (ovulatory vs. anovulatory vs. oral contraceptive pill user) differences in their endogenous E2 and P4 concentrations, completed a self-paced 30-min cycling work trial in warm–dry (2.2 ± 0.2 kPa, 34.1 ± 0.2 °C, 41.4 ± 3.4% RH) and/or warm–humid (3.4 ± 0.1 kPa, 30.2 ± 1.2 °C, 79.8 ± 3.7% RH) conditions that yielded 115 separate trials. Stepwise linear regression was used to explain the variance of the dependent variables. Results Models were able to account for 60% of the variance in Tpeak ($$\overline{R }$$ R ¯ 2: 41% core temperature at the start of work trial, $$\overline{R }$$ R ¯ 2: 15% power output, $$\overline{R }$$ R ¯ 2: 4% [E2]) and 44% of the variance in mean power output ($$\overline{R }$$ R ¯ 2: 35% peak aerobic power, $$\overline{R }$$ R ¯ 2: 9% perceived exertion). Conclusion E2 contributes a small amount toward the core temperature response in trained women, whereby starting core temperature and peak aerobic power explain the greatest variance in Tpeak and work output, respectively.

Hyperthermia stimulates ventilation (hyperthermia-induced hyperventilation). In exercising humans, once the core temperature reaches ~37°C, minute ventilation (VE) increases linearly with rising core temperature, and the slope of the relation between VE and core temperature reflects the sensitivity of the response. We previously reported that sodium bicarbonate ingestion reduces VE during prolonged exercise in the heat without affecting the sensitivity of hyperthermia-induced hyperventilation. Here, we hypothesized that reductions in VE associated with sodium bicarbonate ingestion reflect elevation of the core temperature threshold for hyperthermia-induced hyperventilation. Thirteen healthy young males ingested sodium bicarbonate (0.3 g/kg body weight) (NaHCO3 trial) or sodium chloride (0.208 g/kg body weight) (NaCl trial), after which they performed a cycle exercise at 50% of peak oxygen uptake in the heat (35°C and 50% relative humidity) following a pre-cooling. The pre-cooling enabled detection of an esophageal temperature ( Tes: an index of core temperature) threshold for hyperthermia-induced hyperventilation. The Tes thresholds for increases in VE were similar between the two trials (P = 0.514). The slopes relating VE to Tes also did not differ between trials (P = 0.131). However, VE was lower in the NaHCO3 than the NaCl trial in the range of Tes = 36.8-38.4°C (P < 0.007, main effect of trial). These results suggest that sodium bicarbonate ingestion does not alter the core temperature threshold or sensitivity of hyperthermia-induced hyperventilation during prolonged exercise in the heat; instead, it downshifts the exercise hyperpnea.

What is the central question of this study? Do transmembrane member 16A (TMEM16A) blockers modulate the activation of heat loss responses of sweating and cutaneous vasodilatation? What are the main finding and its importance? Relative to the vehicle control site, TMEM16A blockers T16Ainh-A01 and benzbromarone had no effect on sweat rate or cutaneous vascular conductance during whole-body heating inducing a 1.1 ± 0.1°C increase in core temperature above baseline resting levels. These results suggest that TMEM16A blockers T16Ainh-A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation during whole-body heat stress.Animal and in vitro studies suggest that transmembrane member 16A (TMEM16A), a Ca

What is the central question of this study? Does acute intradermal administration of the antioxidant ascorbate augment local forearm cutaneous vasodilatation and sweating via nitric oxide synthase (NOS)-dependent mechanisms during exercise-heat stress in older adults with uncomplicated controlled hypertension? What is the main finding and its importance? Relative to the control site, ascorbate had no effect on forearm cutaneous vascular conductance (CVC) and sweat rate, although CVC was reduced with NOS inhibition in older adults with hypertension. Acute local administration of ascorbate to forearm skin does not modulate heat loss responses during exercise-heat stress in older adults with hypertension.Nitric oxide synthase (NOS) contributes to the heat loss responses of cutaneous vasodilatation and sweating during exercise. However, the contribution of NOS may be attenuated in individuals with uncomplicated, controlled hypertension due to elevated oxidative stress, which can reduce NO bioavailability. We evaluated the hypothesis that the acute local intradermal administration of the antioxidant ascorbate would enhance cutaneous vasodilatation and sweating via NOS-dependent mechanisms during an exercise-heat stress in adults with hypertension. Habitually active adults who were normotensive (n = 14, 7 females, 62 ± 4 years) or had uncomplicated, controlled hypertension (n = 13, 6 females, 62 ± 5 years) performed 30 min of moderate-intensity (50% of their pre-determined peak oxygen uptake) semi-recumbent cycling in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC) and sweat rate were assessed at four forearm skin sites continuously perfused with (1) lactated Ringer solution (Control), (2) 10 mM antioxidant ascorbate, (3) 10 mM N

The objective of this study was 1) to examine pooled effects of hypertension on nitric oxide (NO)-dependent vasodilation during local heating across multiple nonglabrous skin regions, and 2) explore regional differences. Responses were compared between 14 participants with uncomplicated hypertension controlled with medication (7 females, 61 ± 6 yr) and 14 age-matched nonhypertensive controls (6 females; 60 ± 5 yr). Cutaneous vascular conductance, normalized to maximum vasodilation (%CVCmax), was assessed at the upper chest, abdomen, dorsal forearm, thigh, and lateral calf during local heating. Across all regions, local skin temperatures were simultaneously increased from 33°C to 42°C (1°C·10 s−1) and held until a stable heating plateau was achieved (∼40 min), followed by continuous infusion of 20 mM of NG-nitro-l-arginine methyl ester (l-NAME; ∼40 min) at all sites until a stable l-NAME plateau was achieved. The difference between heating and l-NAME plateaus was defined as the NO-contribution. Statistical equivalence for each heating phase was determined based on equivalence bounds of ±10%CVCmax for between-group differences. Pooled (all-regions) %CVCmax responses were equivalent for baseline (two one-sided t tests; P < 0.001), heating plateau ( P = 0.002), l-NAME plateau ( P = 0.028), and NO-contribution ( P = 0.003). For individual regions, responses were equivalent at baseline for the abdomen, thigh, and calf, the heating plateau for the thigh, and the l-NAME plateau for the calf (all P < 0.05). Conversely, the calf heating plateau was lower in the hypertension group ( t test; P < 0.05). Local heat-induced cutaneous vasodilation was statistically equivalent between individuals with uncomplicated, controlled hypertension, and nonhypertensive age-matched adults when pooled across multiple skin sites. Conversely, individual between-region comparisons were generally too variable to permit definitive conclusions.

Transient receptor potential ankyrin 1 (TRPA1) channel activation induces cutaneous vasodilation in humans in vivo. However, the mechanisms underlying this response remains equivocal. We hypothesized that nitric oxide synthase (NOS) and Ca2+ activated K+ (KCa) channels contribute to the TRPA1 channel-induced cutaneous vasodilation with no involvement of cyclooxygenase (COX). Cutaneous vascular conductance (CVC) in 9 healthy young adults was assessed at 4 dorsal forearm skin sites treated by intradermal microdialysis with (1) 1.985% dimethyl sulfoxide + 0.015% lactated Ringer solution with propylene glycol (vehicle control), (2) 10 mM l-NAME, a nonselective NOS inhibitor, (3) 10 mM ketorolac, a nonselective COX inhibitor, or (4) 50 mM tetraethylammonium, a nonselective KCa channel blocker. Cinnamaldehyde, a TRPA1 channel activator, was administered to each skin site in a dose-dependent manner (2.9%, 8.8%, 26%, and 80%, each lasting ≥30 minutes). Administration of ≥8.8% cinnamaldehyde increased CVC from baseline at the vehicle control site by as much as 27.4% (95% confidence interval of 5.3; P0.001). NOS inhibitor attenuated the cinnamaldehyde-induced increases in CVC at the 8.8%, 26%, and 80% concentrations relative to the vehicle control site (all P ≤ 0.05). In contrast, both the COX inhibitor and KCa channel blockers did not attenuate the cinnamaldehyde induced-increases in CVC relative to the vehicle control site for all concentrations (all P ≥ 0.130). We conclude that in human skin in vivo, NOS plays a role in modulating the regulation of cutaneous vasodilation in response to TRPA1 channel activation with no detectable contributions of COX and KCa channels.

Hyperthermia causes hyperventilation and concomitant hypocapnia and cerebral hypoperfusion. The cerebral hypoperfusion may underlie central fatigue. We demonstrate that sodium bicarbonate ingestion reduces heat-induced hyperventilation and attenuates hypocapnia-related cerebral hypoperfusion during prolonged exercise in the heat. In addition, we show that sodium bicarbonate ingestion reduces ratings of perceived exertion during the exercise. This study provides new insight into the development of an effective strategy for preventing central fatigue during exercise in the heat.

Cutaneous thermal hyperemia during local skin heating to 39°C, which is highly dependent on nitric oxide synthase (NOS), is frequently used to assess endothelium-dependent cutaneous vasodilation. We showed that Na+-K+-ATPase mediates the regulation of cutaneous thermal hyperemia partly via NOS-dependent mechanisms although a component of the Na+-K+-ATPase modulation of cutaneous thermal hyperemia is NOS independent. Thus, as with NOS, Na+-K+-ATPase may be important in the regulation of cutaneous endothelial vascular function.

Whether whole body heat loss and thermoregulatory function (local sweat rate and skin blood flow) are different between summer and autumn and between autumn and winter seasons during exercise with different air flow in humid heat remain unknown. We therefore tested the hypotheses that whole body sweat rate (WBSR), evaporated sweat rate, and thermoregulatory function during cycling exercise in autumn would be higher than in winter but would be lower than in summer under hot-humid environment (32 C, 75% RH). We also tested the hypothesis that the increase of air velocity would enhance evaporated sweat rate and sweating efficiency across winter, summer, and autumn seasons. Eight males cycled for 1 h at 40% V̇o2max in winter, summer, and autumn seasons. Using an electric fan, air velocity increased from 0.2 m/s to 1.1 m/s during the final 20 min of cycling. The autumn season resulted in a lower WBSR, unevaporated sweat rate, and a higher sweating efficiency compared with summer (all P ≤ 0.05) but WBSR and unevaporated sweat rate in autumn were higher than in winter and thus sweating efficiency was lower when compared with winter only at the air velocity of 0.2 m/s (All P ≤ 0.05). Furthermore, evaporated sweat rate and core temperature ( Tcore) were not different among winter, summer, and autumn seasons (All P > 0.19). In conclusion, changes in WBSR across different seasons do not alter Tcore during exercise in a hot humid environment. Furthermore, increasing air velocity enhances evaporated sweat rate and sweating efficiency across all seasons.

The current study investigated whether ambient heat augments the inflammatory and postexercise hepcidin response in women and if menstrual phase and/or self-pacing modulate these physiological effects. Eight trained females (age: 37 ± 7 yr; V̇o2max: 46 ± 7 mL·kg−1·min−1; peak power output: 4.5 ± 0.8 W·kg−1) underwent 20 min of fixed-intensity cycling (100 W and 125 W) followed by a 30-min work trial (∼75% V̇o2max) in a moderate (MOD: 20 ± 1°C, 53 ± 8% relative humidity) and warm-humid (WARM: 32 ± 0°C, 75 ± 3% relative humidity) environment in both their early follicular (days 5 ± 2) and midluteal (days 21 ± 3) phases. Mean power output was 5 ± 4 W higher in MOD than in WARM ( P = 0.02) such that the difference in core temperature rise was limited between environments (−0.29 ± 0.18°C in MOD, P < 0.01). IL-6 and hepcidin both increased postexercise (198% and 38%, respectively); however, neither was affected by ambient temperature or menstrual phase (all P > 0.15). Multiple regression analysis demonstrated that the IL-6 response to exercise was explained by leukocyte and platelet count ( r2 = 0.72, P < 0.01), and the hepcidin response to exercise was explained by serum iron and ferritin ( r2 = 0.62, P < 0.01). During exercise, participants almost matched their fluid loss (0.48 ± 0.18 kg·h−1) with water intake (0.35 ± 0.15 L·h−1) such that changes in body mass (−0.3 ± 0.3%) and serum osmolality (0.5 ± 2.0 osmol·kgH2O−1) were minimal or negligible, indicating a behavioral fluid-regulatory response. These results indicate that trained, iron-sufficient women suffer no detriment to their iron regulation in response to exercise with acute ambient heat stress or between menstrual phases on account of a performance-physiological trade-off.

Transient receptor potential vanilloid 4 (TRPV4) channels exist on vascular endothelial cells and eccrine sweat gland secretory cells in human skin. Here, we assessed whether TRPV4 channels contribute to cutaneous vasodilation and sweating during whole body passive heat stress ( protocol 1) and to cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia ( protocol 2). Intradermal microdialysis was employed to locally deliver pharmacological agents to forearm skin sites, where cutaneous vascular conductance (CVC) and sweat rate were assessed. In protocol 1 (12 young adults), CVC and sweat rate were increased by passive whole body heating, resulting in a body core temperature elevation of 1.2 ± 0.1°C. The elevated CVC and sweat rate assessed at sites treated with TRPV4 channel antagonist (either 200 µM HC-067047 or 125 µM GSK2193874) were not different from the vehicle control site (5% dimethyl sulfoxide). After whole body heating, the TRPV4 channel agonist (100 µM GSK1016790A) was administered to each skin site, eliciting elevations in CVC. Relative to control, this response was partly attenuated by both TRPV4 channel antagonists, confirming drug efficacy. In protocol 2 (10 young adults), CVC was increased following a 5-min arterial occlusion and during local heating from 33 to 42°C. These responses did not differ between the control and the TRPV4 channel antagonist sites (200 µM HC-067047). We show that TRPV4 channels are not required for regulating cutaneous vasodilation or sweating during a whole body passive heat stress. Furthermore, they are not required for regulating cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia.

Cao, Yinhang, Naoto Fujii, Tomomi Fujimoto, Yin-Feng Lai, Takeshi Ogawa, Tsutomu Hiroyama, Yasushi Enomoto, and Takeshi Nishiyasu. CO

Sugar-free carbonated water is consumed worldwide. The consumption of carbonated water is high in summer, when the heat loss responses of sweating and skin vasodilation are activated, and thermal perceptions (thermal sensation and comfort) and mood states are negatively modulated. However, whether ingesting carbonated water under ambient heat exposure modulates cerebral blood flow index, heat loss responses, thermal perceptions, and mood states remains to be determined. In this study, 17 healthy, habitually active, young adults (eight women) ingested 4 °C noncarbonated or carbonated water under 37 °C ambient heat-stressed resting conditions. Both drinks increased the middle cerebral artery mean blood velocity, an index of cerebral blood flow, and mean arterial pressure, with carbonated water exhibiting higher elevations than noncarbonated water (P0.05). However, the heart rate, sweat rate, and skin blood flow during and after drinking remained unchanged between the two conditions (P0.05). The thermal sensation and comfort after drinking remained unchanged between the two conditions (P0.05); but, a drink-induced reduction in sleepiness was higher, and drink-induced elevations in motivation and exhilaration were higher after ingesting carbonated water than those after ingesting noncarbonated water (P0.05). The analyses suggest that in humans under ambient heat-stressed resting conditions, ingestion of cold carbonated water increases the cerebral blood flow index, blood pressure, motivation, and exhilaration, whereas it decreases sleepiness relative to ingestion of noncarbonated cold water. However, ingestion of cold carbonated water fails to modulate thermoregulatory responses and thermal perception as opposed to noncarbonated cold water.

We evaluated the hypothesis that the activation of L-type voltage-gated Ca2+ channels contributes to exercise training-induced augmentation in cholinergic sweating. On separate days, 10 habitually trained and 10 untrained men participated in two experimental protocols. Prior to each protocol, we administered 1% verapamil (Verapamil, L-type voltage-gated Ca2+ channel blocker) and saline (Control) at forearm skin sites on both arms via transdermal iontophoresis. In protocol 1, we administered low (0.001%) and high (1%) doses of pilocarpine at both the verapamil-treated and verapamil-untreated forearm sites. In protocol 2, participants were passively heated by immersing their limbs in hot water (43°C) until rectal temperature increased by 1.0°C above baseline resting levels. Sweat rate at all forearm sites was continuously measured throughout both protocols. Pilocarpine-induced sweating in Control was higher in trained than in untrained men for both the concentrations of pilocarpine (both P ≤ 0.001). Pilocarpine-induced sweating at the low-dose site was attenuated at the Verapamil versus the Control site in both the groups (both P ≤ 0.004), albeit the reduction was greater in trained as compared with in untrained men ( P = 0.005). The verapamil-mediated reduction in sweating remained intact at the high-dose pilocarpine site in the untrained men ( P = 0.004) but not the trained men ( P = 0.180). Sweating did not differ between Control and Verapamil sites with increases in rectal temperature in both groups (interaction, P = 0.571). We show that activation of L-type voltage-gated Ca2+ channels modulates sweat production in habitually trained men induced by a low dose of pilocarpine. However, no effect on sweating was observed during passive heating in either group.

Local skin heating to 42°C causes cutaneous thermal hyperemia largely via nitric oxide (NO) synthase (NOS)-related mechanisms. We assessed the hypothesis that ATP-sensitive K+ (KATP) channels interact with NOS to mediate cutaneous thermal hyperemia. In 13 young adults (6 women, 7 men), cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with 1) lactated Ringer solution (control), 2) 5 mM glibenclamide (KATP channel blocker), 3) 20 mM NG-nitro-l-arginine methyl ester (NOS inhibitor), or 4) a combination of KATP channel blocker and NOS inhibitor. Local skin heating to 42°C was administered at all four treatment sites to elicit cutaneous thermal hyperemia. Thirty minutes after the local heating, 1.25 mM pinacidil (KATP channel opener) and subsequently 25 mM sodium nitroprusside (NO donor) were administered to three of the four sites (each 25–30 min). The local heating-induced prolonged elevation in CVC was attenuated by glibenclamide (19%), but the transient initial peak was not. However, glibenclamide had no effect on the prolonged elevation in CVC in the presence of NOS inhibition. Pinacidil caused an elevation in CVC, but this response was abolished at the glibenclamide-treated skin site, demonstrating its effectiveness as a KATP channel blocker. The pinacidil-induced increase in CVC was unaffected by NOS inhibition, whereas the increase in CVC elicited by sodium nitroprusside was partly (15%) inhibited by glibenclamide. In summary, we showed an interactive effect of KATP channels and NOS for the plateau of cutaneous thermal hyperemia. This interplay may reflect a vascular smooth muscle cell KATP channel activation by NO.

What is the central question of this study? Does inhibition of KWe evaluated the hypothesis that the activation of K

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NEW FINDINGS What is the central question of this study? Nitric oxide modulates cutaneous vasodilatation and sweating during exercise-induced heat stress in young men. However, it remains uncertain whether these effects are reduced in black-African descendants, who commonly demonstrate reduced nitric oxide bioavailability. Therefore, we assessed whether black-African descendants display reduced nitric oxide-dependent cutaneous vasodilatation and sweating compared with Caucasians in these conditions. What is the main finding and its importance? Nitric oxide-dependent cutaneous vasodilatation and sweating were similar between groups, indicating that reduced nitric oxide bioavailability in black-African descendants does not attenuate these heat-loss responses during an exercise-induced heat stress. ABSTRACT Men of black-African descent are at an increased risk of heat-related illness relative to their Caucasian counterparts. This might be attributable, in part, to reduced cutaneous nitric oxide (NO) bioavailability in this population, which might alter local cutaneous vasodilatation and sweating. To evaluate this, we compared these heat-loss responses in young men (18-30 years of age) of black-African (n = 10) and Caucasian (n = 10) descent during rest, exercise and recovery in the heat. Participants were matched for physical characteristics and fitness, and they were all born and raised in the same temperate environment (i.e. Canada; second generation and higher). Both groups rested for 10 min and then performed 50 min of moderate-intensity exercise at 200 W m-2 , followed by 30 min of recovery in hot, dry heat (35°C, 20% relative humidity). Local cutaneous vascular conductance (CVC%max ) and sweat rate (SR) were measured at two forearm skin sites treated with either lactated Ringer solution (control) or 10 mm NG -nitro-l-arginine methyl ester (l-NAME, a nitric oxide (NO) synthase inhibitor). l-NAME significantly reduced CVC%max throughout rest, exercise and recovery in both groups (both P 0.500). l-NAME significantly reduced local SR in both groups (both P

Hypothermia can occur during aquatic exercise despite production of significant amounts of heat by the active muscles. Because the characteristics of human thermoregulatory responses to cold during exercise have not been fully elucidated, we investigated the effect of low-intensity exercise on the shivering response to core cooling in cool water. Eight healthy young men (24 ± 3 yr) were cooled through cool water immersion while resting (rest trial) and during loadless pedaling on a water cycle ergometer (exercise trial). Before the cooling, body temperature was elevated by hot water immersion to clearly detect a core temperature at which shivering initiates. Throughout the cooling period, mean skin temperature remained around the water temperature (25°C) in both trials, whereas esophageal temperature (Tes) did not differ between the trials ( P > 0.05). The Tes at which oxygen uptake (V̇o2) rapidly increased, an index of the core temperature threshold for shivering, was lower during exercise than rest (36.2 ± 0.4°C vs. 36.5 ± 0.4°C, P < 0.05). The sensitivity of the shivering response, as indicated by the slope of the Tes-V̇o2 relation, did not differ between the trials (−441.3 ±177.4 ml·min−1·°C−1 vs. −411.8 ± 268.1 ml·min−1·°C−1, P > 0.05). The thermal sensation response to core cooling, assessed from the slope and intercept of the regression line relating Tes and thermal sensation, did not differ between the trials ( P > 0.05). These results suggest that the core temperature threshold for shivering is delayed during low-intensity exercise in cool water compared with rest although shivering sensitivity is unaffected.

Age-related impairments in cutaneous vascular conductance (CVC) and sweat rate (SR) during exercise may result from increased arginase activity, which can attenuate endogenous nitric oxide (NO) production. We therefore evaluated whether arginase inhibition modulates these heat-loss responses in young ( n = 9, 23 ± 3 yr) and older ( n = 9, 66 ± 6 yr) men during two 30-min bouts of moderate-intensity cycling (Ex1 and Ex2) in the heat (35°C). CVC and SR were measured at forearm skin sites perfused with 1) lactated Ringer’s (control), 2) NG-nitro-L-arginine methyl ester (L-NAME; NO synthase-inhibited), or 3) Nω-hydroxy-nor-arginine and S-(2-boronoethyl)-l-cysteine (Nor-NOHA + BEC; arginase-inhibited). In both groups, CVC was reduced at L-NAME relative to control and Nor-NOHA + BEC (both P < 0.01). Likewise, SR was attenuated with L-NAME compared with control and Nor-NOHA + BEC during each exercise bout in the young men (all P ≤ 0.05); however, no influence of treatment on SR in the older men was observed ( P = 0.14). Based on these findings, we then evaluated responses in 7 older men (64 ± 7 yr) during passively induced elevations in esophageal temperature (∆Tes) equal to those in Ex1 (0.6°C) and Ex2 (0.8°C). L-NAME reduced CVC by 18 ± 20% CVCmaxat a ∆Tesof 0.8°C ( P = 0.03) compared with control, whereas Nor-NOHA + BEC augmented CVC by 20 ± 18% CVCmax, on average, throughout heating (both P ≤ 0.03). SR was not influenced by either treatment ( P = 0.80) Thus, arginase inhibition does not modulate CVC or SR during exercise in the heat but, consistent with previous findings, does augment CVC in older men during passive heating.NEW & NOTEWORTHY In the current study, we demonstrate that local arginase inhibition does not influence forearm cutaneous vasodilatory and sweating responses in young or older men during exercise-heat stress. Consistent with previous findings, however, we observed augmented cutaneous blood flow with arginase inhibition during whole-body passive heat stress. Thus, arginase differentially affects cutaneous vasodilation depending on the mode of heat stress but does not influence sweating during exercise or passive heating.

Hyperthermia causes hyperventilation at rest and during exercise. We previously reported that carotid chemoreceptors partly contribute to the hyperthermia-induced hyperventilation at rest. However, given that a hyperthermia-induced hyperventilation markedly differs between rest and exercise, the results obtained at rest may not be representative of the response in exercise. Therefore, we evaluated whether carotid chemoreceptors contribute to hyperthermia-induced hyperventilation in exercising humans. Eleven healthy young men (23 ± 2 yr) cycled in the heat (37°C) at a fixed submaximal workload equal to ~55% of the individual’s predetermined peak oxygen uptake (moderate intensity). To suppress carotid chemoreceptor activity, 30-s hyperoxia breathing (100% O2) was performed at rest (before exercise) and during exercise at increasing levels of hyperthermia as defined by an increase in esophageal temperature of 0.5°C (low), 1.0°C (moderate), 1.5°C (high), and 2.0°C (severe) above resting levels. Ventilation during exercise gradually increased as esophageal temperature increased (all P ≤ 0.05), indicating that hyperthermia-induced hyperventilation occurred. Hyperoxia breathing suppressed ventilation in a greater manner during exercise (−9 to −13 l/min) than at rest (−2 ± 1 l/min); however, the magnitude of reduction during exercise did not differ at low (0.5°C) to severe (2.0°C) increases in esophageal temperature (all P > 0.05). Similarly, hyperoxia-induced changes in ventilation during exercise as assessed by percent change from prehyperoxic levels were not different at all levels of hyperthermia (~15–20%, all P > 0.05). We show that in young men carotid chemoreceptor contribution to hyperthermia-induced hyperventilation is relatively small at low-to-severe increases in body core temperature induced by moderate-intensity exercise in the heat. NEW & NOTEWORTHY Exercise-induced increases in hyperthermia cause a progressive increase in ventilation in humans. However, the mechanisms underpinning this response remain unresolved. We showed that in young men hyperventilation associated with exercise-induced hyperthermia is not predominantly mediated by carotid chemoreceptors. This study provides important new insights into the mechanism(s) underpinning the regulation of hyperthermia-induced hyperventilation in humans and suggests that factor(s) other than carotid chemoreceptors play a more important role in mediating this response.

Purpose This study assessed the impact of normobaric hypoxia and acute nitrate ingestion on shivering thermogenesis, cutaneous vascular control, and thermometrics in response to cold stress. Method Eleven male volunteers underwent passive cooling at 10 °C air temperature across four conditions: (1) normoxia with placebo ingestion, (2) hypoxia (0.130 FiO2) with placebo ingestion, (3) normoxia with 13 mmol nitrate ingestion, and (4) hypoxia with nitrate ingestion. Physiological metrics were assessed as a rate of change over 45 min to determine heat loss, and at the point of shivering onset to determine the thermogenic thermoeffector threshold. Result Independently, hypoxia expedited shivering onset time (p = 0.05) due to a faster cooling rate as opposed to a change in central thermoeffector thresholds. Specifically, compared to normoxia, hypoxia increased skin blood flow (p = 0.02), leading to an increased core-cooling rate (p = 0.04) and delta change in rectal temperature (p = 0.03) over 45 min, yet the same rectal temperature at shivering onset (p = 0.9). Independently, nitrate ingestion delayed shivering onset time (p = 0.01), mediated by a change in central thermoeffector thresholds, independent of changes in peripheral heat exchange. Specifically, compared to placebo ingestion, no difference was observed in skin blood flow (p = 0.5), core-cooling rate (p = 0.5), or delta change in rectal temperature (p = 0.7) over 45 min, while nitrate reduced rectal temperature at shivering onset (p = 0.04). No interaction was observed between hypoxia and nitrate ingestion. Conclusion These data improve our understanding of how hypoxia and nitric oxide modulate cold thermoregulation.

INTRODUCTION Caffeine is an exercise performance enhancer widely used by individuals engaged in training or competition under heat-stressed conditions. Caffeine ingestion during exercise in the heat is believed to be safe because it does not greatly affect body temperature responses, heart rate, or body fluid status. However, it remains unknown whether caffeine affects hyperthermia-induced hyperventilation or reductions in the cerebral blood flow index. We tested the hypothesis that under conditions inducing severe hyperthermia, caffeine exacerbates hyperthermia-induced hyperventilation and reduces the cerebral blood flow index during exercise. METHODS Using a randomized, single-blind, crossover design, 12 physically active healthy young men (23 ± 2 yr) consumed a moderate dose of caffeine (5 mg·kg-1) or placebo in the heat (37°C). Approximately 60 min after the ingestion, they cycled for ~45 min at a workload equal to ~55% of their predetermined peak oxygen uptake (moderate intensity) until their core temperature increased to 2.0°C above its preexercise baseline level. RESULTS In both trials, ventilation increased and the cerebral blood flow index assessed by middle cerebral artery mean blood velocity decreased as core temperature rose during exercise (P < 0.05), indicating that hyperthermia-induced hyperventilation and lowering of the cerebral blood flow occurred. When core temperature was elevated by 1.5°C or more (P < 0.05), ventilation was higher and the cerebral blood flow was lower throughout the caffeine trial than the placebo trial (P < 0.05). CONCLUSIONS A moderate dose of caffeine exacerbates hyperthermia-induced hyperventilation and reductions in the cerebral blood flow index during exercise in the heat with severe hyperthermia.

Hypoxic modulation of nitric oxide (NO) production pathways in the cutaneous microvasculature and its interaction with cold-induced reflex vasoconstriction, independent of local cooling, have yet to be identified. This study assessed the contribution of NO to nonglabrous microvasculature perfusion during hypoxia and whole body cooling with concomitant inhibition of NO synthase [NOS; via N G-nitro-L-arginine methyl ester (L-NAME)] and the nitrite reductase, xanthine oxidase (via allopurinol), two primary sources of NO production. Thirteen volunteers were exposed to independent and combined cooling via water-perfused suit (5°C) and normobaric hypoxia (FI O2, 0.109 + 0.002). Cutaneous vascular conductance (CVC) was assessed across four sites with intradermal microdialysis perfusion of 1) lactated Ringers solution (control), 2) 20 mmol L-NAME, 3) 10 mol allopurinol, or 4) combined L-NAME/allopurinol. Effects and interactions were assessed via four-way repeated measures ANOVA. Independently, L-NAME reduced CVC (43%, P < 0.001), whereas allopurinol did not alter CVC (P = 0.5). Cooling decreased CVC (P = 0.001), and the reduction in CVC was consistent across perfusates (~30%, P = 0.9). Hypoxia increased CVC (16%, P = 0.01), with this effect abolished by L-NAME infusion (P = 0.04). Cold-induced vasoconstriction was blunted by hypoxia, but importantly, hypoxia increased CVC to a similar extent (39% at the Ringer site) irrespective of environmental temperature; thus, no interaction was observed between cold and hypoxia (P = 0.1). L-NAME restored vasoconstriction during combined cold-hypoxia (P = 0.01). This investigation suggests that reflex cold-induced cutaneous vasoconstriction acts independently of NO suppression, whereas hypoxia-induced cutaneous vasodilatation is dependent on NOS-derived NO production.

NEW FINDINGS What is the central question of this study? Does short-term heat acclimation enhance whole-body evaporative heat loss and augment nitric oxide synthase (NOS)-dependent cutaneous vasodilatation and NOS- and cyclooxygenase (COX)-dependent sweating, in exercising older men? What is the main finding and its importance? Our preliminary data (n = 8) demonstrated that short-term heat acclimation improved whole-body evaporative heat loss, but it did not influence the effects of NOS and/or COX inhibition on cutaneous vasodilatation or sweating in older men during an exercise-heat stress. These outcomes might imply that although short-term heat acclimation enhances heat dissipation in older men, it does not modulate NOS- and COX-dependent control of cutaneous vasodilatation or sweating on the forearm. ABSTRACT Ageing is associated with decrements in whole-body heat loss (evaporative + dry heat exchange), which might stem from alterations in nitric oxide synthase (NOS)- and cyclooxygenase (COX)-dependent cutaneous vasodilatation and sweating. We evaluated whether short-term heat acclimation would (i) enhance whole-body heat loss primarily by increasing evaporative heat loss, and (ii) augment NOS-dependent cutaneous vasodilatation and NOS- and COX-dependent sweating, in exercising older men. Eight older men [mean (SD) age, 59 (8) years] completed a calorimetry and microdialysis trial before and after 7 days of exercise-heat acclimation. For the calorimetry trials, whole-body evaporative and dry heat exchange were assessed using direct calorimetry during 30 min bouts of cycling at light, moderate and vigorous metabolic heat productions (150, 200 and 250 W/m2 , respectively) in dry heat (40°C, 20% relative humidity). For the microdialysis trials, local cutaneous vascular conductance and sweat rate were assessed during 60 min exercise in the heat (35°C, 20% relative humidity) at four dorsal forearm skin sites treated with lactated Ringer solution (control), NOS inhibitor, COX inhibitor or combined NOS and COX inhibitors, via microdialysis. Evaporative heat loss during moderate (P = 0.036) and vigorous (P = 0.021) exercise increased after acclimation. Inhibition of NOS alone reduced cutaneous vascular conductance to a similar extent before and after acclimation (P

Heat shock protein 90 (HSP90) modulates exercise‐induced cutaneous vasodilation in young men via nitric oxide synthase (NOS), but only when core temperature is elevated ~1.0°C. While less is known about modulation of this heat loss response in women during exercise, sex differences may exist. Further, the mechanisms regulating cutaneous vasodilation can differ between exercise‐ and passive‐heat stress. Therefore, in 11 young women (23 ± 3 years), we evaluated whether HSP90 contributes to NOS‐dependent cutaneous vasodilation during exercise (Protocol 1) and passive heating (Protocol 2) and directly compared responses between end‐exercise and a matched core temperature elevation during passive heating. Cutaneous vascular conductance (CVC%max) was measured at four forearm skin sites continuously treated with (a) lactated Ringers solution (control), (b) 178 μM Geldanamycin (HSP90 inhibitor), (c) 10 mM L‐NAME (NOS inhibitor), or (d) combined 178 μM Geldanamycin and 10 mM L‐NAME. Participants completed both protocols during the early follicular (low hormone) phase of the menstrual cycle (0–7 days). Protocol 1: participants rested in the heat (35°C) for 70 min and then performed 50 min of moderate‐intensity cycling (~55% VO2peak) followed by 30 min of recovery. Protocol 2: participants were passively heated to increase rectal temperature by 1.0°C, comparable to end‐exercise. HSP90 inhibition attenuated CVC%max relative to control at end‐exercise (p, We evaluated whether HSP90 contributes to NOS‐dependent cutaneous vasodilation during exercise and passive heating in young women. We directly compared these responses at end‐exercise and the matched core temperature elevation during passive heating. We showed that HSP90 modulates cutaneous vasodilation NOS‐dependently during exercise in young women, while there was no effect of HSP90 inhibition during passive heating, despite a similar NOS contribution.

NEW FINDINGS What is the central question of this study? Does the administration of the adrenergic presynaptic release inhibitor bretylium tosylate modulate sweating during exercise in the heat, and does this response differ between habitually trained and untrained men? What is the main finding and its importance? Iontophoretic administration of bretylium tosylate attenuates sweating during exercise in the heat in habitually trained and untrained men. However, a greater reduction occurred in trained men. The findings demonstrate a role for cutaneous adrenergic nerves in the regulation of eccrine sweating during exercise in the heat and highlight a need to advance our understanding of neural control of human eccrine sweat gland activity. ABSTRACT We recently reported an influence of cutaneous adrenergic nerves on eccrine sweat production in habitually trained men performing an incremental exercise bout in non-heat stress conditions. Based on an assumption that increasing heat stress induces cholinergic modulation of sweating, we evaluated the hypothesis that the contribution of cutaneous adrenergic nerves on sweating would be attenuated during exercise in the heat. Twenty young habitually trained and untrained men (n = 10/group) underwent three successive bouts of 15 min of light-, moderate- and vigorous-intensity cycling (equivalent to 30, 50, and 70% of peak oxygen uptake ( VO2peak ) respectively), each separated by a 15 min recovery while wearing a perfusion suit perfused with warm water (43°C). Sweat rate (ventilated capsule) was measured continuously at two bilateral forearm skin sites treated with 10 mm bretylium tosylate (an inhibitor of neurotransmitter release from adrenergic nerve terminals) and saline (control) via transdermal iontophoresis. A greater sweat rate was measured during vigorous exercise only in trained as compared to untrained men (P = 0.014). In both groups, sweating was reduced at the bretylium tosylate versus control sites, albeit the magnitude of reduction was greater in the trained men (P ≤ 0.024). These results suggest that cutaneous adrenergic nerves modulate sweating during exercise performed under a whole-body heat stress, albeit a more robust response occurs in trained men. While it is accepted that a cholinergic mechanism plays a primary role in the regulation of sweating during an exercise-heat stress, our findings highlight the need for additional studies aimed at understanding the neural control of human eccrine sweating.

New findings What is the central question of this study? β-Adrenergic receptor activation modulates cutaneous vasodilatation and sweating in young adults. In this study, we assessed whether age-related differences in β-adrenergic regulation of these responses exist and whether they differ between men and women. What is the main finding and its importance? We showed that ageing augmented β-adrenergic cutaneous vasodilatation, although the pattern of response differed between men and women. Ageing had no effect on β-adrenergic sweating in men or women. Our findings advance our understanding of age-related changes in the regulation of cutaneous vasodilatation and sweating and provide new directions for research on the significance of enhanced β-adrenergic cutaneous vasodilatation in older adults. Abstract β-Adrenergic receptor agonists, such as isoprenaline, can induce cutaneous vasodilatation and sweating in young adults. Given that cutaneous vasodilatation and sweating responses to whole-body heating and to pharmacological agonists, such as acetylcholine, ATP and nicotine, can differ in older adults, we assessed whether ageing also modulates β-adrenergic cutaneous vasodilatation and sweating and whether responses differ between men and women. In the context of the latter, prior reports showed that the effects of ageing on cutaneous vasodilatation (evoked with ATP and nicotine) and sweating (stimulated by acetylcholine) were sex dependent. Thus, in the present study, we assessed the role of β-adrenergic receptor activation on forearm cutaneous vasodilatation and sweating in 11 young men (24 ± 4 years of age), 11 young women (23 ± 5 years of age), 11 older men (61 ± 8 years of age) and 11 older women (60 ± 8 years of age). Initially, a high dose (100 µm) of isoprenaline was administered via intradermal microdialysis for 5 min to induce maximal β-adrenergic sweating. Approximately 60 min after the washout period, three incremental doses of isoprenaline were administered (1, 10 and 100 µm, each for 25 min) to assess dose-dependent cutaneous vasodilatation. Isoprenaline-mediated cutaneous vasodilatation was greater in both older men and older women relative to their young counterparts. Augmented cutaneous vasodilatory responses were observed at 1 and 10 µm in women and at 100 µm in men. Isoprenaline-mediated sweating was unaffected by ageing, regardless of sex. We show that ageing augments β-adrenergic cutaneous vasodilatation differently in men and women, without influencing β-adrenergic sweating.

Local skin heating to 42°C causes cutaneous thermal hyperemia largely via nitric oxide (NO) synthase (NOS)-related mechanisms. We assessed the hypothesis that ATP-sensitive K

We tested the hypothesis that compared with a moderate-intensity warm-up, a work-matched high-intensity warm-up improves final-sprint power output during the last 30 s of a 120-s supramaximal exercise that mimics the final sprint during events such as the 800-m run, 1,500-m speed skate, or Keirin (cycling race). Nine active young males performed a 120-s supramaximal cycling exercise consisting of 90 s of constantworkload cycling at a workload that corresponds to 110% peak oxygen uptake (VO2peak) followed by 30 s of maximal cycling. This exercise was preceded by 1) no warm-up (control), 2) a 10-min cycling warm-up at a workload of 40% VO2peak (moderate-intensity), or 3) a 5-min cycling warm-up at a workload of 80% VO2peak (high-intensity). Total work was matched between the two warm-up conditions. Both warm-ups increased 5-s peak (observed within 10 s at the beginning of maximal cycling) and 30-s mean power output during the final 30-s maximal cycling compared to no warm-up. Moreover, the high-intensity warm-up provided a greater peak (577±169 vs. 541±175 W, P=0.01) but not mean (482±109 vs. 470±135W, P=1.00) power output than the moderate-intensity warm-up. Both VO2 during the 90-s constant workload cycling and the post-warm-up blood lactate concentration were higher following the high-intensity than moderate-intensity warm-up (all P≤0.05). We show that work-matched moderate- (~40% VO2peak) and high- (~80% VO2peak) intensity warmups both improve final sprint (~30 s) performance during the late stage of a 120-s supramaximal exercise bout, and that a high-intensity warm-up provides greater improvement of short-duration (

We assessed the role of purinergic P2 receptors in the regulation of cutaneous vasodilation in young adults at rest and during intermittent moderate-intensity exercise in the heat (35 °C). P2 receptor blockade augmented resting cutaneous vasodilation but had no influence during and following exercise. This increase was partly diminished by nitric oxide synthase inhibition. These results suggest a functional role of P2 receptors in the regulation of cutaneous vascular tone during ambient heat exposure at rest.

Dietary supplements are widely used as a nutritional strategy to improve and maintain performance and achieve faster recovery in sports and exercise. Exercise-induced muscle damage (EIMD) is caused by mechanical stress and subsequent inflammatory responses including reactive oxygen species and cytokine production. Therefore, dietary supplements with anti-inflammatory and antioxidant properties have the potential to prevent and reduce muscle damage and symptoms characterized by loss of muscle strength and delayed-onset muscle soreness (DOMS). However, only a few supplements are considered to be effective at present. This review focuses on the effects of dietary supplements derived from phytochemicals and listed in the International Olympic Committee consensus statement on muscle damage evaluated by blood myofiber damage markers, muscle soreness, performance, and inflammatory and oxidative stress markers. In this review, the effects of dietary supplements are also discussed in terms of study design (i.e., parallel and crossover studies), exercise model, and such subject characteristics as physical fitness level. Future perspectives and considerations for the use of dietary supplements to alleviate EIMD and DOMS are also discussed.

The roles of nitric oxide synthase (NOS), reactive oxygen species (ROS), and angiotensin II type 1 receptor (AT1R) activation in regulating cutaneous vasodilation and sweating during prolonged (≥60 min) exercise are currently unclear. Moreover, it remains to be determined whether fluid replacement (FR) modulates the above thermoeffector responses. To investigate, 11 young men completed 90 min of continuous moderate intensity (46% V̇o2peak) cycling performed at a fixed rate of metabolic heat production of 600 W (No FR condition). On a separate day, participants completed a second session of the same protocol while receiving FR to offset sweat losses (FR condition). Cutaneous vascular conductance (CVC) and local sweat rate (LSR) were measured at four intradermal microdialysis forearm sites perfused with: 1) lactated Ringer (Control); 2) 10 mM NG-nitro-l-arginine methyl ester (l-NAME, NOS inhibition); 3) 10 mM ascorbate (nonselective antioxidant); or 4) 4.34 nM losartan (AT1R inhibition). Relative to Control (71% CVCmax at both time points), CVC with ascorbate (80% and 83% CVCmax) was elevated at 60 and 90 min of exercise during FR (both P < 0.02) but not at any time during No FR (all P > 0.31). In both conditions, CVC was reduced at end exercise with l-NAME (60% CVCmax; both P < 0.02) but was not different relative to Control at the losartan site (76% CVCmax; both P > 0.19). LSR did not differ between sites in either condition (all P > 0.10). We conclude that NOS regulates cutaneous vasodilation, but not sweating, irrespective of FR, and that ROS influence cutaneous vasodilation during prolonged exercise with FR.