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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.

Purpose: We investigated whether varying the number of repetitions of high-intensity exercise during work-matched warm-ups modulates physiological responses (heart rate, metabolic responses, and core temperature), perceptions (ratings of perceived exertion, effort of breathing), readiness for exercise, and short-term exercise performance. Methods: Ten physically active young males performed a 30-s Wingate anaerobic test (WAnT) following a warm-up consisting of submaximal constant-workload cycling at 60% maximal oxygen uptake with no high-intensity cycling (constant-workload warm-up) or with 1, 4, or 7 repetitions of 10 s of high-intensity cycling at 110% maximal oxygen uptake. All warm-ups were matched for duration (10 min) and total work. Results: Warm-ups with seven repetitions of high-intensity cycling resulted in higher ratings of perceived whole-body exertion and effort of breathing than the constant-workload warm-up. Warm-up with four repetitions of high-intensity cycling produced greater readiness for a 30-s WAnT (7.33 ± 0.73 AU) than the constant-workload warm-up (6.33 ± 0.98 AU) (P = .022). Physiological responses did not differ among the four warm-up conditions, though peak heart rate was slightly higher (~5 beats/min) during warm-up with four or seven repetitions of high-intensity cycling than during the constant-workload warm-up. Peak, mean, and minimum power output during the 30-s WAnT did not differ among the four warm-up conditions. Conclusions: These results suggest that the effects of warm-ups with intermittent high-intensity exercise on physiological responses and short-term high-intensity exercise performance do not greatly differ from a warm-up with a work-matched submaximal constant-workload. However, they appear to modulate perceptions and readiness as a function of the number of repetitions of the high-intensity exercise.

Isomaltulose is a low glycemic and insulinaemic carbohydrate available as a constituent in sports drink. However, it remains unclear whether postexercise rehydration achieved by isomaltulose drink ingestion alone differs as compared to other carbohydrates. Thirteen young men performed intermittent exercise in the heat (35 °C and relative humidity 40%) to induce a state of hypohydration as defined by a 2% loss in body mass. Thereafter, participants were rehydrated by ingesting drinks equal to the volume of body mass loss with either a mixture of 3.25% glucose and 3.25% fructose, 6.5% sucrose (SUC), or 6.5% isomaltulose (ISO) within the first 30 min of a 3-h recovery. The change in plasma volume (ΔPV) from pre-exercise baseline, blood glucose, and plasma insulin concentration were assessed every 30-min. ΔPV was lower in ISO as compared to SUC until 90 min of the recovery (all P ≤ 0.038) with no difference thereafter (all P ≥ 0.391). The ΔPV were paralleled by concomitant changes in blood glucose levels that were greater in ISO as compared to other drinks after 90 min of the recovery (all P ≤ 0.035). Plasma insulin secretion, which potentially enhances renal sodium reabsorption and fluid retention, did not differ between the trials (interaction, P = 0.653). ISO induced a greater net fluid volume retention as compared to SUC (P = 0.010). We showed that rehydration with an isomaltulose drink following exercise-heat stress induces comparable recovery of PV and a greater net fluid retention as compared to other drinks, albeit this response is delayed. The delayed water transport along with glucose absorption may modulate this response. This trial was registered in 25th Sep 2019 at https://www.umin.ac.jp/ as UMIN000038099. (249/250)

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.

We aimed to evaluate whether changes in the noninvasively assessed urinary N-terminal fragment of titin (U-titin) concentration may be associated with those of serum creatine kinase (CK) activity, transverse relaxation time (T

While human eccrine sweat glands respond to adrenergic agonists, there remains a paucity of information on the factors modulating this response. Thus, we assessed the relative contribution of α- and β-adrenergic sweating during a heat exposure and as a function of individual factors of sex and training status. α- and β-adrenergic sweating was assessed in forty-eight healthy young men (n = 35) and women (n = 13) including endurance-trained (n = 12) and untrained men (n = 12) under non-heat exposure (temperate, 25°C; n = 17) and heat exposure (hot, 35°C; n = 48) conditions using transdermal iontophoresis of phenylephrine (α-adrenergic agonist) and salbutamol (β-adrenergic agonist) on the ventral forearm, respectively. Adrenergic sweating was also measured after iontophoretic administration of atropine (muscarinic receptor antagonist) or saline (control) to evaluate how changes in muscarinic receptor activity modulate the adrenergic response to a heat exposure (n = 12). α- and β-adrenergic sweating was augmented in hot compared with temperate conditions (both P ≤ .014), albeit the relative increase was greater in β (~5.4-fold)- as compared to α (~1.5-fold)-adrenergic-mediated sweating response. However, both α- and β-adrenergic sweating was abolished by atropinization (P = .001). Endurance-trained men showed an augmentation in α- (P = .043) but not β (P = .960)-adrenergic sweating as compared to untrained men. Finally, a greater α- and β-adrenergic sweating response (both P ≤ .001) was measured in habitually active men than in women. We show that heat exposure augments α-and β-adrenergic sweating differently via mechanisms associated with altered muscarinic receptor activity. Sex and training status modulate this response.

Human eccrine sweat glands respond to α1-adrenergic receptor agonists. We recently reported that adrenergic mechanisms contribute to sweating in endurance-trained men during an incremental exercise to volitional fatigue. However, it remains unclear if this response is mediated by α1-adrenergic receptor activation. Twelve endurance-trained men performed an incremental cycling bout until exhaustion while wearing a water-perfused suit to clamp skin temperature at ~ 34 °C. Bilateral forearm sweat rates were measured wherein the distal area was treated with either 1% terazosin (α1-adrenergic receptor antagonist) or saline solution on the opposite limb (Control) via transdermal iontophoresis. We also measured proximal bilateral forearm sweat rate in untreated sites to confirm that no between-limb differences in forearm sweat rate occurred. Once sweat rate returned to pre-exercise resting levels at ~ 20 min postexercise, 0.25% phenylephrine (α1-adrenergic receptor agonist) was iontophoretically administered to skin to verify α1-adrenergic receptor blockade. Sweat rates at the proximal untreated right and left forearm sites were similar during exercise (interaction, P = 0.581). Similarly, no effect of terazosin on sweat rate was measured relative to control site (interaction, P = 0.848). Postexercise administration of phenylephrine increased sweat rate at the control site (0.08 ± 0.09 mg cm−2 min−1), which was suppressed by ~ 90% at the terazosin-treated site (0.01 ± 0.02 mg cm−2 min−1) (P = 0.026), confirming that α1-adrenergic receptor blockade was intact. Our findings demonstrate that α1-adrenergic receptors located at eccrine sweat glands do not contribute to eccrine sweating during incremental exercise in young endurance-trained men.

Introduction: Prolonged exercise in the heat stimulates plasma release of atrial natriuretic peptide (ANP) in association with dehydration-induced reductions in blood volume. Elevated plasma ANP levels under these conditions may indirectly attenuate cutaneous blood flow and sweating responses due to the effects of this hormone on central blood volume and plasma osmolality and the resulting stimulation of nonthermal reflexes. However, it remains unclear whether cutaneous blood flow and sweating are directly modulated by ANP at the level of the cutaneous end organs (cutaneous microvessels and eccrine sweat glands) during prolonged exercise in the heat. Objective: Therefore, we evaluated the effects of local ANP administration on forearm cutaneous vascular conductance (CVC) and local sweat rate (LSR) during rest and exercise in the heat. Methods: In 9 habitually active young men (26 ± 6 years) CVC and LSR were evaluated at 3 intradermal microdialysis sites continuously perfused with lactated Ringer solution (control) or ANP (0.1 or 1.0 μM). Participants rested in a non-heat-stress condition (25°C) for approximately 60 min followed by 70 min in the heat (35°C). They then performed 50 min of moderate-intensity cycling (approx. 55% VO2 peak), with a 30-min recovery. Thereafter, 50 mM sodium nitroprusside was administered at all sites to elicit maximum CVC, which was subsequently used to normalize all values (CVC%max). Results: No effects of ANP on CVC%max were observed in the non-heat-stress resting condition compared to the untreated control site (both p > 0.05). Conversely during rest in the heat there was an 11% (5–17%) reduction in CVC%max at the 1.0 μM ANP site relative to the untreated control site (p < 0.05). At the end of exercise CVC%max was attenuated by 12% (1–23%) at the 0.1 μM ANP site and by 21% (7–35%) at the 1.0 μM ANP site relative to the untreated control site (all p < 0.05). Conversely, neither concentration of ANP influenced sweating at any time point (all p > 0.05). Conclusion: Intradermal ANP administration directly attenuated cutaneous blood flow, but not sweating, in habitually active young men during rest and exercise in the heat.

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

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.

Ageing attenuates muscarinic-mediated sweating. However, whether ageing also impairs nicotinic-mediated sweating remains unclear. Further, despite the known sex-related differences in peripheral sweat gland function, it remains unclear whether age-related modifications of muscarinic and nicotinic-mediated sweating, if any, are similar between men and women. We assessed local sweating in young and older healthy men and women (n = 11, each group) at two dorsal forearm skin sites receiving either: (a) methacholine (muscarinic receptor agonist, 5 doses: 0.0125, 0.25, 5, 100, 2000 mmol/L) or (b) nicotine (nicotinic receptor agonist, 5 doses: 1.2, 3.6, 11, 33, 100 mmol/L) via intradermal microdialysis. Age-related reductions in methacholine-induced sweating were observed at low-to-moderate doses (0.0125-5 mmol/L; all P ≤ 0.05) in men, whereas a reduction was only evident at the highest methacholine dose (2000 mmol/L; P ≤ 0.05) in women. No effect of ageing was observed for nicotine-induced sweating (all P > 0.26 for main effects of age, dose and all interactions). We showed that while healthy ageing attenuates low-to-moderate levels of muscarinic-mediated sweating in men, reductions are only observed at high levels of muscarinic-mediated sweating in women. However, healthy ageing does not modulate nicotinic-mediated sweating in either men or women.

The venoarteriolar reflex (VAR) is a local mechanism by which vasoconstriction is mediated in response to venous congestion. This response may minimize tissue overperfusion, preventing capillary damage and oedema. Post-occlusive reactive hyperaemia (PORH) is used to assess microvascular function by performing a brief local arterial occlusion resulting in a subsequent rapid transient vasodilation. In the current study, we hypothesized that type 2 diabetes (T2D) attenuates VAR and PORH responses in forearm skin in vivo. In 11 healthy older adults (Control, 58 ± 8 years) and 13 older adults with controlled T2D (62 ± 10 years), cutaneous blood flow measured by laser-Doppler flowmetry was monitored following a 3-min venous occlusion of 45 mm Hg that elicited the VAR, followed by a 3-min recovery period and then a 5-min arterial occlusion of 240 mm Hg that induced PORH. Finally, sodium nitroprusside, a nitric oxide donor, was administered to induce maximum vasodilation. VAR and PORH variables were similar between groups. By contrast, maximal cutaneous blood flow induced by sodium nitroprusside was lower in the T2D group. Taken together, our observations indicate that T2D impairs vascular smooth muscle responsiveness to nitric oxide, but not VAR and PORH in forearm skin.

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.

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? 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.

We tested the hypothesis that work-matched supramaximal intermittent warm-up improves final-sprint power output to a greater degree than submaximal constant-intensity warm-up during the last 30 s of a 120-s supramaximal exercise simulating the final sprint during sports events lasting approximately 2 min. Ten male middle-distance runners performed a 120-s supramaximal cycling exercise consisting of 90 s of constant-workload cycling at a workload corresponding to 110% maximal oxygen uptake (VO

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.

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.

While the mechanisms underlying the control of cutaneous vasodilation have been extensively studied, there remains a lack of understanding of the different factors that may modulate cutaneous perfusion during an exercise-induced heat stress. We evaluated the hypothesis that heat shock protein 90 (HSP90) contributes to the heat loss response of cutaneous vasodilation via the activation of nitric oxide synthase (NOS) during exercise in the heat. In 11 young males (25 ± 5 yr), cutaneous vascular conductance (CVC) was measured at four forearm skin sites that were continuously treated with 1) lactated Ringer solution (control), 2) NOS inhibition with 10 mM NG-nitro-l-arginine methyl ester (l-NAME), 3) HSP90 inhibition with 178 μM geldanamycin, or 4) a combination of 10 mM l-NAME and 178 μM geldanamycin. Participants rested in a moderate heat stress (35°C) condition for 70 min. Thereafter, they performed a 50-min bout of moderate-intensity cycling (~52% V̇o2peak) followed by a 30-min recovery period. We showed that NOS inhibition attenuated CVC (~40–50%) relative to the control site during pre- and postexercise rest in the heat ( P ≤ 0.05); however, no effect of HSP90 inhibition was observed ( P > 0.05). During exercise, we observed an attenuation of CVC with the separate inhibition of NOS (~40–50%) and HSP90 (~15–20%) compared with control (both P ≤ 0.05). However, the effect of HSP90 inhibition was absent in the presence of the coinhibition of NOS ( P > 0.05). We show that HSP90 contributes to cutaneous vasodilation in young men exposed to the heat albeit during exercise only. We also show that the HSP90 contribution is due to NOS-dependent mechanisms. NEW & NOTEWORTHY We show that heat shock protein 90 functionally contributes to the heat loss response of cutaneous vasodilation during exercise in the heat, and this response is mediated through the activation of nitric oxide synthase. Therefore, interventions that may activate heat shock protein 90 may facilitate an increase in heat dissipation through an augmentation of cutaneous perfusion. In turn, this may attenuate or reduce the increase in core temperature and therefore the level of heat strain.

We evaluated the influence of K+channels (i.e., Ca2+-activated K+(KCa), ATP-sensitive K+(KATP), and voltage-gated K+(KV) channels) and key enzymes (nitric oxide synthase (NOS) and cyclooxygenase (COX)) on nicotine-induced cutaneous vasodilation and sweating. Using intradermal microdialysis, we evaluated forearm cutaneous vascular conductance (CVC) and sweat rate in 2 separate protocols. In protocol 1 (n = 10), 4 separate sites were infused with (i) lactated Ringer (Control), (ii) 50 mmol·L−1tetraethylammonium (KCachannel blocker), (iii) 5 mmol·L−1glybenclamide (KATPchannel blocker), and (iv) 10 mmol·L−14-aminopyridine (KVchannel blocker). In protocol 2 (n = 10), 4 sites were infused with (i) lactated Ringer (Control), (ii) 10 mmol·L−1Nω-nitro-l-arginine (NOS inhibitor), (iii) 10 mmol·L−1ketorolac (COX inhibitor), or (iv) a combination of NOS+COX inhibitors. At all sites, nicotine was infused in a dose-dependent manner (1.2, 3.6, 11, 33, and 100 mmol·L−1; each for 25 min). Nicotine-induced increase in CVC was attenuated by the KCa, KATP, and KVchannel blockers, whereas nicotine-induced increase in sweat rate was reduced by the KCaand KVchannel blockers (P ≤ 0.05). COX inhibitor augmented nicotine-induced increase in CVC (P ≤ 0.05), which was absent when NOS inhibitor was co-administered (P > 0.05). In addition, our secondrary experiment (n = 7) demonstrated that muscarinic receptor blockade with 58 μmol·L−1atropine sulfate salt monohydrate abolished nicotine-induced increases in CVC (1.2–11 mmol·L−1) and sweating (all doses). We show that under a normothermic resting state: (i) KCa, KATP, and KVchannels contribute to nicotinic cutaneous vasodilation, (ii) inhibition of COX augments nicotinic cutaneous vasodilation likely through NOS-dependent mechanism(s), and (iii) KCaand KVchannels contribute to nicotinic sweating.

NEW FINDINGS What is the central question of this study? Do regional differences exist in nitric oxide synthase (NOS)-dependent cutaneous vasodilatation and sweating during exercise-heat stress in young men. What is the main finding and its importance? Exercise-induced increases in cutaneous vasodilatation and sweating were greater on the chest and upper back compared to the forearm, although the NOS contribution to cutaneous vasodilatation was similar across all regions. Conversely, there was a greater NOS-dependent rate of change in sweating on the chest compared to the forearm, with a similar trend on the back. ABSTRACT While it is established that nitric oxide synthase (NOS) is an important modulator of forearm cutaneous vasodilatation and sweating during an exercise-heat stress in young men, it remains unclear if regional differences exist in this response. In 15 habitually active young men (24 ± 4 (SD) years), cutaneous vascular conductance (CVC) and local sweat rate (LSR) were assessed at three body regions. On each of the dorsal forearm, chest and upper-back (trapezius), sites were continuously perfused with either (1) lactated Ringer solution (control) or (2) 10 Mm Nω -nitro-l-arginine (l-NNA, NOS inhibitor), via microdialysis. Participants rested in the heat (35°C) for ∼75 min, followed by 60 min of semi-recumbent cycling performed at a fixed rate of heat production of 200 W m-2 (equivalent to ∼42% VO2peak ). During exercise, the chest and upper-back regions showed higher CVC and LSR responses relative to the forearm (all P 0.05). Conversely, there was a greater NOS contribution to the rate of change for LSR at the chest relative to the forearm (P

NEW FINDINGS What is the central question of this study? We evaluated whether regional variations exist in NO-dependent cutaneous vasodilatation and sweating during cholinergic stimulation. What is the main finding and its importance? Peak cutaneous vasodilatation and sweating were greater on the torso than the forearm. Furthermore, we found that NO was an important modulator of cholinergic cutaneous vasodilatation, but not sweating, across body regions, with a greater contribution of NO to cutaneous vasodilatation in the limb compared with the torso. These findings advance our understanding of the mechanisms influencing regional variations in cutaneous vasodilator and sweating responses to pharmacological stimulation. ABSTRACT Regional variations in cutaneous vasodilatation and sweating exist across the body. Nitric oxide (NO) is an important modulator of these heat loss responses in the forearm. However, whether regional differences in NO-dependent cutaneous vasodilatation and sweating exist remain uncertain. In 14 habitually active young men (23 ± 4 years of age), cutaneous vascular conductance (CVC%max ) and local sweat rates were assessed at six skin sites. On each of the dorsal forearm, chest and upper back (trapezius), sites were continuously perfused with either lactated Ringer solution (control) or 10 mm Nω -nitro-l-arginine (l-NNA; an NO synthase inhibitor) dissolved in Ringer solution, via microdialysis. At all sites, cutaneous vasodilatation and sweating were induced by co-administration of the cholinergic agonist methacholine (1, 10, 100, 1000 and 2000 mm; 25 min per dose) followed by 50 mm sodium nitroprusside (20-25 min) to induce maximal vasodilatation. The l-NNA attenuated CVC%max relative to the control conditions for all regions (all P 0.05). Peak local sweat rate was higher at the back relative to the forearm (P

BackgroundAlthough numerous studies have reported the effect of inspiratory muscle training for improving exercise performance, the outcome of whether exercise performance is improved by inspiratory muscle training is controversial. Therefore, this study investigated the influence of inspiratory muscle-loaded exercise training (IMLET) on peak oxygen uptake (VO2peak), respiratory responses, and exercise performance under normoxic (N) and hypoxic (H) exercise conditions. We hypothesised that IMLET enhances respiratory muscle strength and improves respiratory response, thereby improvingVO2peakand work capacity under H condition.MethodsSixteen university track runners (13 men and 3 women) were randomly assigned to the IMLET (n = 8) or exercise training (ET) group (n = 8). All subjects underwent 4 weeks of 20-min 60%VO2peakcycling exercise training, thrice per week. IMLET loaded 50% of maximal inspiratory pressure during exercise. At pre- and post-training periods, subjects performed exhaustive incremental cycling under normoxic (N; 20.9 ± 0%) and hypoxic (H; 15.0 ± 0.1%) conditions.ResultsAlthough maximal inspiratory pressure (PImax) significantly increased after training in both groups, the extent of PImax increase was significantly higher in the IMLET group (from 102 ± 20 to 145 ± 26 cmH2O in IMLET; from 111 ± 23 to 127 ± 23 cmH2O in ET;P VO2peakand maximal work load (Wmax) similarly increased both under N and H conditions after training (P maxdecrease under H condition was lower in the IMLET group at post-training test than at pre-training (from − 14.7 ± 2.2% to − 12.5 ± 1.7%;P ConclusionsOur IMLET enhanced the respiratory muscle strength, and the decrease in work capacity under hypoxia was reduced regardless of the increase inVO2peak.

New findings What is the central question of this study? Does ageing augment muscarinic, nicotinic and/or ATP-mediated cutaneous vasodilatation in women? What is the main finding and its importance? Ageing augments nicotinic and ATP-induced, but not muscarinic, cutaneous vasodilatation in women. This will stimulate future studies assessing the pathophysiological significance of the augmented microvascular responsiveness in older women compared to their young counterparts. Abstract We previously reported that ageing attenuates adenosine triphosphate (ATP)-induced, but not muscarinic and nicotinic, cutaneous vasodilatation in men, and that ageing may augment cutaneous vascular responses in women. In the present study, we evaluated the hypothesis that ageing augments muscarinic, nicotinic and/or ATP-mediated cutaneous vasodilatation in healthy women. In 11 young (23 ± 5 years) and 11 older (60 ± 8 years) women, cutaneous vascular conductance was evaluated at three forearm skin sites that were perfused with (1) methacholine (muscarinic receptor agonist, 5 doses: 0.0125, 0.25, 5, 100, 2000 mm), (2) nicotine (nicotinic receptor agonist, 5 doses: 1.2, 3.6, 11, 33, 100 mm), or (3) ATP (purinergic receptor agonist, 5 doses: 0.03, 0.3, 3, 30, 300 mm). Each agonist was administered for 25 min per dose. Methacholine-induced increases in cutaneous vascular conductance were not different between groups at all doses (all P > 0.05). However, a nicotine-induced elevation in cutaneous vascular conductance at the lowest concentration (1.2 mm) was greater in older vs. young women (43 ± 15 vs. 26 ± 10%max, P = 0.04). ATP-induced increases in cutaneous vascular conductance at moderate and high doses (3 and 30 mm) were also greater in older relative to young women (3 mm, 44 ± 11 vs. 28 ± 10%max, P = 0.02; 30 mm, 83 ± 14 vs. 64 ± 17%max, P = 0.05). Therefore, ageing augments nicotinic and ATP-induced, but not muscarinic, cutaneous vasodilatation in women.

New findings What is the central question of this study? What is the role of nicotinic receptors in the regulation of normothermic cutaneous blood flow and cutaneous vasodilatation and sweating during whole-body heating induced following resting in a non-heat-stress condition? What is the main finding and its importance? Nicotinic receptors modulated cutaneous vascular tone during rest in a non-heat-stress condition and in the early stage of heating, but they had a limited role in mediating cutaneous vasodilatation when core temperature increased >0.4°C. Further, the contribution of nicotinic receptors to sweating was negligible during whole-body heating. Our findings provide new insights into the role of nicotinic receptors in end-organ function of skin vasculature and sweat glands in humans. Abstract Nicotinic receptors are present in human skin including cutaneous vessels and eccrine sweat glands as well as peripheral nerves. We tested the hypothesis that nicotinic receptors do not contribute to the control of cutaneous vascular tone in the normothermic state, but are involved in mediating cutaneous vasodilatation and sweating during a whole-body passive heat stress in humans. We first performed a nicotinic receptor blocker verification protocol in six young adults (one female) wherein increases in cutaneous vascular conductance and sweating elicited by 10 mm nicotine were blocked by administration of 500 µm hexamethonium to confirm effective blockade. Thereafter, 12 young males participated in a passive heating protocol. After an instrumentation period in a non-heat-stress condition, participants rested for a 10 min baseline period. Thereafter, oesophageal temperature was increased by 1.0°C using water-perfusion suits. Cutaneous vascular conductance, sweat rate, active sweat gland density and sweat output per individual gland were assessed with and without 500 µm hexamethonium administered via intradermal microdialysis. Hexamethonium reduced cutaneous vascular conductance by 22-34% during normothermia and the early stage of heating. However, this effect was diminished as oesophageal temperature increased >0.4°C. Active sweat gland density was reduced by hexamethonium when oesophageal temperature was elevated by 0.4-0.6°C above baseline resting. However, this was paralleled by a marginal increase in sweat gland output. Consequently, sweat rate remained unchanged. We showed that nicotinic receptors modulate cutaneous perfusion during normothermia and the early stage of heating, but not when core temperature increases >0.4°C. Additionally, they play a limited role in mediating sweating during heating.

Objectives Heat shock protein 90 (HSP90) contributes to cutaneous vasodilatation during exercise in the heat through nitric oxide (NO) synthase (NOS)-dependent mechanisms in young adults. We hypothesized that similar responses would be observed in older middle-aged adults. Methods In nineteen habitually active older middle-aged (56 ± 5 years) men (n = 9) and women (n = 10), cutaneous vascular conductance (CVC) was measured at four forearm skin sites continuously treated with (a) lactated Ringers solution (Control), (b) 10 mmol/L L-NAME (NOS inhibitor), (c) 178 μmol/L geldanamycin (HSP90 inhibitor), or (d) 10 mmol/L L-NAME and 178 μmol/L geldanamycin combined. Participants rested in an upright semi-recumbent position in the heat (35°C) for 70 minutes, followed by a 50-minute bout of moderate-intensity cycling (~55% peak oxygen uptake) and a 30-minute recovery period in the heat. Results In both men and women, we observed no significant effects of HSP90 inhibition on CVC throughout rest, exercise, and recovery in the heat (all P > 0.27). Conversely, NOS inhibition and dual NOS and HSP90 inhibition attenuated CVC relative to Control throughout the protocol (all P ≤ 0.05). Conclusions While NOS mediates cutaneous vasodilatation during rest, exercise, and recovery in the heat, HSP90 does not measurably influence this response in habitually active older middle-aged men or women under these conditions.

Objective High aerobic fitness may prevent age-related decrements in cutaneous vasodilation while type 2 diabetes may exacerbate this decline. The mechanisms underlying these responses remain unclear, but may be due to an excess of reactive oxygen species. We hypothesized that superoxide scavenging or NADPH oxidase inhibition would improve cutaneous vasodilation in older adults exercising in the heat, particularly in healthy low-fit individuals and those with type 2 diabetes. Methods Twenty seven older adults were evenly separated into three groups (healthy low-fit: VO2peak = 24.4 ± 2.4 ml·kg−1·min−1, 61 ± 8 years; healthy high-fit: 42.5 ± 9.7 ml·kg−1·min−1, 56 ± 6 years; type 2 diabetes: 30.0 ± 7.6, ml·kg−1·min−1, 58 ± 7 years). The healthy low-fit and type 2 diabetes groups performed two successive 30-min cycling bouts at 65%VO2peak in the heat (35°C), separated by 30-min rest. The high-fit group cycled at the same absolute heat load (and therefore requirement for heat loss) as their healthy low-fit counterparts during the first exercise bout (Ex1) and at the same relative intensity (65%VO2peak) during the second (Ex2). Forearm cutaneous vascular conductance (CVC%max) was measured at microdialysis sites perfused with: 1) lactated Ringer's solution (control); 2) 10 mM NG-nitro-L-arginine-methyl-ester (L-NAME, nitric oxide synthase inhibitor); 3) 100 μM apocynin (NADPH oxidase inhibitor); 4) 10 μM tempol (superoxide dismutase mimetic), with responses compared at baseline, end-Ex1, and end-Ex2. Results In all groups, L-NAME consistently reduced CVC%max relative to the other treatment sites by ~16–21% during Ex1 and by ~22–27% during Ex2 (all P 0.05). Conclusion Superoxide and NADPH oxidase do not modulate cutaneous vasodilation in healthy low- or high-fit older adults exercising in the heat, regardless of aerobic fitness level or relative exercise intensity employed, nor do they influence cutaneous vasodilation during an exercise-heat stress in those with type 2 diabetes. However, NOS remains an important modulator of cutaneous vasodilation during exercise in all groups.

NEW FINDINGS What is the central question of this study? Acetylcholine released from cholinergic nerves can activate both muscarinic and nicotinic receptors. Although each receptor can independently induce cutaneous vasodilatation and eccrine sweating, it remains to be elucidated whether the two receptors interact in order to mediate these responses. What is the main finding and its importance? We show that although nicotinic receptor activation does not modulate muscarinic cutaneous vasodilatation, it lowers the muscarinic receptor agonist threshold at which onset for eccrine sweating (augmentation of muscarinic eccrine sweating) occurs in young men in normothermic resting conditions. These results provide new insights into the physiological significance of nicotinic receptors in the regulation of cutaneous perfusion and eccrine sweating. Acetylcholine released from cholinergic nerves can activate both muscarinic and nicotinic receptors; each is known independently to induce cutaneous vasodilatation and eccrine sweating in humans. However, it is not known whether the two receptors interact in order to mediate cutaneous vasodilatation and eccrine sweating. In 10 young men (27 ± 6 years old), cutaneous vascular conductance and sweat rate were evaluated at intradermal microdialysis sites that were continuously perfused with either lactated Ringer's solution (control) or three different concentrations of nicotine (0.1, 1 and 10 mm), a nicotinic receptor agonist. Co-administration of methacholine, a muscarinic receptor agonist, was performed at all skin sites in a dose-proportional fashion (0.0125, 0.25, 5, 100 and 2000 mm, each for 25 min). Administration of nicotine alone caused dose-dependent transient increases in cutaneous vascular conductance and sweat rate (all P ≤ 0.05), which thereafter returned to pre-nicotine levels, except that a portion of transient responses remained with continuous administration of 10 mm nicotine (both P ≤ 0.05). Cutaneous vascular conductance was increased by administration of ≥0.25 mm methacholine at the control site, and this response was likewise observed in the presence of co-administration of all doses of nicotine used (all P ≤ 0.05). Sweat rate at the control site was increased by administration of ≥0.25 mm methacholine, but the lowest dose of methacholine (0.0125 mm) was able to increase sweat rate in the presence of 10 mm nicotine (P ≤ 0.05). We conclude that nicotinic receptor activation lowers the muscarinic receptor agonist threshold for eccrine sweating (augmentation of muscarinic sweating) but does not affect muscarinic cutaneous vasodilatation in young men in normothermic resting conditions.

β-adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, however, the mechanisms underpinning this response remains unresolved. We evaluated the hypotheses that 1) nitric oxide synthase (NOS) contributes to β-adrenergic cutaneous vasodilatation, whereas cyclooxygenase (COX) limits the vasodilatation, and 2) COX contributes to β-adrenergic sweating. In 10 young males (25 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites infused with 1) lactated Ringer's (control), 2) 10 mm L-NNA, a non-specific NOS inhibitor, 3) 10 mM ketorolac, a non-specific COX inhibitor, or 4) a combination of L-NNA and ketorolac. All sites were co-administered with a high dose isoproterenol (100 μM) for 3 min to maximally induce β-adrenergic sweating (β-adrenergic sweating is significantly blunted by subsequent activations). Approximately 60 min after washout period, three incremental doses of isoproterenol were co-administered (1, 10, 100 μM each for 25 min). Increases in CVC induced by the first and second 100 μM isoproterenol were attenuated by L-NNA alone, and those in response to all doses of isoproterenol were reduced by L-NNA with co-infusion of ketorolac (all P≤0.05). Ketorolac alone augmented increases in CVC induced by 10 and second 100 μM isoproterenol (both P≤0.05). While isoproterenol-induced sweating was not affected by the separate administration of L-NNA or ketorolac (all P>0.05), their combined administration augmented sweating elicited by the first 3-min 100 μM isoproterenol (P = 0.05). We show that while NOS contributes to β-adrenergic cutaneous vasodilatation, COX restrains the vasodilatation. Finally, combined inhibition of NOS and COX augments β-adrenergic sweating. (248/250) This article is protected by copyright. All rights reserved

Both cyclooxygenase (COX) and nitric oxide synthase (NOS) contribute to sweating, whereas NOS alone contributes to cutaneous vasodilation during exercise in the heat. Here, we evaluated if Type 1 diabetes mellitus (T1DM) modulates these responses. Adults with ( n = 11, 25 ± 5 yr) and without ( n = 12, 24 ± 4 yr) T1DM performed two bouts of 30-min cycling at a fixed rate of heat production of 400 W in the heat (35°C); each followed by a 20- and 40-min recovery period, respectively. Sweat rate and cutaneous vascular conductance (CVC) were measured at four intradermal microdialysis sites treated with either 1) lactated Ringer (vehicle control site), 2) 10 mM ketorolac (nonselective COX inhibitor), 3) 10 mM NG-nitro-l-arginine methyl ester (nonselective NOS inhibitor), or 4) a combination of both inhibitors. In nondiabetic adults, separate and combined inhibition of COX and NOS reduced exercise sweat rate ( P ≤ 0.05), and the magnitude of reductions were similar across sites. In individuals with T1DM, inhibition of COX resulted in an increase in sweat rate of 0.10 ± 0.09 and 0.09 ± 0.08 mg·min−1·cm−2for the first and second exercise bouts, respectively, relative to vehicle control site ( P ≤ 0.05), whereas NOS inhibition had no effect on sweating. In both groups, NOS inhibition reduced CVC during exercise ( P ≤ 0.05), although the magnitude of reduction did not differ between the nondiabetic and T1DM groups ( exercise 1: −28 ± 10 vs. −23 ± 8% max, P = 0.51; exercise 2: −31 ± 12 vs. −24 ± 10% max, P = 0.38). We show that in individuals with T1DM performing moderate intensity exercise in the heat, NOS-dependent sweating but not cutaneous vasodilation is attenuated, whereas COX inhibition increases sweating.

KEY POINTS In young adults, cyclooxygenase (COX) contributes to the heat loss responses of cutaneous vasodilatation and sweating, and this may be mediated by prostacyclin-induced activation of nitric oxide synthase (NOS) and calcium-activated potassium (KCa) channels. This prostacyclin-induced response may be diminished in older relative to young adults because ageing is known to attenuate COX-dependent heat loss responses. We observed that, although prostacyclin does not mediate sweating in young and older males, it does modulate cutaneous vasodilatation, although the magnitude of increase is similar between groups. We also found that, although NOS and KCa channels contribute to prostacyclin-induced cutaneous vasodilatation in young males, these contributions are diminished in older males. Our findings provide new insight into the mechanisms governing heat loss responses and suggest that the age-related diminished COX-dependent heat loss responses reported in previous studies may be a result of the reduced COX-derived production of prostanoids (e.g., prostacyclin) rather than the decreased sensitivity of prostanoid receptors. ABSTRACT Cyclooxygenase (COX) contributes to the regulation of cutaneous vasodilatation and sweating; however, the mechanism(s) underpinning this response remain unresolved. We hypothesized that prostacyclin (a COX-derived product) may directly mediate cutaneous vasodilatation and sweating through nitric oxide synthase (NOS) and calcium-activated potassium (KCa) channels in young adults. However, these responses would be diminished in older adults because ageing attenuates COX-dependent cutaneous vasodilatation and sweating. In young (25 ± 4 years) and older (60 ± 6 years) males (nine per group), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites: (i) control; (ii) 10 mm NG -nitro-l-arginine (l-NNA), a non-specific NOS inhibitor; (iii) 50 mm tetraethylammonium (TEA), a non-specific KCa channel blocker; and (iv) 10 mm l-NNA + 50 mm TEA. All four sites were coadministered with prostacyclin in an incremental manner (0.04, 0.4, 4, 40 and 400 μm each for 25 min). Prostacyclin-induced increases in CVC were similar between groups (all concentrations, P > 0.05). l-NNA and TEA, as well as their combination, lowered CVC in young males at all prostacyclin concentrations (P ≤ 0.05), with the exception of l-NNA at 0.04 μm (P > 0.05). In older males, CVC during prostacyclin administration was not influenced by l-NNA (all concentrations), TEA (4-400 μm) or their combination (400 μm) (P > 0.05). No effect on sweat rate was observed in either group (all concentrations, P > 0.05). We conclude that, although prostacyclin does not mediate sweating, it modulates cutaneous vasodilatation to a similar extent in young and older males. Furthermore, although NOS and KCa channels contribute to the prostacyclin-induced cutaneous vasodilatation in young males, these contributions are diminished in older males.

Acetylcholine released from cholinergic nerves is involved in heat loss responses of cutaneous vasodilation and sweating. K+ channels are thought to play a role in regulating cholinergic cutaneous vasodilation and sweating, though which K+ channels are involved in their regulation remains unclear. We evaluated the hypotheses that 1) Ca2+-activated K+ (KCa), ATP-sensitive K+ (KATP), and voltage-gated K+ (KV) channels all contribute to cholinergic cutaneous vasodilation; and 2) KV channels, but not KCa and KATP channels, contribute to cholinergic sweating. In 13 young adults (24 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at intradermal microdialysis sites that were continuously perfused with: 1) lactated Ringer (Control), 2) 50 mM tetraethylammonium (KCa channel blocker), 3) 5 mM glybenclamide (KATP channel blocker), and 4) 10 mM 4-aminopyridine (KV channel blocker). At all sites, cholinergic cutaneous vasodilation and sweating were induced by coadministration of methacholine (0.0125, 0.25, 5, 100, and 2,000 mM, each for 25 min). The methacholine-induced increase in CVC was lower with the KCa channel blocker relative to Control at 0.0125 (1 ± 1 vs. 9 ± 6%max) and 5 (2 ± 5 vs. 17 ± 14%max) mM methacholine, whereas it was lower in the presence of KATP (69 ± 7%max) and KV (57 ± 14%max) channel blocker compared with Control (79 ± 6%max) at 100 mM methacholine. Furthermore, methacholine-induced sweating was lower at the KV channel blocker site (0.42 ± 0.17 mg·min−1·cm−2) compared with Control (0.58 ± 0.15 mg·min−1·cm−2) at 2,000 mM methacholine. In conclusion, we show that KCa, KATP, and KV channels play a role in cholinergic cutaneous vasodilation, whereas only KV channels contribute to cholinergic sweating in normothermic resting humans.

Cyclooxygenase (COX) contributes to cutaneous vasodilation and sweating responses; however, the mechanisms underpinning these responses remain unknown. We hypothesized that prostaglandin E1 (PGE1) and E2 (PGE2) (COX-derived vasodilator products) directly mediate cutaneous vasodilation and sweating through nitric oxide synthase (NOS)-dependent mechanisms in young adults. Furthermore, we hypothesized that this response is diminished in older adults, since aging attenuates COX-dependent cutaneous vasodilation and sweating. In 9 young (22 ± 5 yr) and 10 older (61 ± 6 yr) adults, cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites receiving incremental doses (0.05, 0.5, 5, 50, 500 μM each for 25 min) of PGE1 or PGE2 with and without coadministration of 10 mM Nω-nitro-l-arginine, a nonspecific NOS inhibitor. Nω-nitro-l-arginine attenuated PGE1-mediated increases in CVC at all concentrations in young adults, whereas it reduced PGE2-mediated increases in CVC at lower concentrations (0.05–0.5 μM) in older adults (all P < 0.05). However, the magnitude of the PGE1- and PGE2-mediated increases in CVC did not differ between groups (all P > 0.05). Neither PGE1 nor PGE2 increased sweat rate at any of the administered concentrations for either the young or older adults (all P > 0.05). We show that although cutaneous vascular responsiveness to PGE1 and PGE2 is similar between young and older adults, the cutaneous vasodilator response is partially mediated through NOS albeit via low-to-high concentrations of PGE1 in young adults and low concentrations of PGE2 in older adults, respectively. We also show that in both young and older adults, PGE1 and PGE2 do not increase sweat rate under normothermic conditions.

KEY POINTS Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilatation during exercise in the heat. Similarly, reports show that Na(+) /K(+) -ATPase activation can modulate sweating and microvascular circulation. In light of the fact that NO can activate Na(+) /K(+) -ATPase, we evaluated whether there is an interaction between Na(+) /K(+) -ATPase and NOS in the regulation of heat loss responses during an exercise-induced heat stress. We demonstrate that Na(+) /K(+) -ATPase and NOS do not synergistically influence local forearm sweating during moderate intensity (fixed rate of metabolic heat production of 500 W) exercise in the heat (35°C). Conversely, we show an interactive role between NOS and Na(+) /K(+) -ATPase in the modulation of cutaneous vasodilatation. These findings provide novel insight regarding the mechanisms underpinning the control of sweating and cutaneous vasodilatation during exercise in the heat. Given that ouabain may be prescribed as a cardiac glycoside in clinical settings, potential heat loss impairments with ouabain administration should be explored. ABSTRACT Nitric oxide (NO) synthase (NOS) contributes to the heat loss responses of sweating and cutaneous vasodilatation. Given that NO can activate Na(+) /K(+) -ATPase, which also contributes to sweating and microvasculature regulation, we evaluated the separate and combined influence of Na(+) /K(+) -ATPase and NOS on sweating and cutaneous vasodilatation. Thirteen young (23±3 years) males performed two 30 min semi-recumbent cycling bouts in the heat (35°C) at a fixed rate of metabolic heat production (500 W) followed by 20 and 40 min recoveries, respectively. Local sweat rate (LSR) and cutaneous vascular conductance (CVC) were measured at four forearm skin sites continuously perfused via intradermal microdialysis with either: (1) lactated Ringer solution (Control); (2) 6 mᴍ ouabain (Ouabain), a Na(+) /K(+) -ATPase inhibitor; (3) 10 mᴍ l-N(G) -nitroarginine methyl ester (l-NAME), a NOS inhibitor; or (4) 6 mᴍ ouabain and 10 mᴍ l-NAME (Ouabain+l-NAME). At the end of both exercise bouts relative to Control, LSR was attenuated with Ouabain (54-60%), l-NAME (12-13%) and Ouabain+l-NAME (68-74%; all P < 0.05). Moreover, the sum of attenuations from Control induced by independent administration of Ouabain and l-NAME was similar to the combined infusion of Ouabain+l-NAME (both P ≥ 0.74). Compared to Control, CVC at the end of both exercise bouts was similar with Ouabain (both P ≥ 0.30), but attenuated with l-NAME (%CVCmax reduction from Control, 24-25%). Furthermore, CVC at the Ouabain+l-NAME site (38-39%; all P < 0.01) was attenuated compared to Control and did not differ from baseline resting values (both P ≥ 0.81). We show that Na(+) /K(+) -ATPase and NOS do not synergistically mediate sweating, whereas they influence cutaneous blood flow in an interactive manner during exercise in the heat.

KEY POINTS Endothelin-1 (ET-1) is a potent endothelial-derived vasoconstrictor that may modulate cholinergic cutaneous vascular regulation. Endothelin receptors are also expressed on the human eccrine sweat gland, although it remains unclear whether ET-1 modulates cholinergic sweating. We investigated whether ET-1 attenuates cholinergic cutaneous vasodilatation and sweating through a nitric oxide synthase (NOS)-dependent mechanism. Our findings show that ET-1 attenuates methacholine-induced cutaneous vasodilatation through a NOS-independent mechanism. We also demonstrate that ET-1 attenuates cutaneous vasodilatation in response to sodium nitroprusside, suggesting that ET-1 diminishes the dilatation capacity of vascular smooth muscle cells. We show that ET-1 does not modulate methacholine-induced sweating at any of the administered concentrations. Our findings advance our knowledge pertaining to the peripheral control underpinning the regulation of cutaneous blood flow and sweating and infer that ET-1 may attenuate the heat loss responses of cutaneous blood flow, but not sweating. ABSTRACT The present study investigated the effect of endothelin-1 (ET-1) on cholinergic mechanisms of end-organs (i.e. skin blood vessels and sweat glands) for heat dissipation. We evaluated the hypothesis that ET-1 attenuates cholinergic cutaneous vasodilatation and sweating through a nitric oxide synthase (NOS)-dependent mechanism. Cutaneous vascular conductance (CVC) and sweat rate were assessed in three protocols: in Protocol 1 (n = 8), microdialysis sites were perfused with lactated Ringer solution (Control), 40 pm, 4 nm or 400 nm ET-1; in Protocol 2 (n = 11) sites were perfused with lactated Ringer solution (Control), 400 nm ET-1, 10 mm N(G) -nitro-l-arginine (l-NNA; a NOS inhibitor) or a combination of 400 nm ET-1 and 10 mm l-NNA; in Protocol 3 (n = 8), only two sites (Control and 400 nm ET-1) were utilized to assess the influence of ET-1 on the dilatation capacity of vascular smooth muscle cells (sodium nitroprusside; SNP). Methacholine (MCh) was co-administered in a dose-dependent manner (0.0125, 0.25, 5, 100, 2000 mm, each for 25 min) at all skin sites. ET-1 at 400 nm (P 0.05) significantly attenuated increases in CVC in response to 0.25 and 5 mm MCh. A high dose of ET-1 (400 nm) co-infused with l-NNA further attenuated CVC during 0.25, 5 and 100 mm MCh administration relative to the ET-1 site (all P

Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS-dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger ( n = 12, 23 ± 4 yr) and older ( n = 12, 60 ± 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35°C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults.

Previous studies indicate that sex-related differences exist in the regulation of cutaneous vasodilation, however, the mechanisms remain unresolved. We assessed if sex-differences in young adults exist for cholinergic, nicotinic, and β-adrenergic cutaneous vasodilation with a focus on nitric oxide synthase (NOS), cyclooxygenase (COX), and K+ channel mechanisms. In twelve young men and thirteen young women, four intradermal forearm skin sites were perfused with the following: 1) lactated Ringer's solution (control), 2) 10 mM Nω-nitro- l -arginine, a non-selective NOS inhibitor, 3) 10 mM ketorolac, a non-selective COX inhibitor, or 4) 50 mM BaCl2, a nonspecific K+ channel blocker. At all four sites, cutaneous vasodilation was induced by 1) 10 mM nicotine, a nicotinic receptor agonist, 2) 100 μM isoproterenol, a nonselective β-adrenergic receptor agonist, and 3) 2 mM and 2000 mM acetylcholine, an acetylcholine receptor agonist. Nicotine and isoproterenol were administered for 3 min, whereas each acetylcholine dose was administered for 25 min. Regardless of treatment site, cutaneous vasodilation in response to nicotine and a high dose of acetylcholine (2000 mM) were lower in women than men. By contrast, isoproterenol induced cutaneous vasodilation was greater in women vs. men. Irrespective of sex, NOS inhibition or K+ channel blockade attenuated isoproterenol-mediated cutaneous vasodilation, whereas K+ channel blockade decreased nicotine-induced cutaneous vasodilation. Taken together, our findings indicate that while the mechanisms underlying cutaneous vasodilation are comparable between young men and women, sex-related differences in the magnitude of cutaneous vasodilation do exist and this response differs as a function of the receptor agonist.

Under conditions of extreme heat stress, the process of autophagy has previously been shown to protect human cells, but the exact body temperature at which autophagic activation occurs is largely unknown. Further, the interplay between autophagy, the heat shock response (HSR), inflammation, and apoptosis have yet to be examined together under temperature conditions representative of human internal body temperatures at rest (37 °C) or under severe heat stress conditions (41 °C). Thus, the purpose of this study was to examine threshold changes in autophagy, the HSR, inflammation, and apoptosis to increasing levels of ex vivo heat stress. Whole blood was collected from 20 young (23 ± 4 years; 10 men, 10 women) physically active participants. Peripheral blood mononuclear cells (PBMCs) were isolated immediately (baseline) and after 90-min of whole blood heating in 37, 39, and 41 °C water baths, representative of normal resting (non-heat stress) as well as moderate and severe heat stress conditions in humans, respectively. At 37 °C, increased autophagic activity was demonstrated, with no change in the HSR, and inflammation. Subsequently, responses of autophagy, the HSR, and inflammation increased with a moderate heat stress (39 °C), with further increases in only autophagy and the HSR under a severe heat stress of 41 °C. We observed no increase in apoptosis under any temperature condition. Our findings show that in human PBMCs, the autophagy and HSR systems may act cooperatively to suppress apoptotic signaling following heat stress, which may in part be mediated by an acute inflammatory response.

Protease-activated receptor 2 (PAR2) exists in the endothelial cells of skin vessels and eccrine sweat glands. We evaluated the hypothesis that exogeneous activation of PAR2 augments cutaneous vasodilatation and sweating during rest and exercise in the heat. In 10 young males (23 ± 5 y), cutaneous vascular conductance (CVC) and sweat rate were measured at four forearm skin sites treated with either 1) lactated Ringer (Control), 2) 0.05 mM, 3) 0.5 mM, or 4) 5 mM SLIGKV-NH(2) (PAR2 agonist). Participants initially rested in a semi-recumbent posture under a normothermic ambient condition (25°C) for ~60 min. Thereafter, ambient temperature was increased to 35°C while the participants rested for an additional 60 min. Participants then performed a 50-min bout of cycling (~55% of their pre-determined peak oxygen uptake) followed by a 30-min recovery period. Administration of 5 mM SLIGKV-NH(2) increased cutaneous vascular conductance relative to the Control site during normothermic resting (P ≤ 0.05). However, we showed that relative to the Control site, no effect on CVC was observed for any administered dose of SLIGKV-NH(2) (0.05-5 mM) during rest (33–39%max CVC), end-exercise (68–70%max CVC), and postexercise recovery (49–53%max CVC) in the heat (all P > 0.05). There were no differences in sweat rate between the Control and all SLIGKV-NH(2)-treated sites throughout the protocol (0.21–0.23, 1.20–1.27, and 0.32–0.33 mg∙min(−1)∙cm(−2) for rest, end-exercise, and postexercise in the heat, respectively, all P > 0.05). We show that while exogeneous PAR2 activation induces cutaneous vasodilatation during normothermic rest, it does not influence the cutaneous blood flow and sweating responses during rest, exercise or recovery in the heat.

We recently reported that the nonselective cyclooxygenase (COX) inhibitor ketorolac attenuated sweating but not cutaneous vasodilation during moderate‐intensity exercise in the heat. However, the specific contributions of COX‐1 and COX‐2 to the sweating response remained to be determined. We tested the hypothesis that COX‐1 but not COX‐2 contributes to sweating with no role for either COX isoform in cutaneous vasodilation during moderate‐intensity exercise in the heat. In thirteen young males (22 ± 2 years), sweat rate and cutaneous vascular conductance were measured at three forearm skin sites that were continuously treated with (1) lactated Ringer's solution (Control), (2) 150 μmmol·L−1 celecoxib, a selective COX‐2 inhibitor, or (3) 10 mmol L−1 ketorolac, a nonselective COX inhibitor. Participants first rested in a non heat stress condition (≥85 min, 25°C) followed by a further 70‐min rest period in the heat (35°C). They then performed 50 min of moderate‐intensity cycling (~55% peak oxygen uptake) followed by a 30‐min recovery period. At the end of exercise, sweat rate was lower at the 150 μmol·L−1 celecoxib (1.51 ± 0.25 mg·min−1·cm−2) and 10 mmol·L−1 ketorolac (1.30 ± 0.30 mg·min−1·cm−2) treated skin sites relative to the Control site (1.89 ± 0.27 mg·min−1·cm−2) (both P ≤ 0.05). Additionally, sweat rate at the ketorolac site was attenuated relative to the celecoxib site (P ≤ 0.05). Neither celecoxib nor ketorolac influenced cutaneous vascular conductance throughout the experiment (both P > 0.05). We showed that both COX‐1 and COX‐2 contribute to sweating but not cutaneous vasodilation during moderate‐intensity exercise in the heat in young men.

It remains unknown whether cutaneous adrenergic nerves functionally contribute to sweat production during exercise. This study examined whether cutaneous adrenergic nerve blockade attenuates sweating during incremental exercise, specifically in habitually trained individuals. Accordingly, 10 habitually trained and 10 untrained males (V̇o2max: 56.7 ± 5.4 and 38.9 ± 6.7 ml·kg−1·min−1, respectively; P < 0.001) performed incremental semirecumbent cycling (20 W/min) until exhaustion. Sweat rates (ventilated capsule) were measured at two bilateral forearm skin sites on which either 10 mM bretylium tosylate (BT) (an inhibitor of neurotransmitter release from sympathetic adrenergic nerve terminals) or saline (Control) was transdermally administered via iontophoresis. BT treatment delayed sweating onset in both groups (∼0.66 min; P = 0.001) and suppressed the sweat rate relative to the Control treatment at ≥70% relative total exercise time in trained individuals (each 10% increment; all P ≤ 0.009) but not in untrained counterparts ( P = 0.122, interaction between relative time × treatment). Changes in total sweat production at the BT site relative to the Control site were greater in trained individuals than in untrained counterparts (area under the curve, −0.86 ± 0.67 and −0.22 ± 0.39 mg/cm2, respectively; P = 0.023). In conclusion, we demonstrated that cutaneous adrenergic nerves do modulate sweating during incremental exercise, which appeared to be more apparent in habitually trained men (e.g., ≥70% maximum workload). Although our results indicated that habitual exercise training may augment neural adrenergic sweat production during incremental exercise, additional studies are required to confirm this possibility. NEW & NOTEWORTHY We demonstrated for the first time that cutaneous adrenergic nerves do modulate sweating during high-intensity exercise in humans (≥70% maximum workload). In addition, neural adrenergic sweating appeared to be greater in habitually trained individuals than in untrained counterparts, although further studies are necessary to confirm such a possibility. Nonetheless, the observations presented herein advance our understanding on human thermoregulation while providing new evidence for the neutral mediation of adrenergic sweating during exercise.