Search

A proposed mechanism underlying the effect of bacillus Calmette–Guerin (BCG) treatment for bladder cancer cells is as follows: BCG-induced crosslinking of cell-surface receptors results in the activation of signaling cascades, including cell-cycle regulators. However, the clinical significance of cell-cycle regulators such as p21 and p27 is controversial. Here we investigated the relationship between BCG exposure and p21 and p27. We used confocal laser microscopy to examine the expression levels of pKi67, p21 and p27 in T24 cells (derived from human urothelial carcinoma) exposed six times to BCG. We performed dual immunofluorescence staining methods for p21 and p27 and observed the localization of nuclear and cytoplasm expressions. We investigated the priority of p27 over p21 regarding nuclear expression by using p27 Stealth RNAi™ (p27-siRNA). With 2-h BCG exposure, the nuclear-expression level of p21 and p27 was highest, while pKi67 was lowest. The percentage of double nuclear-expression of p21 and p27 in BCG cells was significantly higher than that in control cells during the 1st to 6th exposure (P

New Findings What is the central question of this study? We evaluated whether oxidative stress attenuates the contribution of nitric oxide to sweating during high-intensity exercise. What is the main finding and its importance? In contrast to our previous report of an oxidative stress-mediated reduction in nitric oxide-dependent cutaneous vasodilatation in this cohort during intense exercise, we demonstrated no influence of local ascorbate administration on the sweating response during moderate- (∼51% peak oxygen uptake) or high-intensity exercise (∼72% peak oxygen uptake). These new findings provide important mechanistic insight into how exercise-induced oxidative stress impacts sudomotor activity. Nitric oxide (NO)-dependent sweating is diminished during high- but not moderate-intensity exercise. We evaluated whether this impairment stems from increased oxidative stress during high-intensity exercise. On two separate days, 11 young (24 ± 4 years) men cycled in the heat (35°C) at a moderate [500 W; 52 ± 6% peak oxygen uptake (VO2 peak )] or high (700 W; 71 ± 5% VO2 peak ) rate of metabolic heat production. Each session included two 30 min exercise bouts separated by a 20 min recovery period. Local sweat rate was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with the following: (i) lactated Ringer solution (Control); (ii) 10 mm ascorbate (Ascorbate; non-selective antioxidant); (iii) 10 mm NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor); or (iv) 10 mm ascorbate plus 10 mm l-NAME (Ascorbate + l-NAME). During moderate exercise, sweat rate was attenuated at the l-NAME and Ascorbate + l-NAME sites (both ∼1.0 mg min−1 cm−2; all P

Atrial natriuretic peptide (ANP) increases during exercise in the heat wherein heat loss responses of sweating and cutaneous vasodilatation are activated. Hence ANP might be involved in the regulation of sweating and cutaneous vasodilatation. However, whether ANP directly mediates sweating and cutaneous vasodilatation needs to be clarified. Also, muscarinic receptor activation induces sweating and cutaneous vasodilatation, however, it remains to be determined whether ANP modulates these responses. In this study, in 11 young males (25 ± 5 years), cutaneous vascular conductance and sweat rate were assessed at intradermal microdialysis sites that were continuously perfused with either lactated Ringer (Control) or 3 different concentrations of ANP (0.1, 1, 10 µM). All 4 sites were co-administrated with methacholine, a muscarinic receptor agonist, in a dose-dependent fashion (0.0125, 0.25, 5, 100, and 2000 mM, 25 min for each). ANP at all concentrations did not increase sweat rate and cutaneous vascular conductance as compared with pre-ANP infusion values (all P > 0.05). Methacholine increased both sweat rate and cutaneous vascular conductance (all P ≤ 0.05). However, the responses were unaffected by co-administration of ANP relative to methacholine only, even as assessed in context of the methacholine concentration required to elicit 50% of the maximal response (EC50) (all P > 0.05). We show that exogenous ANP administration intradermally does not directly modulate sweating and cutaneous vasodilatation under room temperature conditions in resting young adults. Further, there is no effect of ANP on muscarinic sweating and cutaneous vasodilatation.

Elevating core temperature at rest causes increases in minute ventilation (V̇e), which lead to reductions in both arterial CO2 partial pressure (hypocapnia) and cerebral blood flow. We tested the hypothesis that in resting heated humans this hypocapnia diminishes the ventilatory sensitivity to rising core temperature but does not explain a large portion of the decrease in cerebral blood flow. Fourteen healthy men were passively heated using hot-water immersion (41°C) combined with a water-perfused suit, which caused esophageal temperature (Tes) to reach 39°C. During heating in two separate trials, end-tidal CO2 partial pressure decreased from the level before heating (39.4 ± 2.0 mmHg) to the end of heating (30.5 ± 6.3 mmHg) ( P = 0.005) in the Control trial. This decrease was prevented by breathing CO2-enriched air throughout the heating such that end-tidal CO2 partial pressure did not differ between the beginning (39.8 ± 1.5 mmHg) and end (40.9 ± 2.7 mmHg) of heating ( P = 1.00). The sensitivity to rising Tes (i.e., slope of the Tes − V̇E relation) did not differ between the Control and CO2-breathing trials (37.1 ± 43.1 vs. 16.5 ± 11.1 l·min−1·°C−1, P = 0.31). In both trials, middle cerebral artery blood velocity (MCAV) decreased early during heating (all P < 0.01), despite the absence of hyperventilation-induced hypocapnia. CO2 breathing increased MCAV relative to Control at the end of heating ( P = 0.005) and explained 36.6% of the heat-induced reduction in MCAV. These results indicate that during passive heating at rest ventilatory sensitivity to rising core temperature is not suppressed by hypocapnia and that most of the decrease in cerebral blood flow occurs independently of hypocapnia. NEW & NOTEWORTHY Hyperthermia causes hyperventilation and concomitant hypocapnia and cerebral hypoperfusion. The last may underlie central fatigue. We are the first to demonstrate that hyperthermia-induced hyperventilation is not suppressed by the resultant hypocapnia and that hypocapnia explains only 36% of cerebral hypoperfusion elicited by hyperthermia. These new findings advance our understanding of the mechanisms controlling ventilation and cerebral blood flow during heat stress, which may be useful for developing interventions aimed at preventing central fatigue during hyperthermia.

NEW FINDINGS What is the central question of this study? It remains to be determined whether type 2 diabetes attenuates muscarinic and nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. What is the main finding and its importance? We show that type 2 diabetes specifically attenuates purinergic cutaneous vasodilatation without influencing muscarinic and nicotinic cutaneous vasodilatation and sweating. Our results provide valuable new information regarding the receptor-specific influence of type 2 diabetes on microvascular and sudomotor function. ABSTRACT The present study evaluated whether type 2 diabetes (T2D) attenuates muscarinic and/or nicotinic cutaneous vasodilatation and sweating as well as purinergic cutaneous vasodilatation. Cutaneous vascular conductance and sweat rate were evaluated in 12 healthy non-diabetic older adults (Control, 60 ± 8 years) and 13 older adults with T2D (62 ± 10 years) at three intradermal forearm skin sites perfused with the following: (i) methacholine (muscarinic receptor agonist, five doses: 0.0125, 0.25, 5, 100 and 2000 mm); (ii) nicotine (nicotinic receptor agonist, five doses: 1.2, 3.6, 11, 33 and 100 mm); or (iii) ATP (purinergic receptor agonist, five doses: 0.03, 0.3, 3, 30 and 300 mm). Each agonist was administered for 25 min per dose. At the end of the protocol, 50 mm sodium nitroprusside was administered to all skin sites to elicit maximal cutaneous vasodilatation. Cutaneous vascular conductance during methacholine and nicotine administration did not differ between groups (all P > 0.05). In contrast, cutaneous vascular conductance during administration of 30 mm (42 ± 28 versus 63 ± 26% maximum, P ≤ 0.05) and 300 mm ATP (56 ± 24 versus 71 ± 20% maximum, P ≤ 0.05) was attenuated in individuals with T2D in comparison to the Control participants. Furthermore, cutaneous vascular conductance during administration of 50 mm sodium nitroprusside was lower in individuals with T2D relative to Control subjects (P = 0.04). Methacholine- and nicotine-induced sweating was similar between groups (all P > 0.05). Thus, T2D attenuates purinergic cutaneous vasodilatation without affecting muscarinic and nicotinic cutaneous vascular and sweating responses.

Local skin heating to 42 °C causes rapid increases in cutaneous perfusion (initial peak), followed by a brief nadir and subsequent sustained elevation (plateau). Several studies have demonstrated that nitric oxide synthase (NOS) largely contributes to the plateau response during local heating. In this study, we tested the hypothesis that voltage-gated potassium (Kv) channels contribute to the plateau of the cutaneous vasodilation during local heating through NOS-dependent mechanisms. Eleven young males (25 ± 4 years) participated in this study wherein cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with either 1) lactated Ringer (Control), 2) 10 mM 4-aminopyridine (Kv channel blocker), 3) 10 mM Nω-Nitro-L-arginine (NOS inhibitor), or 4) a combination of 4-aminopyridine and Nω-Nitro-L-arginine. In comparison to the Control site, the inhibition of Kv channels alone attenuated the increase in CVC observed at the initial peak, nadir, and plateau phases measured during local heating; in contrast, the inhibition of NOS alone attenuated the increase in CVC at the nadir and plateau phases only (e.g., plateau response: Control site: 59 ± 5%max, Kv channel blockade site: 49 ± 8%max, NOS inhibition site: 35 ± 11%max, combined inhibition site: 40 ± 12%max). Further, no effect of Kv channel blockade on CVC was measured at any phase of the local heating response when the modulating influence of NOS was simultaneously removed. We show that Kv channels and NOS contribute to the local heating mediated sustained increase (i.e., plateau) in cutaneous vasodilation in an interactive manner. (243/250 words).

Aging and chronic disease such as type 2 diabetes (T2D) are associated with impairments in the body9s ability to dissipate heat. To reduce the risk of heat‐related injuries in these heat vulnerable individuals, it is necessary to identify interventions that can attenuate this impairment. We evaluated the hypothesis that intradermal administration of ascorbate improves cutaneous vasodilation and sweating in older adults via nitric oxide synthase (NOS)‐dependent mechanisms during exercise in the heat and whether these improvements, if any, are greater in individuals with T2D. Older males with ( n = 12, 61 ± 9 years) and without ( n = 12, 64 ± 7 years) T2D performed two 30‐min bouts of cycling at a fixed rate of metabolic heat production of 500 W (~70% peak oxygen uptake) in the heat (35°C); each followed by a 20‐ and 40‐min recovery, respectively. Cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis sites treated with either (1) lactated Ringer (Control), (2) 10 mmol/L ascorbate (an antioxidant), (3) 10 mmol/L L ‐NAME (non‐selective NOS inhibitor), or (4) a combination of ascorbate + L ‐NAME. In both groups, ascorbate did not modulate CVC or sweating during exercise relative to Control (all P > 0.05). In comparison to Control, L ‐NAME alone or combined with ascorbate attenuated CVC during exercise (all P ≤ 0.05) but had no influence on sweating (all P > 0.05). We show that in both healthy and T2D older adults, intradermal administration of ascorbate does not improve cutaneous vasodilation and sweating during exercise in the heat. However, NOS plays an important role in mediating cutaneous vasodilation.

We recently showed the varying roles of Ca2+-activated (KCa), ATP-sensitive (KATP), and voltage-gated (KV) K+ channels in regulating cholinergic cutaneous vasodilation and sweating in normothermic conditions. However, it is unclear whether the respective contributions of these K+ channels remain intact during dynamic exercise in the heat. Eleven young (23 ± 4 yr) men completed a 30-min exercise bout at a fixed rate of metabolic heat production (400 W) followed by a 40-min recovery period in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC) and local sweat rate were assessed at four forearm skin sites perfused via intradermal microdialysis with: 1) lactated Ringer solution (control); 2) 50 mM tetraethylammonium (nonspecific KCa channel blocker); 3) 5 mM glybenclamide (selective KATP channel blocker); or 4) 10 mM 4-aminopyridine (nonspecific KV channel blocker). Responses were compared at baseline and at 10-min intervals during and following exercise. KCa channel inhibition resulted in greater CVC versus control at end exercise ( P = 0.04) and 10 and 20 min into recovery (both P < 0.01). KATP channel blockade attenuated CVC compared with control during baseline ( P = 0.04), exercise (all P ≤ 0.04), and 10 min into recovery ( P = 0.02). No differences in CVC were observed with KV channel inhibition during baseline ( P = 0.15), exercise (all P ≥ 0.06), or recovery (all P ≥ 0.14). With the exception of KV channel inhibition augmenting sweating during baseline ( P = 0.04), responses were similar to control with all K+ channel blockers during each time period (all P ≥ 0.07). We demonstrated that KCa and KATP channels contribute to the regulation of cutaneous vasodilation during rest and/or exercise and recovery in the heat.

We evaluated the association between aerobic power (defined by peak oxygen consumption; V O 2peak ) and the contribution of nitric oxide synthase (NOS) to the sweating response in young and older individuals during exercise in the heat. Data from 44 young (24 ± 1 years) and 48 older (61 ± 2 years) males with mean VO 2peak of 47.8 ± 2.4 (range, 28.0–62.3) and 39.1 ± 2.3 (range, 26.4–55.7) mLO 2 kg −1 min −1 , respectively, were compiled from our prior studies. Participants performed two 15‐ to 30‐min bouts of exercise at a fixed rate of metabolic heat production of 400 or 500 W, each separated by 15–20 min recovery in the heat (35°C, relative humidity of 20%). Forearm sweat rate (ventilated capsule technique) was measured at two skin sites that were continuously and simultaneously administered with lactated Ringers solution (Control) or 10 mmol/L N G ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME, nonselective NOS inhibitor) via intradermal microdialysis. Sweat rate during the final 5 min of each exercise bout was lower with L ‐NAME compared to the Control in both groups (all P 0.05). The magnitude of the attenuation in sweat rate induced by L ‐NAME compared to the Control was not correlated with V O 2peak (all P ≥ 0.46) while this attenuation was negatively correlated with the sweat rate at the Control in both groups and in both exercise bouts (all P 0.01, R ≤ −0.43). These results suggest that NOS‐dependent sweating is not associated with aerobic power per se , while it becomes evident in individuals who produce larger sweat rates during exercise irrespective of age.

We evaluated the influence of K

New Findings What is the central question of this study? It remains unknown whether ageing modulates prostacyclin-induced cutaneous vasodilatation in women. What is the main finding and its importance? Prostacyclin induced cutaneous vasodilatation, albeit the magnitude of increase at lower concentrations of prostacyclin was greater in older relative to young women. This response was associated with greater contributions of nitric oxide synthase and calcium-activated potassium channels. Our results suggest that administration of prostacyclin might be an effective therapy to reverse microvascular hypoperfusion, especially in older women. We previously reported that prostacyclin induces cutaneous vasodilatation but not sweating in younger and older men. Furthermore, we demonstrated that nitric oxide synthase and calcium-activated potassium (KCa) channels contribute to the prostacyclin-induced cutaneous vasodilatation in younger men, although these contributions are diminished in older men. Given that the effects of ageing might differ between men and women, the above results cannot simply be applied to women. In this study, cutaneous vascular conductance and sweat rate were evaluated in younger (mean ± SD, 22 ± 3 years old) and older (55 ± 7 years old) women (10 per group) at four intradermal forearm skin sites treated as follows: (i) lactated Ringer solution without any drug (control); (ii) 10 mm NG-nitro-l-arginine (l-NNA), a non-specific nitric oxide synthase inhibitor; (iii) 50 mm tetraethylammonium (TEA), a non-specific KCa channel blocker; or (iv) 10 mm l-NNA plus 50 mm TEA. All four sites were co-administered with prostacyclin in an incremental manner (0.04, 0.4, 4, 40 and 400 μm, each for 25 min). Surprisingly, increases in cutaneous vascular conductance in response to 0.04–4 μm prostacyclin were greater in older relative to younger women (all P ≤ 0.05), and these age-related differences were diminished when both l-NNA and TEA were administered simultaneously (all P > 0.05). No effect on sweat rate was observed in either group (all concentrations, P > 0.05). We show that although prostacyclin does not mediate sweating, it induces cutaneous vasodilatation, and this response elicited by lower concentrations of prostacyclin is greater in older relative to younger women. This greater cutaneous vasodilatation in older women is likely to be attributable to nitric oxide synthase- and KCa channel-dependent mechanisms.

Metaboreceptors can modulate cutaneous blood flow and sweating during heat stress but the mechanisms remain unknown. Fourteen participants (31 ± 13 years) performed 1‐min bout of isometric handgrip (IHG) exercise at 60% of their maximal voluntary contraction followed by a 3‐min occlusion (OCC), each separated by 10 min, initially under low (LHS, to activate sweating without changes in core temperature) and high (HHS, whole‐body heating to a core temperature increase of 1.0°C) heat stress conditions. Cutaneous vascular conductance (CVC) and sweat rate were measured continuously at four forearm skin sites perfused with 1) lactated Ringer's solution (Control), 2) 10 mmol L‐NAME [inhibits nitric oxide synthase (NOS)], 3) 10 mmol Ketorolac [inhibits cyclooxygenase (COX)], or 4) 4 mmol theophylline (THEO; inhibits adenosine receptors). Relative to pre‐IHG levels with Control, NOS inhibition attenuated the metaboreceptor‐mediated increase in sweating under LHS and HHS ( P ≤ 0.05), albeit the attenuation was greater under LHS ( P ≤ 0.05). In addition, a reduction from baseline was observed with THEO under LHS during OCC ( P ≤ 0.05), but not HHS (both P > 0.05). In contrast, CVC was lower than Control with L‐NAME during OCC in HHS ( P ≤ 0.05), but not LHS ( P > 0.05). We show that metaboreceptor activation modulates CVC via the stimulation of NOS and adenosine receptors, whereas NOS, but not COX or adenosine receptors, contributes to sweating at all levels of heating.

To investigate the effect of voluntary hypocapnic hyperventilation or moderate hypoxia on metabolic and heart rate responses during high-intensity intermittent exercise. Ten males performed three 30-s bouts of high-intensity cycling [Ex1 and Ex2: constant-workload at 80% of the power output in the Wingate anaerobic test (WAnT), Ex3: WAnT] interspaced with 4-min recovery periods under normoxic (Control), hypocapnic or hypoxic (2500 m) conditions. Hypocapnia was developed through voluntary hyperventilation for 20 min prior to Ex1 and during each recovery period. End-tidal CO2 pressure was lower before each exercise in the hypocapnia than control trials. Oxygen uptake ( $$\dot{V}{\text{O}}_{ 2}$$ ) was lower in the hypocapnia than control trials (822 ± 235 vs. 1645 ± 245 mL min−1; mean ± SD) during Ex1, but not Ex2 or Ex3, without a between-trial difference in the power output during the exercises. Heart rates (HRs) during Ex1 (127 ± 8 vs. 142 ± 10 beats min−1) and subsequent post-exercise recovery periods were lower in the hypocapnia than control trials, without differences during or after Ex2, except at 4 min into the second recovery period. $$\dot{V}{\text{O}}_{ 2}$$ did not differ between the control and hypoxia trials throughout. These results suggest that during three 30-s bouts of high-intensity intermittent cycling, (1) hypocapnia reduces the aerobic metabolic rate with a compensatory increase in the anaerobic metabolic rate during the first but not subsequent exercises; (2) HRs during the exercise and post-exercise recovery periods are lowered by hypocapnia, but this effect is diminished with repeated exercise bouts, and (3) moderate hypoxia (2500 m) does not affect the metabolic response during exercise.

Two thermolytic thermoregulatory responses, cutaneous vasodilation and sweating, begin when core temperature reaches a critical threshold, after which response magnitudes increase linearly with increasing core temperature; thus the slope indicates response sensitivity. We evaluated the influence of hypocapnia induced by voluntary hyperventilation on the core temperature threshold and sensitivity of thermoregulatory responses. Ten healthy males performed 15 min of cycling at 117 W (29.5°C, 50% RH) under three breathing conditions: 1) spontaneous ventilation, 2) voluntary normocapnic hyperventilation, and 3) voluntary hypocapnic hyperventilation. In the hypocapnic hyperventilation trial, end-tidal CO2 pressure was reduced throughout the exercise, whereas it was maintained around the normocapnic level in the other two trials. Cutaneous vascular conductances at the forearm and forehead were evaluated as laser-Doppler signal/mean arterial blood pressure, and the forearm sweat rate was measured using the ventilated capsule method. Esophageal temperature threshold was higher for the increase in cutaneous vascular conductance in the hypocapnic than normocapnic hyperventilation trial at the forearm (36.88 ± 0.36 vs. 36.68 ± 0.34°C, P < 0.05) and forehead (36.89 ± 0.31 vs. 36.75 ± 0.31°C, P < 0.05). The slope relating esophageal temperature to cutaneous vascular conductance was decreased in the hypocapnic than normocapnic hyperventilation trial at the forearm (302 ± 177 vs. 420 ± 178% baseline/°C, P < 0.05) and forehead (236 ± 164 vs. 358 ± 221% baseline/°C, P < 0.05). Neither the threshold nor the slope for the forearm sweat rate differed significantly between the hypocapnic or normocapnic hyperventilation trials. These findings indicate that in exercising humans, hypocapnia induced by voluntary hyperventilation does not influence sweating, but it attenuates the cutaneous vasodilatory response by increasing its threshold and reducing its sensitivity.

Sodium drink is used as a countermeasure against body fluid loss. However, high concentrations of sodium may cause gastrointestinal upset (e.g., diarrhea). We sought to determine the sodium concentration that induces hypervolemia with a minimal risk of gastrointestinal disturbance.Eight healthy active males rested in a chair and ingested a given amount (16-17 ml kg body mass(-1)) of water (W) or solution containing 60, 120 or 180 mmol l(-1) Na(+) (60, 120 and 180Na trials) in 6 equal portions at 10 min intervals. To standardize their hydration status, subjects consumed the same meal and water 2 h before each trial. Drink trials were performed on separate days, and the order was randomized. The change in plasma volume (PV) from pre-drink status was estimated from the hemoglobin concentration and hematocrit every 30 min for 150 min after initiation of drinking.Subjects began trials in a euhydrated state, as reflected by their plasma osmolality (in mmol l(-1): W, 289.4 ± 1.4; 60Na, 287.0 ± 3.5; 120Na, 287.6 ± 2.3; 180Na, 288.9 ± 3.3). At 120 min, PV had not increased from the pre-drink value in the W (-0.8 ± 4.5 %) or 60Na (2.4 ± 4.9 %) trials, but it increased to similar degrees in the 120Na (7.2 ± 4.6 %) and 180Na (9.4 ± 6.6 %) trials. No diarrhea was reported in the W or 60Na trials, but it was reported in the 120Na (n = 1) and 180Na (n = 6) trials.Beverages containing 120 mmol l(-1) Na(+) induce hypervolemia with a minimum incidence of gastrointestinal problems.

We recently found that young cigarette smokers display cutaneous vascular dysfunction relative to nonsmokers, which is partially due to reduced nitric oxide (NO) synthase (NOS)-dependent vasodilation. In this study, we tested the hypothesis that reducing oxidative stress improves NO bioavailability, enhancing cutaneous vascular function in young smokers. Ten healthy young male smokers, who had smoked for 6.3 ± 0.7 yr with an average daily consumption of 9.1 ± 0.7 cigarettes, were tested. Cutaneous vascular conductance (CVC) during local heating to 42°C at a rate of 0.1°C/s was evaluated as laser-Doppler flux divided by mean arterial blood pressure and normalized to maximal CVC, induced by local heating to 44°C plus sodium nitroprusside administration. We evaluated plateau CVC during local heating, which is known to be highly dependent on NO, at four intradermal microdialysis sites with 1) Ringer solution (control); 2) 10 μM 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol), a superoxide dismutase mimetic; 3) 10 mM Nω-nitro-l-arginine (l-NNA), a nonspecific NOS inhibitor; and 4) a combination of 10 μM tempol and 10 mM l-NNA. Tempol increased plateau CVC compared with the Ringer solution site (90.0 ± 2.3 vs. 77.6 ± 3.9%maximum, P = 0.028). Plateau CVC at the combination site (56.8 ± 4.5%maximum) was lower than the Ringer solution site ( P < 0.001) and was not different from the l-NNA site (55.1 ± 4.6%maximum, P = 0.978), indicating the tempol effect was exclusively NO dependent. These data suggest that in young smokers, reducing oxidative stress improves cutaneous thermal hyperemia to local heating by enhancing NO production.

Nitric oxide (NO) is a signalling molecule that contributes to the control of many physiological pathways, including the heat-loss response of skin vasodilatation. Recently, NO has been implicated in the control of sweating during exercise in young adults. We tested the hypothesis that ageing reduces NO-dependent sweating during exercise in the heat. Ten young (23 ± 3 years old) and 10 older men (64 ± 5 years old), matched for body surface area, performed three successive 15 min bouts of exercise (Ex1, Ex2 and Ex3) at the same rate of metabolic heat production (300 W m(-2)) in the heat (35°C, 20% relative humidity). Exercise periods were interspersed with 15 min recovery periods. Local sweat rate (ventilated capsule) was measured on two forearm skin sites, which were continuously perfused via intradermal microdialysis with 0.9% saline as control (CON) or 10 mm N(G)-nitro-l-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. Local sweat rate at the end of Ex1 was lower in the CON conditions in the older versus young men (0.69 ± 0.19 versus 0.90 ± 0.17 mg min(-1) cm(-2), P = 0.018). In the young men, local sweat rate was reduced in the L-NAME-treated conditions compared with the CON conditions at the end of Ex1 (0.67 ± 0.14 versus 0.90 ± 0.17 mg min(-1) cm(-2), P = 0.004), Ex2 (0.78 ± 0.20 versus 1.03 ± 0.20 mg min(-1) cm(-2), P = 0.013) and Ex3 (0.78 ± 0.20 versus 1.03 ± 0.21 mg min(-1) cm(-2), P = 0.014). In the older men, there was no main effect of treatment conditions on local sweat rate (P = 0.537) such that local sweat rates in the L-NAME-treated and CON conditions were similar (Ex1, 0.65 ± 0.20 versus 0.69 ± 0.19 mg min(-1) cm(-2); Ex2, 0.80 ± 0.27 versus 0.91 ± 0.29 mg min(-1) cm(-2); and Ex3, 0.84 ± 0.31 versus 0.94 ± 0.38 mg min(-1) cm(-2)). We conclude that ageing attenuates the influence of NO in the control of local forearm sweating observed in young adults during short 15 min bouts of exercise in the heat. This mechanism may, in part, explain the age-related impairments in sweating.

This physiology study assesses whole-body heat loss in physically active middle-aged and older men with vs without type 2 diabetes after aerobic cycling to evaluate whether type 2 diabetes impairs heat loss and by what mechanism.

Transient receptor potential vanilloid 4 (TRPV4) channels exist in the endothelial cells of cutaneous blood vessels and the secretory cells of eccrine sweat glands. We assessed if exogenous TRPV4 channel activation elicits cutaneous vasodilatation and sweating in humans in vivo, and if so, whether this response is mediated by nitric oxide synthase (NOS)- cyclooxygenase (COX)- and/or Ca2+-sensitive K+ (KCa) channel-related mechanisms. In ten healthy young adults (24±2 years, 5 women), cutaneous vascular conductance and sweat rate were assessed at four dorsal forearm skin sites continuously treated with either: 1) lactated Ringer's solution (Control), 2) 20 mM L-NAME, a non-selective NOS inhibitor, 3) 10 mM ketorolac, a non-selective COX inhibitor, or 4) 50 mM TEA, a non-selective KCa channel blocker. A potent and selective TRPV4 channel agonist, GSK1016790 A (GSK101), was administered to each skin site in a dose-dependent manner (1, 10, 100, 1000 μM each for ≥30min) via intradermal microdialysis. Administration of 100 and 1000 μM GSK101 increased cutaneous vascular conductance from pre-infusion level at the Control site (48±12 and 57±9%max, respectively, P≤0.004). This response was markedly (53–83%) attenuated by NOS inhibition, COX inhibition, or KCa channel blockade (all P≤0.037), except KCa channel blockade had no effect during 1000 μM GSK101 administration. GSK101 did not influence sweat rate regardless of skin site. We showed that in human skin in vivo, exogenous activation of TRPV4 channels mediates cutaneous vasodilatation, but not sweating through NOS, COX, and KCa channel mechanisms.

We tested whether expiratory flow limitation (EFL) occurs in endurance athletes in a moderately hypobaric hypoxic environment equivalent to 2500 m above sea level and, if so, whether EFL inhibits peak ventilation (urn:x-wiley:2051817X:media:phy213996:phy213996-math-0001Epeak), thereby exacerbating the hypoxia‐induced reduction in peak oxygen uptake (urn:x-wiley:2051817X:media:phy213996:phy213996-math-0002O2peak). Seventeen young male endurance runners performed incremental exhaustive running on separate days under hypobaric hypoxic (560 mmHg) and normobaric normoxic (760 mmHg) conditions. Oxygen uptake (urn:x-wiley:2051817X:media:phy213996:phy213996-math-0003O2), minute ventilation (urn:x-wiley:2051817X:media:phy213996:phy213996-math-0004E), arterial O2 saturation (SpO2), and operating lung volume were measured throughout the incremental exercise. Among the runners tested, 35% exhibited EFL (EFL group, n = 6) in the hypobaric hypoxic condition, whereas the rest did not (Non‐EFL group, n = 11). There were no differences between the EFL and Non‐EFL groups for urn:x-wiley:2051817X:media:phy213996:phy213996-math-0005Epeak and urn:x-wiley:2051817X:media:phy213996:phy213996-math-0006O2peak under either condition. Percent changes in urn:x-wiley:2051817X:media:phy213996:phy213996-math-0007Epeak (4 ± 4 vs. 2 ± 4%) and urn:x-wiley:2051817X:media:phy213996:phy213996-math-0008O2peak (−18 ± 6 vs. −16 ± 6%) from normobaric normoxia to hypobaric hypoxia also did not differ between the EFL and Non‐EFL groups (all P > 0.05). No differences in maximal running velocity, SpO2, or operating lung volume were detected between the two groups under either condition. These results suggest that under the moderate hypobaric hypoxia (2500 m above sea level) frequently used for high‐attitude training, ~35% of endurance athletes may exhibit EFL, but their ventilatory and metabolic responses during maximal exercise are similar to those who do not exhibit EFL.

During exposure to high altitude, hypoxia develops because of reductions in barometric pressure and partial pressure of O2. Although several studies have examined the effects of hypoxia on exercise performance and physiological responses, such as maximal minute ventilation (urn:x-wiley:2051817X:media:phy214002:phy214002-math-0002Emax) and maximal oxygen uptake (urn:x-wiley:2051817X:media:phy214002:phy214002-math-0003O2max), how barometric pressure reduction (hypobaria) modulates them remains largely unknown. In this study, 11 young men performed incremental treadmill running tests to exhaustion under three conditions chosen at random: normobaric normoxia (NN; 763 ± 5 mmHg of barometric pressure, equivalent to sea level), hypobaric hypoxia (HH; 492 ± 1 mmHg of barometric pressure, equivalent to 3500 m above sea level (m a.s.l.)), and hypobaric normoxia (HN; 492 ± 1 mmHg of barometric pressure while breathing 32.2 ± 0.1% O2 to match the inspiratory O2 content under NN). urn:x-wiley:2051817X:media:phy214002:phy214002-math-0004Emax was higher in HN than in NN (160.9 ± 10.7 vs. 150.7 ± 10.0 L min−1, P < 0.05). However, no differences in urn:x-wiley:2051817X:media:phy214002:phy214002-math-0005O2max and arterial oxyhemoglobin saturation were observed between NN and HN (all P > 0.05). Time to exhaustion was longer in HN than in NN (932 ± 83 vs. 910 ± 79 s, P < 0.05). These results suggest that reduced air density during exposure to an altitude of 3500 m a.s.l. increases maximal ventilation and extends time to exhaustion without affecting oxygen consumption or arterial oxygen saturation.

We investigated whether heat‐induced hyperventilation can be voluntarily prevented, and, if so, how this modulates respiratory mechanics and cerebral blood flow in resting heated humans. In two separate trials, 10 healthy men were passively heated using lower body hot‐water immersion and a water‐perfused garment covering their upper body (both 41°C) until esophageal temperature (T es) reached 39°C or volitional termination. In each trial, participants breathed normally (normal‐breathing) or voluntarily controlled minute ventilation (V E) at a level equivalent to that observed after 5 min of heating (controlled‐breathing). Respiratory gases, middle cerebral artery blood velocity (MCAV), work of breathing, and end‐expiratory and inspiratory lung volumes were measured. During normal‐breathing, V E increased as T es rose above 38.0 ± 0.3°C, whereas controlled‐breathing diminished the increase in V E (V E at T es = 38.6°C: 25.6 ± 5.9 and 11.9 ± 1.3 L min−1 during normal‐ and controlled‐breathing, respectively, P

Cigarette smoking attenuates acetylcholine (ACh)-induced cutaneous vasodilation in humans, but the underlying mechanisms are unknown. We tested the hypothesis that smokers have impaired nitric oxide (NO)- and cyclooxygenase (COX)-dependent cutaneous vasodilation to ACh infusion. Twelve young smokers, who have smoked more than 5.2 ± 0.7 yr with an average daily consumption of 11.4 ± 1.2 cigarettes, and 12 nonsmokers were tested. Age, body mass index, and resting mean arterial pressure were similar between the groups. Cutaneous vascular conductance (CVC) was evaluated as laser-Doppler flux divided by mean arterial pressure, normalized to maximal CVC (local heating to 43.0°C plus sodium nitroprusside administration). We evaluated the increase in CVC from baseline to peak (CVCΔpeak) and area under the curve of CVC (CVCAUC) during a bolus infusion (1 min) of 137.5 μM ACh at four intradermal microdialysis sites: 1) Ringer (control), 2) 10 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor), 3) 10 mM ketorolac (COX inhibitor), and 4) combination of l-NAME + ketorolac. CVCΔpeakand CVCAUCat the Ringer site in nonsmokers were greater than in smokers (CVCΔpeak, 42.9 ± 5.1 vs. 22.3 ± 3.5%max, P < 0.05; and CVCAUC, 8,085 ± 1,055 vs. 3,145 ± 539%max·s, P < 0.05). In nonsmokers, CVCΔpeakand CVCAUCat the l-NAME site were lower than the Ringer site (CVCΔpeak, 29.5 ± 6.2%max, P < 0.05; and CVCAUC, 5,377 ± 1,109%max·s, P < 0.05), but in smokers, there were no differences between the Ringer and l-NAME sites (CVCΔpeak, 16.8 ± 4.3%max, P = 0.11; and CVCAUC, 2,679 ± 785%max·s, P = 0.30). CVCΔpeakand CVCAUCwere reduced with ketorolac in nonsmokers (CVCΔpeak, 13.3 ± 3.6%max, P < 0.05; and CVCAUC, 1,967 ± 527%max·s, P < 0.05) and smokers (CVCΔpeak, 7.8 ± 1.8%max, P < 0.05; and CVCAUC, 1,246 ± 305%max·s, P < 0.05) and at the combination site in nonsmokers (CVCΔpeak, 15.9 ± 3.1%max, P < 0.05; and CVCAUC, 2,660 ± 512%max·s, P < 0.05) and smokers (CVCΔpeak, 11.5 ± 2.6%max, P < 0.05; and CVCAUC, 1,693 ± 409%max·s, P < 0.05), but the magnitudes were greater in nonsmokers ( P < 0.05). These results suggest that impaired ACh-induced skin vasodilation in young smokers is related to diminished NO- and COX-dependent vasodilation.

What is the central question of this study? Protease-activated receptor 2 (PAR2) is located in the endothelial cells of skin vessels and eccrine sweat glands. However, a functional role of PAR2 in the control of cutaneous blood flow and sweating remains to be assessed in humans in vivo. What is the main finding and its importance? Our results demonstrate that in normothermic resting humans in vivo, activation of PAR2 elicits cutaneous vasodilatation partly through nitric oxide synthase-dependent mechanisms, but does not mediate sweating. These results provide important new insights into the physiological significance of PAR2 in human skin. Protease-activated receptor 2 (PAR2) is present in human skin, including keratinocytes, endothelial cells of skin microvessels and eccrine sweat glands. However, whether PAR2 contributes functionally to the regulation of cutaneous blood flow and sweating remains entirely unclear in humans in vivo. We hypothesized that activation of PAR2 directly stimulates cutaneous vasodilatation and sweating via actions of nitric oxide synthase (NOS) and cyclo-oxygenase (COX). In 12 physically active young men (29 ± 5 years old), cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis forearm skin sites that were treated with the following: (i) lactated Ringer's solution (control); (ii) 10 mm N

β-Adrenergic receptor agonists such as isoproterenol induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. Using intradermal microdialysis, we evaluated the roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in β-adrenergic cutaneous vasodilatation and sweating elicited by administration of isoproterenol. We show that while NOS contributes to β-adrenergic cutaneous vasodilatation, COX restricts cutaneous vasodilatation. We also show that combined inhibition of NOS and COX augments β-adrenergic sweating These new findings advance our basic knowledge regarding the physiological control of cutaneous blood flow and sweating, and provide important and new information to better understand the physiological significance of β-adrenergic receptors in the skin.β-Adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain 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 solution (control), (2) 10 mm N

We recently showed that intradermal administration of endothelin-1 diminished endothelium-dependent and -independent cutaneous vasodilation. We evaluated the hypothesis that Rho kinase may be a mediator of this response. We also sought to evaluate if endothelin-1 increases sweating. In 12 adults (25 ± 6 yr), we measured cutaneous vascular conductance (CVC) and sweating during 1) endothelium-dependent vasodilation induced via administration of incremental doses of methacholine (0.25, 5, 100, and 2,000 mM each for 25 min) and 2) endothelium-independent vasodilation induced via administration of 50 mM sodium nitroprusside (20–25 min). Responses were evaluated at four skin sites treated with either 1) lactated Ringer solution (Control), 2) 400 nM endothelin-1, 3) 3 mM HA-1077 (Rho kinase inhibitor), or 4) endothelin-1+HA-1077. Pharmacological agents were intradermally administered via microdialysis. Relative to the Control site, endothelin-1 attenuated endothelium-dependent vasodilation (CVC at 2,000 mM methacholine, 80 ± 10 vs. 56 ± 15%max, P < 0.01); however, this response was not detected when the Rho kinase inhibitor was simultaneously administered (CVC at 2,000 mM methacholine for Rho kinase inhibitor vs. endothelin-1 + Rho kinase inhibitor sites: 73 ± 9 vs. 72 ± 11%max, P > 0.05). Endothelium-independent vasodilation was attenuated by endothelin-1 compared with the Control site (CVC, 92 ± 13 vs. 70 ± 14%max, P < 0.01). However, in the presence of Rho kinase inhibition, endothelin-1 did not affect endothelium-independent vasodilation (CVC at Rho kinase inhibitor vs. endothelin-1+Rho kinase inhibitor sites: 81 ± 9 vs. 86 ± 10%max, P > 0.05). There was no between-site difference in sweating throughout ( P > 0.05). We show that in young adults, Rho kinase is an important mediator of the endothelin-1-mediated attenuation of endothelium-dependent and -independent cutaneous vasodilation, and that endothelin-1 does not increase sweating.

During exercise, cutaneous vasodilation and sweating responses occur, whereas these responses rapidly decrease during postexercise recovery. We hypothesized that the activation of endothelin A (ETA) receptors, but not endothelin B (ETB) receptors, attenuate cutaneous vasodilation during high-intensity exercise and contribute to the subsequent postexercise suppression of cutaneous vasodilation. We also hypothesized that both receptors increase sweating during and following high-intensity exercise. Eleven men (24 ± 4 yr) performed an intermittent cycling protocol consisting of two 30-min bouts of moderate- (40% V̇o2peak) and high-intensity (75% V̇o2peak) exercise in the heat (35°C), each separated by a 20- and 40-min recovery period, respectively. Cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal microdialysis skin sites: 1) lactated Ringer (control), 2) 500 nM BQ123 (a selective ETA receptor blocker), 3) 300 nM BQ788 (a selective ETB receptor blocker), or 4) a combination of BQ123 + BQ788. There were no between-site differences in CVC during each exercise bout (all P > 0.05); however, CVC following high-intensity exercise was greater at BQ123 (56 ± 9%max) and BQ123 + BQ788 (55 ± 14%max) sites relative to the control site (43 ± 12%max) (all P ≤ 0.05). Sweat rate did not differ between sites throughout the protocol (all P > 0.05). We show that neither ETA nor ETB receptors modulate cutaneous vasodilation and sweating responses during and following moderate- and high-intensity exercise in the heat, with the exception that ETA receptors may partly contribute to the suppression of cutaneous vasodilation following high-intensity exercise.

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.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 N

Elevation of core temperature leads to increases in ventilation in both resting subjects and those engaged in prolonged exercise. We compared the characteristics of the hyperthermic hyperventilation elicited during passive heating at rest and during prolonged moderate and light exercise. Twelve healthy men performed three trials: a rest trial in which subjects were passively heated using hot-water immersion (41°C) and a water-perfused suit and two exercise trials in which subjects exercised at 25% (light) or 50% (moderate) of peak oxygen uptake in the heat (37°C and 50% relative humidity) after first using water immersion (18°C) to reduce resting esophageal temperature ( Tes). This protocol enabled detection of a Tes threshold for hyperventilation during the exercise. When minute ventilation (V̇e) was expressed as a function of Tes, 9 of the 12 subjects showed Tes thresholds for hyperventilation in all trials. The Tes thresholds for increases in V̇e during light and moderate exercise (37.1 ± 0.4 and 36.9 ± 0.4°C) were both significantly lower than during rest (38.3 ± 0.6°C), but the Tes thresholds did not differ between the two exercise intensities. The sensitivity of V̇e to increasing Tes (slope of the Tes-V̇e relation) above the threshold was significantly lower during moderate exercise (8.7 ± 3.5 l·min−1·°C−1) than during rest (32.5 ± 24.2 l·min−1·°C−1), but the sensitivity did not differ between light (10.4 ± 13.0 l·min−1·°C−1) and moderate exercise. These results suggest the core temperature threshold for hyperthermic hyperventilation and the hyperventilatory response to increasing core temperature in passively heated subjects differs from that in exercising subjects, irrespective of whether the exercise is moderate or light.

Static and dynamic exercise is accompanied by increases in arterial blood pressure, heart rate and sympathetic nerve activity. It has been hypothesized that these cardiovascular responses are mediated by central command as well as by feedback mechanisms operating via afferent nerves (group III and IV fibers) that arise from skeletal muscles, are sensitive to mechanical (the so-called muscle mechanoreflex) and metabolic changes (the so-called muscle metaboreflex), and are modulated by arterial and cardiopulmonary baroreflexes. In this review, discussion is focused on the roles of the arterial baroreflex and muscle metaboreflex in cardiovascular regulation during exercise. In the first part of the review, brief discussion is made of the functions of these two reflexes during exercise; in the second part, their interactions are looked at in more detail. It is thought that during heavy exercise, the arterial baroreflex and the muscle metaboreflex are both activated, and interact in ways that lead to modulation of the primary cardiovascular reflex responses. Two types of interaction have been demonstrated. In the first, the arterial baroreflex acts to oppose pressor responses induced via the muscle metaboreflex. The second type of interaction involves the modulation of arterial baroreflex function during muscle metaboreflex activation. The authors offer commentary on these two types of interaction, including recent knowledge.

Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Our aim was to determine the muscle metaboreflex threshold and gain in humans by creating an open-loop relationship between active muscle blood flow and hemodynamic responses during a rhythmic handgrip exercise. Eleven healthy subjects performed the exercise at 5 or 15% of maximal voluntary contraction (MVC) in random order. During the exercise, forearm blood flow (FBF), which was continuously measured using Doppler ultrasound, was reduced in five steps by manipulating the inner pressure of an occlusion cuff on the upper arm. The FBF at each level was maintained for 3 min. The initial reductions in FBF elicited no hemodynamic changes, but once FBF fell below a threshold, mean arterial blood pressure (MAP) and heart rate (HR) increased and total vascular conductance (TVC) decreased in a linear manner. The threshold FBF during the 15% MVC trial was significantly higher than during the 5% MVC trial. The gain was then estimated as the slope of the relationship between the hemodynamic responses and FBFs below the threshold. The gains for the MAP and TVC responses did not differ between workloads, but the gain for the HR response was greater in the 15% MVC trial. Our findings thus indicate that increasing the workload shifts the threshold for the muscle metaboreflex to higher blood flows without changing the gain of the reflex for the MAP and TVC responses, whereas it enhances the gain for the HR response.

We tested the hypothesis that short-term exercise-heat acclimation (EHA) attenuates hyperthermia-induced hyperventilation in humans exercising in a hot environment. Twenty-one male subjects were divided into the two groups: control (C, n = 11) and EHA (n = 10). Subjects in C performed exercise-heat tests [cycle exercise for ~75 min at 58% \( \dot{V}_{{{\text{O}}_{{ 2 {\text{peak}}}} }} \) (37°C, 50% relative humidity)] before and after a 6-day interval with no training, while subjects in EHA performed the tests before and after exercise training in a hot environment (37°C). The training entailed four 20-min bouts of exercise at 50% \( \dot{V}_{{{\text{O}}_{{ 2 {\text{peak}}}} }} \) separated by 10 min of rest daily for 6 days. In C, comparison of the variables recorded before and after the no-training period revealed no changes. In EHA, the training increased resting plasma volume, while it reduced esophageal temperature (Tes), heart rate at rest and during exercise, and arterial blood pressure and oxygen uptake (\( \dot{V}_{{{\text{O}}_{2} }} \)) during exercise. The training lowered the Tes threshold for increasing forearm vascular conductance (FVC), while it increased the slope relating FVC to Tes and the peak FVC during exercise. It also lowered minute ventilation (\( \dot{V}_{\text{E}} \)) during exercise, but this effect disappeared after removing the influence of \( \dot{V}_{{{\text{O}}_{2} }} \) on \( \dot{V}_{\text{E}} \). The training did not change the slope relating ventilatory variables to Tes. We conclude that short-term EHA lowers ventilation largely by reducing metabolism, but it does not affect the sensitivity of hyperthermia-induced hyperventilation during submaximal, moderate-intensity exercise in humans.

We examined the degree to which ventilatory sensitivity to rising body temperature (the slope of the regression line relating ventilation and body temperature) is altered by restoration of arterial Pco2 to the eucapnic level during prolonged exercise in the heat. Thirteen subjects exercised for ∼60 min on a cycle ergometer at 50% of peak O2 uptake with and without inhalation of CO2-enriched air. Subjects began breathing CO2-enriched air at the point that end-tidal Pco2 started to decline. Esophageal temperature (Tes), minute ventilation (V̇e), tidal volume (VT), respiratory frequency ( fR), respiratory gases, middle cerebral artery blood velocity, and arterial blood pressure were recorded continuously. When V̇e, VT, fR, and ventilatory equivalents for O2 uptake (V̇e/V̇o2) and CO2 output (V̇e/V̇co2) were plotted against changes in Tes from the start of the CO2-enriched air inhalation (ΔTes), the slopes of the regression lines relating V̇e, VT, V̇e/V̇o2, and V̇e/V̇co2 to ΔTes (ventilatory sensitivity to rising body temperature) were significantly greater when subjects breathed CO2-enriched air than when they breathed room air (V̇e: 19.8 ± 10.3 vs. 8.9 ± 6.7 l·min−1·°C−1, VT: 18 ± 120 vs. −81 ± 92 ml/°C; V̇e/V̇o2: 7.4 ± 5.5 vs. 2.6 ± 2.3 units/°C, and V̇e/V̇co2: 7.6 ± 6.6 vs. 3.4 ± 2.8 units/°C). The increase in V̇e was accompanied by increases in VT and fR. These results suggest that restoration of arterial Pco2 to nearly eucapnic levels increases ventilatory sensitivity to rising body temperature by around threefold.

This paper was accepted for publication in the journal Journal of Applied Physiology and the definitive published version is available at https://doi.org/10.1152/japplphysiol.00089.2018.

We tested the hypothesis that hyperthermic hyperventilation in part reflects enhanced chemoreceptor ventilatory O(2) drive, and that the resultant hypocapnia attenuates ventilatory responses and/or middle cerebral artery mean blood velocity (MCAV(mean)) in resting humans. Eleven healthy subjects were passively heated for 50-80 min, causing oesophageal temperature (T(oes)) to increase by 1.6 degrees C. During heating, minute ventilation increased (P < 0.05), while end-tidal CO(2) pressure (P(ET,CO(2))) and MCAV(mean) declined. A hyperoxia test in which three breaths of hyperoxic air were inspired was performed once before heating and three times during the heating. When we observed hypocapnia (P(ET,CO(2)) below 40 mmHg), P(ET,CO(2)) was restored to the eucapnic level by adding 100% CO(2) to the inspired air immediately before the last two tests. Minute ventilation was significantly reduced by hyperoxia, and that reduction gradually increased with increasing T(oes). However, the percentage decrease in from the normoxic level was small (20-29%) and unchanged during heating. When P(ET,CO(2)) was restored to eucapnic levels, was unchanged, but MCAV(mean) was partly restored to the level seen prior to heating (28.1% restoration at T(oes) 37.6 degrees C and 38.1% restoration at T(oes) 38.0 degrees C). These findings suggest that although hyperthermia increases chemoreceptor ventilatory O(2) drive in resting humans, the relative contribution of the chemoreceptor ventilatory O(2) drive to hyperthermic hyperventilation is small ( approximately 20%) and unaffected by increasing core temperature. Moreover, hypocapnia induced by hyperthermic hyperventilation reduces cerebral blood flow but not ventilatory responses.

We tested the hypotheses that arterial baroreflex (ABR) control over muscle sympathetic nerve activity (MSNA) in humans does not remain constant throughout a bout of leg cycling ranging in intensity from very mild to exhausting. ABR control over MSNA (burst incidence, burst strength and total MSNA) was evaluated by analysing the relationship between beat-to-beat spontaneous variations in diastolic arterial pressure (DAP) and MSNA in 15 healthy subjects at rest and during leg cycling in a seated position at five workloads: very mild (10 W), mild (82 ± 5.0 W), moderate (126 ± 10.2 W), heavy (156 ± 14.3 W), and exhausting (190 ± 21.2 W). The workload was incremented every 6 min. The linear relationships between DAP and MSNA variables were significantly shifted downward during very mild exercise, but then shifted progressively upward as exercise intensity increased. During heavy and exhausting exercise, moreover, the DAP–MSNA relationships were also significantly shifted rightward from the resting relationship. The sensitivity of ABR control over burst incidence and total MSNA was significantly lower during very mild exercise than during rest, and the sensitivity of the burst incidence control remained lower than the resting level at all higher exercise intensities. By contrast, the sensitivity of the total MSNA control recovered to the resting level during mild and moderate exercise, and was significantly increased during heavy and exhausting exercise (versus rest). We conclude that, in humans, ABR control over MSNA is not uniform throughout a leg cycling exercise protocol in which intensity was varied from very mild to exhausting. We suggest that this non-uniformity of ABR function is one of the mechanisms by which sympathetic and cardiovascular responses are matched to the exercise intensity.

Continuous measurement of leg blood flow (LBF) using Doppler ultrasound with simultaneous noninvasive mean arterial blood pressure (MAP) measurement permits beat-to-beat estimates of leg vascular resistance (LVR) in humans. We tested the hypothesis that the beat-to-beat fluctuations in LVR and the dynamic relationship between MAP and LVR are modulated by the activation of muscle metaboreflex. Twelve healthy subjects performed a 1-min isometric handgrip exercise at 50% maximal voluntary contraction, which was followed by a period of imposed postexercise muscle ischemia (PEMI). We then employed transfer function analysis to examine the dynamic relationships between MAP and LBF and between MAP and LVR, both at rest (control) and during PEMI. We found the following. 1) The spectral power for LBF and LVR in low-frequency ( approximately 0.03-0.15 Hz) range significantly increased from control during PEMI without a significant change in the high-frequency ( approximately 0.15-0.35 Hz) power. 2) During PEMI, the transfer function gains for MAP-LBF and MAP-LVR relationships in the low-frequency ( approximately 0.05-0.15 Hz) range were significantly increased during PEMI (vs. control) but were unchanged in the high-frequency ( approximately 0.2-0.3 Hz) range. 3) The phases for MAP-LBF and MAP-LVR relationships were not different during control and PEMI. The phase for MAP-LVR relationship revealed that changes in MAP were followed by directionally similar changes in LVR, which is consistent with the characteristics of intrinsic vascular regulatory mechanisms such as the myogenic response of the resistance arteries. We suggest that, in humans, modulation of the dynamic MAP-LVR relationship during activation of the muscle metaboreflex reflects complex interactions between intrinsic vascular regulatory mechanisms and sympathetic vascular regulation.

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.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) compared to lower doses (40 pm and 4 nm) (all 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 0.05). Cutaneous vasodilatation in response to SNP was significantly blunted after administration of 400 nm ET-1 (P 0.05). We show that ET-1 attenuates cutaneous vasodilatation through a NOS-independent mechanism, possibly through a vascular smooth muscle cell-dependent mechanism, and methacholine-induced sweating is not altered by ET-1.

Acetylcholine released from cholinergic nerves is a key neurotransmitter contributing to heat stress-induced cutaneous vasodilation and sweating. Given that sympathetic cholinergic nerves also release ATP, ATP may play an important role in modulating cholinergic cutaneous vasodilation and sweating. However, the pattern of response may differ between males and females given reports of sex-related differences in the peripheral mechanisms governing these heat loss responses. Cutaneous vascular conductance (CVC, laser-Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated in 17 young adults (8 males, 9 females) at four intradermal microdialysis skin sites continuously perfused with: 1) lactated Ringer (Control), 2) 0.3 mM ATP, 3) 3 mM ATP, or 4) 30 mM ATP. At all skin sites, methacholine was coadministered in a concentration-dependent manner (0.0125, 0.25, 5, 100, 2,000 mM, each for 25 min). In both males and females, CVC was elevated with the lone infusion of 30 mM ATP (both P < 0.05), but not with 0.3 and 3 mM ATP compared with control (all P >0.27). However, 0.3 mM ATP induced a greater increase in CVC compared with control in response to 100 mM methacholine infusion in males ( P < 0.05). In females, 0.3 mM ATP infusion resulted in a lower concentration of methacholine required to elicit a half-maximal response (EC50) ( P < 0.05). In both males and females, methacholine-induced sweating was unaffected by any concentration of ATP (all P > 0.44). We demonstrate that ATP enhances cholinergic cutaneous vasodilation albeit the pattern of response differs between males and females. Furthermore, we show that ATP does not modulate cholinergic sweating.

Our recent work showed that nitric oxide (NO)-dependent sweating and cutaneous vasodilation are diminished in young males during intermittent exercise at high (700 W) relative to moderate (400 W) r...

This study evaluated the separate and combined roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in forearm sweating and cutaneous vasodilatation in older adults during intermittent exercise in the heat. Twelve healthy older (62 ± 7 years) males performed two 30 min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C, 20% relative humidity). The exercise bouts were followed by 20 and 40 min of recovery, respectively. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) were evaluated at four skin sites that were continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control), (2) 10 mm ketorolac (non-selective COX inhibitor), (3) 10 mm N(G) -nitro-l-arginine methyl ester (l-NAME; non-selective NOS inhibitor) or (4) a combination of 10 mm ketorolac + 10 mm l-NAME. Sweating was not different between the four sites during either exercise bout (main effect P = 0.92) (average of last 5 min of second exercise, Control, 0.80 ± 0.06; ketorolac, 0.77 ± 0.09; l-NAME, 0.74 ± 0.07; ketorolac + l-NAME, 0.77 ± 0.09 mg min(-1) cm(-2) ). During both exercise bouts, relative to CVC evaluated at the Control site (average of last 5 min of second exercise, 69 ± 6%max), CVC was similar at the ketorolac site (P = 0.62; 66 ± 4%max) whereas it was attenuated to a similar extent at both the l-NAME (49 ± 8%max) and ketorolac + l-NAME (54 ± 8%max) sites (both P0.05). Thus, we demonstrate that NOS and COX are not functionally involved in forearm sweating whereas only NOS contributes to forearm cutaneous vasodilatation in older adults during intermittent exercise in the heat.

In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation along with whether and how ATP increases sweating remains uncertain. Recent work has implicated nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine in the modulation of cutaneous vasodilatation and sweat production during both local (i.e. localized heating) and whole-body heat stress (i.e. exercise-induced heat stress). We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via NOS, COX and/or adenosine. We show that in humans in vivo, intradermal administration of ATP induces pronounced vasodilatation which is partially mediated by NOS, but neither COX nor adenosine influences ATP-mediated vasodilatation, and ATP alone does not induce an increase in sweating. These findings advance our basic physiological knowledge regarding control of skin blood flow and sweating, and provide insight into the mechanisms governing thermoeffector activity, which has major implications for whole-body heat exchange and therefore core temperature regulation in humans during heat stress.In humans in vivo, the mechanisms behind ATP-mediated cutaneous vasodilatation and whether and how ATP increases sweating remain uncertain. We evaluated whether ATP-mediated cutaneous vasodilatation and sweating is mediated via nitric oxide synthase (NOS), cyclooxygenase (COX) and/or adenosine-dependent mechanisms. Cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) and sweat rate (ventilated capsule) were evaluated at intradermal microdialysis forearm skin sites, each receiving pharmacological agents (two separate protocols). In Protocol 1 (n = 12), sites were perfused with: (1) lactated Ringer solution (Control), (2) 10 mm N(ω) -nitro-l-arginine (l-NNA, a NOS inhibitor), (3) 10 mm ketorolac (Ketorolac, a COX inhibitor) or (4) a combination of 10 mm l-NNA + 10 mm ketorolac (l-NNA + Ketorolac). In Protocol 2 (n = 8), sites were perfused with: (1) lactated Ringer solution (Control) or (2) 4 mm theophylline (Theophylline, an adenosine receptor inhibitor). At all sites, ATP was simultaneously perfused at 0.12, 1.2, 12, 120 and 1200 nm min(-1) (each for 20 min). Relative to CVC at the Control site with ATP infused at 120 nm min(-1) (71 ± 9% of max CVC), CVC at the Ketorolac site was comparable (64 ± 13% of max CVC, P = 0.407), but lower at l-NNA (51 ± 15% of max CVC, P = 0.040) and l-NNA + Ketorolac (51 ± 13% of max CVC, P = 0.049) sites. Conversely, across the four skin sites at any other ATP infusion rate (all P0.174), no differences in CVC were observed. Theophylline did not influence CVC at any ATP infusion rate (all P0.234). Furthermore, no ATP infusion rate elicited an increase in sweating from baseline at any skin site (all P0.235). We show that NOS, but neither COX nor adenosine receptors, modulates ATP-mediated cutaneous vasodilatation, whereas ATP does not directly increase sweating.

We tested the hypothesis that arterial baroreflex (ABR)-mediated beat-to-beat control over muscle sympathetic nerve activity (MSNA) is progressively modulated as orthostatic stress increases in humans, but that this control becomes impaired just before the onset of orthostatic syncope. In 17 healthy subjects, the ABR control over MSNA (burst incidence, burst strength and total MSNA) was evaluated by analysing the relationship between beat-to-beat spontaneous variations in diastolic blood pressure (DAP) and MSNA during supine rest (control) and during progressive, stepwise increases in lower body negative pressure (LBNP) that were incremented by -10 mmHg every 5 min until presyncope (nine subjects) or -60 mmHg was reached. (1) The linear relationships between DAP and burst strength and between DAP and total MSNA were shifted progressively upward as LBNP increased until the level at which syncope occurred. The relationship between DAP and burst incidence, however, gradually shifted upward from control only to LBNP = -30 mmHg; there was no further upward shift at higher LBNPs. (2) Although the slope of the relationship between DAP and burst strength and between DAP and total MSNA remained constant at all LBNPs tested, except at the level where syncope occurred, the slope of the relationship between DAP and burst incidence was reduced at LBNPs of -40 mmHg and higher (versus control). (3) In syncopal subjects, the slopes of the relationships between DAP and burst incidence, burst strength, and total MSNA were all substantially reduced during the 1-2 min period prior to the onset of syncope. Taken together, these results suggest baroreflex control over MSNA is progressively modulated as orthostatic stress increases, so that its sensitivity is substantially reduced during the period immediately preceding the severe hypotension associated with orthostatic syncope.