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

Objective: Cardiovascular disease (CVD) is a leading cause of mortality in persons with SCI. While macrovascular remodeling and function after SCI is well documented, changes in the microvascular structure and function are comparably understudied, but importantly predict CVD risk. Specifically, the integrity of venoarteriolar (VAR), myogenic (MYO) and maximal vasodilation responses are largely unknown after SCI, especially in persons with tetraplegia (TP) at highest risk of CVD. This is the first to examine the differences in VAR (cuff inflation), MYO (limb dependency) and maximal vasodilation responses of the microvasculature between able bodied (AB) versus those with TP and paraplegia (PP). Design: Observational. Setting: Laboratory. Participants: Eight AB, 6 TP, and 8 PP persons. Interventions: One forearm and calf were treated topically with lidocaine 2.5%/prilocaine 2.5% while contralateral limb served as a control. Laser doppler flowmeters were applied over treated and control sites during limb dependency, cuff inflation and local skin heating (Tloc) up to 42°C. Outcome measures: Skin vascular resistance (SkVR) change with cuff inflation and limb dependency and maximal cutaneous vascular conductance (CVC) during local heating. Results: Change in SkVR was not significantly different between groups or extremity (upper vs. lower) during cuff inflation or limb dependency. However, CVC at Tloc 42°C was significantly different in the lower extremity (LE) of TP and PP (P = 0.007, 0.35) compared to AB. Conclusion: Increases in SkVR during cuff inflation (VAR) and limb dependency (VAR and MYO) are unaltered after SCI, however maximal vasodilation in the LE post-SCI is higher than AB persons.

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.

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.

Menthol is a vasoactive compound that is widely used in topical analgesic agents. Menthol induces cutaneous vasodilation, however the underlying mechanisms are unknown. Determining the rates of appearance and clearance of menthol in the skin is important for optimizing topical treatment formulation and dosing. The purpose of this study was to determine the mechanisms contributing to menthol-mediated cutaneous vasodilation and to establish a time course for menthol appearance/clearance in the skin. Ten young (23±1 years, 5 males 5 females) subjects participated in two protocols. In study 1, four intradermal microdialysis fibers were perfused with increasing doses of menthol (0.1-500mM) and inhibitors for nitric oxide (NO), endothelium derived hyperpolarizing factors (EDHFs), and sensory nerves. Skin blood flow was measured with laser Doppler flowmetry and normalized to %CVCmax. In study 2, two intradermal microdialysis fibers were perfused with lactated Ringer's solution. 0.017mL•cm-2 of a 4% menthol gel was placed over each fiber. 5μL samples of dialysate from the microdialysis fibers were collected every 30 minutes and analyzed for the presence of menthol with high performance gas chromatography/mass spectrometry. Skin blood flow (laser speckle contrast imaging) and subjective ratings of menthol sensation were simultaneously obtained with dialysate samples. In study 1, menthol induced cutaneous vasodilation at all doses ≥100mM (all p0.05). In study 2, significant menthol was detected in dialysate 30 minutes post menthol application (0.89ng, p=0.0002). Relative to baseline, cutaneous vasodilation was elevated from minutes 15-45 and ratings of menthol sensation were elevated from minute 5-60 post menthol application (all p

Exposure to hot environments augments cutaneous vasodilation and sweating during exercise compared with these responses in cooler environments. The effects of hypobaric hypoxia on these responses are less clear, as are the effects of heat and simulated altitude combined. We evaluated the individual and potential additive effects of environmental heat and hypobaric hypoxia on skin blood flow and sweating responses during exercise. Thirteen volunteers (11 M, 2 F; age 25.3 ± 6.1 yr; height 177 ± 9 cm; weight 81.2 ± 16.8 kg) completed 30 min of steady-state (SS) exercise on a cycle ergometer at 50% V̇o2peak during four separate conditions: 1) sea level thermoneutral (SLTN; 250 m, 20°C, 30–50% RH), 2) sea level hot (SLH; 250 m, 35°C, 30% RH), 3) simulated altitude thermoneutral (ATN; 3,000 m, 20°C, 30–50% RH), and 4) simulated altitude hot (AH; 3,000 m, 35°C, 30% RH). Skin blood flow and local sweating rate (LSR) were recorded on the ventral forearm. During exercise, SS cutaneous vascular conductance in AH (63 ± 31% peak) and SLH (52 ± 19% peak) were significantly higher than both SLTN (20 ± 9% peak, P < 0.001) and ATN (25 ± 12% peak, P < 0.05) but were not different from each other ( P > 0.05). SS LSR was similarly increased in the hot environments but unaffected by simulated altitude. We propose that multiple antagonistic mechanisms during exposure to 3,000-m simulated altitude result in no net effect on skin blood flow or sweating responses during exercise in thermoneutral or hot environments.

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.

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.

We tested the hypothesis that a high fat meal (HFM) would impair cutaneous vasodilation, while thermotherapy (TT) would reverse the detrimental effects. Eight participants were instrumented with skin heaters and laser-Doppler (LD) probes and tested in three trials: control, HFM, and HFM + TT. Participants wore a water-perfused suit perfused with 33°C (control and HFM) or 50°C (HFM + TT) water. Participants consumed 1 g fat/kg body weight. Blood samples were taken at baseline and two hours post-HFM. Blood pressure was measured every 5–10 minutes. Microvascular function was assessed via skin local heating from 33°C to 39°C two hours after HFM. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). HFM had no effect on initial peak (48 ± 4 %CVCmax) compared to control (49 ± 4 %CVCmax) but attenuated the plateau (51 ± 4 %CVCmax) compared to control (63 ± 4 %CVCmax,P< 0.001). Initial peak was augmented in HFM + TT (66 ± 4 %CVCmax) compared to control and HFM (P< 0.05), while plateau (73 ± 3 %CVCmax) was augmented only compared to the HFM trial (P< 0.001). These data suggest that HFM negatively affects cutaneous vasodilation but can be minimized by TT.

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.

Niacin is effective in treating dyslipidemias but causes cutaneous vasodilation or flushing, a side effect that limits its clinical use. Blocking prostaglandins in humans reduces but does not consistently eliminate flushing, indicating additional mechanisms may contribute to flushing. The transient receptor potential vanilloid 1 (TRPV1) channel, when activated, causes cutaneous vasodilation and undergoes tachyphylaxis similar to that seen with niacin. Using a murine model, early phase niacin-induced flushing was examined and TRPV1 channel involvement demonstrated using pharmacologic blockade, desensitization, and genetic knockouts (TRPV1 KO). The TRPV1 antagonist AMG9810 reduced the magnitude of the initial and secondary peaks and the rapidity of the vasodilatory response (slope). TRPV1 desensitization by chronic capsaicin reduced the initial peak and slope. TRPV1 KO mice had a lower initial peak, secondary peak, and slope compared with wild-type mice. Chronic niacin reduced the initial peak, secondary peak, and slope in wild-type mice but had no effect in knockout mice. Furthermore, chronic niacin diminished the response to capsaicin in wild-type mice. Overall, these data demonstrate an important role for TRPV1 channels in niacin-induced flushing, both in the acute response and with chronic administration. That niacin-induced flushing is a complex cascade of events, which should inform pharmacological intervention against this side effect.

The skin is an accessible model circulation for studying vascular function and dysfunction across the lifespan. Age-related changes, as well as those associated with disease progression, often appear first in the cutaneous circulation. Furthermore, impaired vascular signaling and attendant endothelial dysfunction, the earliest indicators of cardiovascular pathogenesis, occur in a similar fashion across multiple tissue beds throughout the body, including the skin. Because microvascular dysfunction is a better predictor of long-term outcomes and adverse cardiovascular events than is large vessel disease, an understanding of age-associated changes in the control of the human cutaneous microcirculation is important. This review focuses on 1) the merits of using skin-specific methods and techniques to study vascular function, 2) microvascular changes in aged skin (in particular, the role of the endothelial-derived dilator nitric oxide), and 3) the impact of aging on heat-induced changes in skin vasodilation. While skin blood flow is controlled by multiple, often redundant, mechanisms, our laboratory has used a variety of distinct thermal provocations of this model circulation to isolate specific age-associated changes in vascular function. Skin-specific approaches and techniques, such as intradermal microdialysis coupled with laser-Doppler flowmetry (in vivo) and biochemical analyses of skin biopsy samples (in vitro), have allowed for the targeted pharmacodissection of the mechanistic pathways controlling skin vasoreactivity and study of the impact of aging and disease states. Aged skin has an attenuated ability to vasodilate in response to warm stimuli and to vasoconstrict in response to cold stimuli.

We tested the hypothesis that inhibition of cutaneous sensory nerves would attenuate reflex cutaneous vasodilation in response to an increase in core temperature. Nine subjects were equipped with four microdialysis fibers on the forearm. Two sites were treated with topical anesthetic EMLA cream for 120 min. Sensory nerve inhibition was verified by lack of sensation to a pinprick. Microdialysis fibers were randomly assigned as 1) lactated Ringer (control); 2) 10 mM nitro-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase; 3) EMLA + lactated Ringer; and 4) EMLA + l-NAME. Laser-Doppler flowmetry was used as an index of skin blood flow, and blood pressure was measured via brachial auscultation. Subjects wore a water-perfused suit, and oral temperature was monitored as an index of core temperature. The suit was perfused with 50°C water to initiate whole body heat stress to raise oral temperature 0.8°C above baseline. Cutaneous vascular conductance (CVC) was calculated and normalized to maximal vasodilation (%CVCmax). There was no difference in CVC between control and EMLA sites (67 ± 5 vs. 69 ± 6% CVCmax), but the onset of vasodilation was delayed at EMLA compared with control sites. The l-NAME site was significantly attenuated compared with control and EMLA sites (45 ± 5% CVCmax; P < 0.01). Combined EMLA + l-NAME site (25 ± 6% CVCmax) was attenuated compared with control and EMLA ( P < 0.001) and l-NAME only ( P < 0.01). These data suggest cutaneous sensory nerves contribute to reflex cutaneous vasodilation during the early, but not latter, stages of heat stress, and full expression of reflex cutaneous vasodilation requires functional sensory nerves and NOS.

We tested the hypothesis that cutaneous vasodilation during local skin heating in humans could be manipulated based upon the ability to desensitize TRPV4 ion channels by applying the thermal stimuli in a series of pulses. Each subject was instrumented with intradermal microdialysis probes in the dorsal forearm skin and perfused with 0.9% saline at 1.5 μl/min with local skin temperature controlled with a Peltier unit (9 cm2) at 34°C. Local skin temperature was manipulated for 50 min in two classic ways: a step increase to 38°C (0.1°C/s, n = 10), and a step increase to 42°C (n = 10). To desensitize TRPV4 ion channels local skin temperature was manipulated in the following way: pulsed increase to 38°C (1 pulse per min, 30 s duration, 1.0°C/s, n = 10), and 4) pulsed increase to 42°C (1.0°C/s, n = 9). Skin blood flow (SkBF, laser Doppler) was recorded directly over the middle microdialysis probe and the dialysate from all three probes were collected during baseline (34°C) and each skin heating period. The overall cutaneous vascular conductance (CVC) response to local heating was estimated from the area under the % CVCmax-time curve. The appearance of the neuropeptide calcitonin gene related peptide (CGRP) in dialysate did not change with skin heating in any protocol. For the skin temperature challenge of 34 to 38°C, the area under the % CVCmax-time curve averaged 1196 ± 295 (SD) % CVCmax•min, which was larger than the 656 ± 282% CVCmax•min during pulsed heating (p < 0.05). For the skin temperature challenge of 34 to 42°C, the area under the % CVCmax-time curve averaged 2678 ± 458% CVCmax•min, which was larger than the 1954 ± 533% CVCmax•min during pulsed heating (p < 0.05). The area under the % CVCmax•min curve, was directly proportional to the accumulated local skin thermal stress (in °C•min) (r2 = 0.62, p < 0.05, n = 39). This association indicates a critical role of local integration of thermosensitive receptors in mediating the cutaneous vasodilator response to local skin heating. Given that we saw no differences in the levels of CGRP in dialysate, the role of the vasoactive peptide CGRP in the cutaneous vasodilator response to local skin heating is not supported by our data.

Reflex cutaneous vasodilation in response to passive heating is attenuated in human aging. This diminished response is mediated, in part, by age-associated reductions in endothelial function; however, the contribution of altered skin sympathetic nervous system activity (SSNA) is unknown. We hypothesized that 1) healthy older adults would demonstrate blunted SSNA responses to increased core temperature compared with young adults and 2) the decreased SSNA response would be associated with attenuated cutaneous vasodilation. Reflex vasodilation was elicited in 13 young [23 ± 1 (SE) yr] and 13 older (67 ± 2 yr) adults using a water-perfused suit to elevate esophageal temperature by 1.0°C. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome (the dorsum of foot) were continuously measured. SSNA was normalized to, and expressed as, a percentage of baseline. Cutaneous vascular conductance (CVC) was calculated as flux/mean arterial pressure and expressed as a percentage of maximal CVC (local heating, 43°C). Reflex vasodilation was attenuated in older adults ( P < 0.001). During heating, SSNA increased in both groups ( P < 0.05); however, the response was significantly blunted in older adults ( P = 0.01). The increase in SSNA during heating was linearly related to cutaneous vasodilation in both young ( R2 = 0.87 ± 0.02, P < 0.01) and older ( R2 = 0.76 ± 0.05, P < 0.01) adults; however, slope of the linear regression between ΔSSNA and ΔCVC was reduced in older compared with young (older: 0.05 ± 0.01 vs. young: 0.08 ± 0.01; P < 0.05). These data demonstrate that age-related impairments in reflex cutaneous vasodilation are mediated, in part, by blunted efferent SSNA during hyperthermia.

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.

This study investigated if nitric oxide (NO) and/or prostaglandin (PG) are responsible for cutaneous vasodilation during warm moxibustion-like thermal stimulation (WMTS).For two protocols, two microdialysis membranes were placed in the medial forearm skin. In the first protocol (n=8), the sites were randomly assigned and perfused with N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME), an NO synthase inhibitor or Ringer's solution (control site). Similarly, two microdialysis membranes were placed in the medial forearm skin in the second protocol (n=6). One site was perfused with ketorolac (Keto), the cyclo-oxygenase (COX) pathway inhibitor, and the other site was perfused with Ringer's solution (control site). In both protocols, cutaneous vasodilation was induced using WMTS with an electronic warm moxibustion treatment appliance. After 10 minutes of baseline recording, WMTS was applied to the forearm skin for 20 minutes and recovery was monitored over a period of 20 minutes. Skin blood flow (SkBF) at each site was measured using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure (BP).The study was conducted in a laboratory at the Kansai University of Health Sciences.The subjects were 14 healthy male volunteers.WMTS was applied to the medial forearm skin using an electronic warm moxibustion treatment appliance.SkBF, skin temperature (Tsk), core body temperature (Tc), heart rate (HR), and BP were outcome measures.In the first protocol, peak CVC values during WMTS at the site perfused with l-NAME were significantly decreased, compared to those at the control site (p0.05). In the second protocol, peak CVC values during WMTS did not differ between the control site and the Keto site (p0.05).These data demonstrate that NO is involved in the mechanism of cutaneous vasodilation induced by WMTS. Furthermore, increases in CVC despite inhibition of the COX pathway suggest that PG does not contribute to cutaneous vasodilation during WMTS.

To clarify the influence of internal and skin temperature on the active cutaneous vasodilation during exercise, the body temperature thresholds for the onset of active vasodilation during light or moderate exercise under different ambient temperature conditions were compared. Seven male subjects performed 30 min of a cycling exercise at 20 % or 50 % of peak oxygen uptake in a room maintained at 20, 24, or 28 °C. Esophageal (Tes) and mean skin temperature (Tsk) as measured by a thermocouple, deep thigh temperature (Tdt) by the zero-heat-flow (ZHF) method, and forearm skin blood flow by laser-Doppler flowmetry (LDF) were monitored. The mean arterial pressure (MAP) was also monitored non-invasively, and the cutaneous vascular conductance (CVC) was calculated as the LDF/MAP. Throughout the experiment, the Tsk at ambient temperatures of 20, 24, and 28 °C were approximately 30, 32, and 34 °C, respectively, for both 20 % and 50 % exercise. During 50 % exercise, the Tes or Tdt thresholds for the onset of the increase in CVC were observed to be similar among the 20, 24, and 28 °C ambient conditions. During 20 % exercise, the increase in Tes and Tdt was significantly lower than those found at 50 %, and the onset of the increase in CVC was only observed at 28 °C. These results suggest that the onset of active vasodilation was affected more strongly by the internal or exercising tissue temperatures than by the skin temperatures during exercise performed at a moderate load in comparison to a light load under Tsk variations ranging from 30 °C to 34 °C. Therefore, the modification by skin temperature of the central control on cutaneous vasomotor tone during exercise may differ between different exercise loads.

Mechanisms underlying the cutaneous vasodilation in response to an increase in core temperature remain unresolved. The purpose of this study was to determine a potential contribution of transient receptor potential vanilloid type 1 (TRPV-1) channels to reflex cutaneous vasodilation. Twelve subjects were equipped with four microdialysis fibers on the ventral forearm, and each site randomly received 1) 90% propylene glycol + 10% lactated Ringer (vehicle control); 2) 10 mM l-NAME; 3) 20 mM capsazepine to inhibit TRPV-1 channels; 4) combined 10 mM l-NAME + 20 mM capsazepine. Whole body heating was achieved via water-perfused suits sufficient to raise oral temperature at least 0.8°C above baseline. Maximal skin blood flow was achieved by local heating to 43°C and infusion of 28 mM nitroprusside. Systemic arterial pressure (SAP) was measured, and skin blood flow was monitored via laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/SAP and normalized to maximal vasodilation (%CVCmax). Capsazepine sites were significantly reduced compared with control (50 ± 4%CVCmax vs. 67 ± 5%CVCmax, respectively; P < 0.05). l-NAME (33 ± 3%CVCmax) and l-NAME + capsazepine (30 ± 4%CVCmax) sites were attenuated compared with control ( P < 0.01) and capsazepine ( P < 0.05); however, there was no difference between l-NAME and combined l-NAME + capsazepine. These data suggest TRPV-1 channels participate in reflex cutaneous vasodilation and TRPV-1 channels may account for a portion of the NO component. TRPV-1 channels may have a direct neural contribution or have an indirect effect via increased arterial blood temperature. Whether the TRPV-1 channels directly or indirectly contribute to reflex cutaneous vasodilation remains uncertain.

The aim of this study was to assess whether the three-compartment model of mean body temperature (Tb3) calculated from the esophageal temperature (Tes), temperature in deep tissue of exercising muscle (Tdt), and mean skin temperature (Tsk) has the potential to provide a better match with the thermoregulatory responses than the two-component model of mean body temperature (Tb2) calculated from Tes and Tsk. Seven male subjects performed 40 min of a prolonged cycling exercise at 30% maximal oxygen uptake at 21°C or 31°C (50% relative humidity). Throughout the experiment, Tsk, Tb2, Tb3, and Tdt were significantly (P < 0.01) lower at 21°C than at 31°C temperature conditions, while Tes was similar under both conditions. During exercise, an increase in cutaneous vascular conductance (skin blood flow / mean arterial pressure) over the chest (%CVCc) was observed at both 21°C and 31°C, while no increase was observed at the forearm at 21°C. Furthermore, the Tb3 and Tdt threshold for the onset of the increase in %CVCc was similar, but the Tes and Tb2 threshold differed significantly (P < 0.05) between the conditions tested. These results suggest that active cutaneous vasodilation at the chest is related more closely to Tb3 or Tdt than that measured by Tes or Tb2 calculated by Tes and Tsk during exercise at both 21°C and 31°C.

Hypoxia decreases core body temperature in animals and humans during cold exposure. In addition, hypoxia increases skin blood flow in thermoneutral conditions, but the impact of hypoxic vasodilation on vasoconstriction during cold exposure is unknown. In this study, skin blood flow was assessed using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure and normalized to baseline ( n = 7). Subjects were exposed to four different conditions in the steady state (normoxia and poikilocapnic, isocapnic, and hypercapnic hypoxia) and were cooled for 10 min using a water-perfused suit in each condition. CVC increased during all three hypoxic exposures (all P < 0.05 vs. baseline), and the magnitude of these steady-state responses was not affected by changes in end-tidal CO2 levels. During poikilocapnic and hypercapnic hypoxia, cold exposure reduced CVC to the same levels observed during normoxic cooling ( P > 0.05 vs. normoxia), whereas CVC remained elevated throughout cold exposure during isocapnic hypoxia ( P < 0.05 vs. normoxia). The magnitude of vasoconstriction during cold stress was similar in all conditions ( P > 0.05). Thus the magnitude of cutaneous vasodilation during steady-state hypoxia is not affected by CO2 responses. In addition, the magnitude of reflex vasoconstriction is not altered by hypoxia, such that the upward shift in skin blood flow (hypoxic vasodilation) is maintained during whole body cooling.

We previously identified impaired cutaneous vasodilation and sweating in grafted skin 5 to 9 months postsurgery. The aim of this investigation was to test the hypothesis that cutaneous vasodilation, but not sweating, is restored as the graft heals. Skin blood flow and sweat rate were assessed from grafted skin and adjacent noninjured skin in three groups of subjects: 5 to 9 months postsurgery (n = 13), 2 to 3 years postsurgery (n = 13), and 4 to 8 years postsurgery (n = 13) during three separate protocols: 1) whole-body heating and cooling, 2) local administration of vasoactive drugs, and 3) local heating and cooling. Cutaneous vasodilation and sweating during whole-body heating were significantly lower (P < .001) in grafted skin when compared with noninjured skin across all groups and demonstrated no improvements with recovery time postsurgery. Maximal endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) cutaneous vasodilation remained attenuated (P < .001) in grafted skin up to 4 to 8 years postsurgery, indicating postsynaptic impairments. In grafted skin, cutaneous vasoconstriction during whole-body and local cooling was preserved, whereas vasodilation to local heating was impaired, regardless of the duration postsurgery. Split-thickness skin grafts have impaired cutaneous vasodilation and sweating up to 4 to 8 years postsurgery, thereby limiting the capability of this skin’s contribution to thermoregulation during a heats stress. In contrast, grafted skin has preserved vasoconstrictor capacity.

Microdialysis enables in-depth mechanistic study of the cutaneous circulation in humans. However, whether the insertion or presence of the microdialysis fiber (MDF) affects the skin circulation or its responses is unknown. We tested whether the cutaneous vascular response to whole body heating (WBH) was affected by MDF or by pretreatment with ice (part 1) or local anesthesia (LA; part 2). Eleven subjects participated, 9 in part 1 and 8 in part 2 (5 participated in both). In both parts, four sites on the forearm were selected, providing untreated control, MDF only, ice or LA only, and combined MDF plus ice or LA. A tube-lined suit controlled whole body skin temperature, which was raised to approximately 38 degrees C for WBH. Skin sites were instrumented with laser-Doppler flow probes. Data were expressed as cutaneous vascular conductance (CVC). Baseline levels were not different among sites (P0.05). In part 1, the internal temperature for the onset of vasodilation was higher (P0.05) with MDF with or without ice pretreatment than at untreated control sites (control 36.6 +/- 0.1 degrees C, Ice 36.5 +/- 0.1, MDF 36.8 +/- 0.1 degrees C, and Ice+MDF 36.8 +/- 0.1 degrees C). Peak CVC during WBH was decreased (P0.05) by MDF (control 73 +/- 7 vs. MDF 59 +/- 6% of maximal CVC). Ice (73 +/- 6% of maximal CVC) or Ice+MDF (69 +/- 6% of maximal CVC) did not affect (P0.05) peak CVC compared with control. In part 2, the temperature threshold for the onset of vasodilation was increased by MDF with or without LA treatment and by LA alone (P0.05; control 36.6 +/- 0.1 degrees C, MDF 36.7 +/- 0.1 degrees C, LA 36.8 +/- 0.1 degrees C, and LA+MDF 36.8 +/- 0.1 degrees C). Peak CVC was decreased by MDF (control 69 +/- 6% of maximal CVC vs. MDF 58 +/- 8% of maximal CVC; P0.05). LA only (65 +/- 10% of maximal CVC) or MDF in the presence of LA (73 +/- 12% of maximal CVC) did not affect (P0.05) peak CVC compared with control. Thus LA or MDF increases the temperature threshold for the onset of vasodilation. MDF alone decreases the peak vasodilator response in CVC to WBH; however, this attenuation did not occur if ice or LA is used before MDF placement. Ice or LA alone do not affect the peak response in CVC to WBH. How those treatments prevent or reverse the effect of MDF placement is presently unclear.

Contains fulltext : 80850thijssen.pdf (Publisher’s version ) (Closed access) Spinal cord injury (SCI) induces vascular adaptations below the level of the lesion, such as impaired cutaneous vasodilation. However, the mechanisms underlying these differences are unclear. The aim of this study is to examine arm and leg cutaneous vascular conductance (CVC) responses to local heating in 17 able-bodied controls (39 +/- 13 yr) and 18 SCI subjects (42 +/- 8 yr). SCI subjects were counterbalanced for functional electrostimulation (FES) cycling exercise (SCI-EX, n = 9) or control (SCI-C, n = 9) and reanalyzed after 8 wk. Arm and leg skin blood flow were measured by laser-Doppler flowmetry during local heating (42 degrees C), resulting in an axon-reflex mediated first peak, nadir, and a primarily nitric oxide-dependent plateau phase. Data were expressed as a percentage of maximal CVC (44 degrees C). CVC responses to local heating in the paralyzed leg, but also in the forearm of SCI subjects, were lower than in able-bodied controls (P < 0.05 and 0.01, respectively). The 8-wk intervention did not change forearm and leg CVC responses to local heating in SCI-C and SCI-EX, but increased femoral artery diameter in SCI-EX (P < 0.05). Interestingly, findings in skin microvessels contrast with conduit arteries, where physical (in)activity contributes to adaptations in SCI. The lower CVC responses in the paralyzed legs might suggest a role for inactivity in SCI, but the presence of impaired CVC responses in the normally active forearm suggests other mechanisms. This is supported by a lack of adaptation in skin microcirculation after FES cycle training. This might relate to the less frequent and smaller magnitude of skin blood flow responses to heat stimuli, compared with controls, than physical inactivity per se.

Human skin blood flow increases in response to increased body core and local skin temperature via distinct reflex and local mechanisms requiring functional nitric oxide (NO) for full expression. The mechanisms mediating cutaneous vasodilation are impaired with primary aging, resulting in attenuated vasodilation. This article highlights recent findings of how age-related vascular impairments in NO signaling contribute to attenuated cutaneous vasodilation.

The aim of this investigation was to identify the consequences of skin grafting on cutaneous vasodilation and sweating in split-thickness grafted skin during indirect whole-body heating 5 to 9 months after surgery. In addition, thermoregulatory function was examined at donor skin sites on a separate day. Skin blood flow and sweat rate (SR) were assessed from both grafted (n = 14) or donor skin (n = 11) and compared with the respective adjacent control skin during indirect whole-body heating. Cutaneous vascular conductance (CVC) was calculated from the ratio of skin blood flow (arbitrary units; au) to mean arterial pressure. Whole-body heating significantly increased internal temperature (37.0 +/- 0.1 degrees C to 37.8 +/- 0.1 degrees C; P < .05). Cutaneous vasodilation (ie, the increase in CVC from baseline, deltaCVC) during whole-body heating was significantly attenuated in grafted skin (deltaCVC = 0.14 +/- 0.15 au/mm Hg) compared with adjacent control skin (deltaCVC = 0.84 +/- 0.11 au/mm Hg; P < .05). Increases in sweat rate (deltaSR) were also significantly lower in grafted skin (deltaSR = 0.08 +/- 0.08 mg/cm2/min) compared with adjacent control skin (deltaSR = 1.16 +/- 0.20 mg/ cm2/min; P < .05). Cutaneous vasodilation and sweating during heating were not significantly different between donor sites (deltaCVC = 0.71 +/- 0.19 au/mm Hg; deltaSR = 1.04 +/- 0.15 mg/cm2/min) and adjacent control skin (deltaCVC = 0.50 +/- 0.10 au/mm Hg; deltaSR = 0.83 +/- 0.17 mg/cm2/min). Greatly attenuated or absence of cutaneous vasodilation and sweating suggests impairment of thermoregulatory function in grafted skin, thereby, diminishing the contribution of this skin to overall temperature control during a heat stress.

Skin blood flow and sweating are two key thermoregulatory responses that help regulate body temperature in heat-stressed human beings. Adjustments in skin blood flow and sweating in response to thermal stimuli are mediated by local and reflex neural mechanisms (Johnson et al. 2014). Local thermosensitive mechanisms are important, as the application of heating to a particular area of the skin results in a localized elevation of blood flow and sweating in the heated skin. However, the precise pathways underpinning heat loss responses to heat stress, particularly those involving ATP as a mediator signal, are not fully established or understood. Heat stress-induced hyperthermia is associated with increases in intravascular ATP and accompanied by vasodilatation of the human skin and deep limb tissue vasculatures (Pearson et al. 2011; Heinonen et al. 2011). This supports a mechanistic coupling between the rise in intravascular ATP and the concomitant increase in local perfusion (Kalsi & Gonzalez-Alonso, 2012). However, sympathetic cholinergic nerves, which are known to modulate heat loss responses, co-release ATP with acetylcholine. These sensory nerves are therefore potential sources of ATP in the dermal interstitium. This raises the possibility that ATP may act as a thermal mediator signal, involved in the regulation of vasomotor and sudomotor activity in conditions of hyperthermia. In support of this idea, intradermal administration of ATP has been shown to induce cutaneous vasodilatation in human beings in vivo (Wingo et al. 2010), but the downstream mediators and its effect on sweating have not been investigated. Mechanistically, ATP can bind to P2Y purinergic receptors located in the cutaneous vasculature, and the sweat gland, and trigger cutaneous vasodilatation and increase sweating via at least three pathways: (i) activation of nitric oxide synthase (NOS), (ii) activation of cyclooxygenase (COX) and/or (iii) via the action of the ATP degradation compound adenosine. In this issue of The Journal of Physiology, Fujii et al. (2015) report the findings from an outstanding series of integrative physiology studies in human beings. The authors systematically investigated the roles of NOS and COX in the cutaneous vascular and sweating responses to intradermal administration of ATP, as well as the contribution of adenosine to ATP-induced skin vasodilatation in vivo. A major finding was that intradermal ATP infusion at a rate of 120 and 1200 nmol min−1 causes significant cutaneous vasodilatation. Co-infusion of the NOS inhibitor Nω–nitro-l-arginine (l-NNA) blunted about one-fourth of the ATP-evoked vasodilator response, implicating NOS as a mediator. The study also excluded two other potential regulatory pathways; blockade of COX or adenosine with co-infusion of ketorolac or theophylline did not alter the vasodilator response to intradermal ATP infusion. Lastly, none of the study protocols increased sweating. These observations collectively advance the basic physiological understanding of the control of skin blood flow and sweating. By showing that part of the vasodilator response to intradermal ATP administration is mediated by NOS and by providing conclusive evidence that ATP does not directly increase sweating in vivo, these data suggest that skin blood flow and sweating are not regulated by the same thermal mediator signal. The physiological relevance of interstitial ATP on thermal hyperaemia was not addressed in the study of Fujii et al. (2015). ATP needs to accumulate in the dermal interstitium for this ubiquitous molecule to exert its cutaneous vasodilator effects directly by binding to interstitial purinergic receptors. However, recent evidence suggests that local heating does not result in an accumulation of ATP in the interstitial space of human skin, and thus such accumulation is not necessary for local thermal hyperaemia to occur (Gifford et al. 2012). This observation and the additional finding by Fujii and coworkers that the intradermal administration of ATP at low infusion rates (0.12–12 nmol min−1) does not increase skin blood flow indicate that under physiological conditions ATP-mediated cutaneous vasodilatation is more likely to occur via the activation of purinergic receptors residing in the vascular endothelium. Although further research is needed to establish the physiological relevance of intravascular versus interstitial ATP in thermoeffector activity, the timely investigation of Fujii et al. (2015) highlights the capacity of ATP to be the elusive thermal mediator igniting skin perfusion in heat-stressed human beings, but not the signal that increases sweating.

The specific mechanisms by which skin blood flow increases in response to a rise in core body temperature via cutaneous active vasodilation are poorly understood. The primary purpose of this study was to determine whether the cyclooxygenase (COX) pathway contributes to active vasodilation during whole body heat stress ( protocol 1; n = 9). A secondary goal was to verify that the COX pathway does not contribute to the cutaneous hyperemic response during local heating ( protocol 2; n = 4). For both protocols, four microdialysis fibers were placed in forearm skin. Sites were randomly assigned and perfused with 1) Ringer solution (control site); 2) ketorolac (KETO), a COX-1/COX-2 pathway inhibitor; 3) NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor; and 4) a combination of KETO and l-NAME. During the first protocol, active vasodilation was induced using whole body heating with water-perfused suits. The second protocol used local heaters to induce a local hyperemic response. Red blood cell flux (RBC flux) was indexed at all sites using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC; RBC flux/mean arterial pressure) was normalized to maximal vasodilation at each site. During whole body heating, CVC values at sites perfused with KETO (43 ± 9% CVCmax), l-NAME (35 ± 9% CVCmax), and combined KETO/l-NAME (22 ± 8% CVCmax) were significantly decreased with respect to the control site (59 ± 7% CVCmax) ( P < 0.05). Additionally, CVC at the combined KETO/l-NAME site was significantly decreased compared with sites infused with KETO or l-NAME alone ( P < 0.05). In the second protocol, the hyperemic response to local heating did not differ between the control site and KETO site or between the l-NAME and KETO/l-NAME site. These data suggest that prostanoids contribute to active vasodilation, but do not play a role during local thermal hyperemia.

Objective: Pressure-induced vasodilation (PIV) allows skin blood flow to increase in response to locally applied pressure and may be protective against pressure ulcers. We previously showed that PIV was absent in 1-week diabetic mice exhibiting no neuropathy. Our aim was to determine whether the diabetes-induced PIV alteration could be prevented. Methods and results: Diabetic mice received no treatment or a daily treatment with either sorbinil, alagebrium or alpha-lipoic acid (LPA) for 1 week. Laser Doppler flowmetry was used to evaluate PIV as well as endothelium-dependent vasodilation following iontophoretic delivery of acetylcholine (ACh). The effect of each treatment on oxidative stress was examined by plasma 8-isoprostane assay. LPA was the sole treatment to prevent both PIV and ACh vasodilation alterations, with a significant reduction of oxidative stress in diabetic mice. Both PIV and ACh-vasodilation were abolished in LPA-treated diabetic mice following injection of N ω-nitro-l-arginine ( p

Age-related changes in neurogenic vasodilation mediated by sensory nerves may alter local skin blood flow (SkBF) responses in older individuals. The purpose of this study was to determine the age-specific modification of cutaneous vasodilation by capsaicin-sensitive primary afferent (CSPA) nerves during local heating. Nine young (18-30 yr), eight middle-aged (40-55 yr), and eight older (65-80 yr) healthy men participated in the experiments. Two local-heating protocols (rapid and slow) were performed before and after 1 wk of capsaicin pretreatment (CP), used to desensitize CSPAs. All temperatures were below those that elicit pain. SkBF was measured with a laser-Doppler imager and indexed to percentage of maximal cutaneous vascular conductance (%CVCmax). CP caused a significant reduction in %CVCmax in the middle-aged and older groups during slow heating ( P < 0.05), without affecting %CVCmax in the young group. During rapid heating, CP significantly reduced (53.9 ± 4.4 vs. 74.4 ± 7.4% CVCmax, P < 0.05), but did not abolish, the initial sensory nerve-mediated rise in SkBF in the young group. No significant effects of CP on SkBF were observed during rapid heating in the middle-aged or older groups. These results indicate that, with advanced age, CSPA activity is more important to the maximal SkBF response during prolonged local heating, whereas it has a reduced role in the initial SkBF peak elicited by rapid local heating. In summary, CSPA activity contributes modestly to the overall SkBF response to local heating in an age-specific manner.

The activation of cutaneous vasodilation and sweating are essential to the regulation of core temperature during exercise in the heat. We assessed the effect of graduated compression induced by wearing stockings on cutaneous vasodilation and sweating during exercise in the heat (30°C). On two separate occasions, nine young males exercised for 45 min or until core temperature reached ~1.5°C above baseline resting while wearing either (1) stockings causing graduated compression (graduate compression stockings, GCS), or (2) loose‐fitting stockings without compression (Control). Forearm vascular conductance was evaluated by forearm blood flow (venous occlusion plethysmography) divided by mean arterial pressure to estimate cutaneous vasodilation. Sweat rate was estimated using the ventilated capsule technique. Core and skin temperatures were measured continuously. Exercise duration was similar between conditions (Control: 42.2 ± 3.6 min vs. GCS: 42.2 ± 3.6 min, P = 1.00). Relative to Control, GCS increased forearm vascular conductance during the late stages (≥30 min) of exercise (e.g., at 40 min, 15.6 ± 5.6 vs. 18.0 ± 6.0 units, P = 0.01). This was paralleled by a greater sensitivity (23.1 ± 9.1 vs. 32.1 ± 15.0 units°C −1 , P = 0.043) and peak level (14.1 ± 5.1 vs. 16.3 ± 5.7 units, P = 0.048) of cutaneous vasodilation as evaluated from the relationship between forearm vascular conductance with core temperature. However, the core temperature threshold at which an increase in forearm vascular conductance occurred did not differ between conditions (Control: 36.9 ± 0.2 vs. GCS: 37.0 ± 0.3°C, P = 0.13). In contrast, no effect of GCS on sweating was measured (all P > 0.05). We show that the use of GCS during exercise in the heat enhances cutaneous vasodilation and not sweating.

Local heating of the skin is commonly used to assess cutaneous microvasculature function. Controversy exists as to whether there are limb or sex differences in the nitric oxide (NO)-dependent contribution to this vasodilation, as well as the NO synthase (NOS) isoform mediating the responses. We tested the hypotheses that 1) NO-dependent vasodilation would be greater in the calf compared with the forearm; 2) total NO-dependent dilation would not be different between sexes within limb; and 3) women would exhibit greater neuronal NOS (nNOS)-dependent vasodilation in the calf. Two microdialysis fibers were placed in the skin of the ventral forearm and the calf of 19 (10 male and 9 female) young (23 ± 1 yr) adults for the local delivery of Ringer solution (control) or 5 mM Nω-propyl-l-arginine (NPLA; nNOS inhibition). Vasodilation was induced by local heating (42°C) at each site, after which 20 mM NG-nitro-l-arginine methyl ester (l-NAME) was perfused for within-site assessment of NO-dependent vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial pressure and normalized to maximum (28 mM sodium nitroprusside, 43°C). Total NO-dependent vasodilation in the calf was lower compared with the forearm in both sexes (Ringer: 42 ± 5 vs. 62 ± 4%; P < 0.05; NPLA: 37 ± 3 vs. 59 ± 5%; P < 0.05) and total NO-dependent vasodilation was lower in the forearm for women (Ringer: 52 ± 6 vs. 71 ± 4%; P < 0.05; NPLA: 47 ± 6 vs. 68 ± 5%; P < 0.05). NPLA did not affect total or NO-dependent vasodilation across limbs in either sex ( P > 0.05). These data suggest that the NO-dependent component of local heating-induced cutaneous vasodilation is lower in the calf compared with the forearm. Contrary to our original hypothesis, there was no contribution of nNOS to NO-dependent vasodilation in either limb during local heating.

The hypothesis that baroreceptor unloading during dynamic limits cutaneous vasodilation by withdrawal of active vasodilator activity was tested in seven human subjects. Increases in forearm skin blood flow (laser-Doppler velocimetry) at skin sites with (control) and without alpha-adrenergic vasoconstrictor activity (vasodilator only) and in arterial blood pressure (noninvasive) were measured and used to calculate cutaneous vascular conductance (CVC). Subjects performed two similar dynamic exercise (119 +/- 8 W) protocols with and without baroreceptor unloading induced by application of -40 mmHg lower body negative pressure (LBNP). The LBNP condition was reversed (i.e., either removed or applied) after 15 min while exercise continued for an additional 15 min. During exercise without LBNP, the increase in body core temperature (esophageal temperature) required to elicit active cutaneous vasodilation averaged 0.25 +/- 0.08 and 0.31 +/- 0.10 degrees C (SE) at control and vasodilator-only skin sites, respectively, and increased to 0.44 +/- 0.10 and 0.50 +/- 0.10 degrees C (P0.05 compared with without LBNP) during exercise with LBNP. During exercise baroreceptor unloading delayed the onset of cutaneous vasodilation and limited peak CVC at vasodilator-only skin sites. These data support the hypothesis that during exercise baroreceptor unloading modulates active cutaneous vasodilation.

It has previously been observed that (a) following 15 min of intense exercise, esophageal temperature (Tes), remains elevated at a plateau value equal to that at which active vasodilation had occurred during exercise (i.e., esophageal temperature threshold for cutaneous vasodilation [ThVD]); and (b) exercise/recovery cycles of identical intensity and duration, when sequential, result in progressively higher Tes at the beginning and end of exercise. In the latter case, parallel increases in both the exercise ThVD and postexercise plateau of Tes were noted. This study was conducted to determine if the elevated postexercise Tes is related to increases in whole-body heat content. On separate occasions, 9 subjects completed 3 bouts of treadmill exercise at 70% [Formula: see text] max, 29 °C ambient temperature. Each exercise bout lasted either 15, 30, or 45 min and was followed by 60 min of inactive recovery. Esophageal temperatures were similar at the start of each exercise bout, but the rise in Tes during exercise nearly doubled from 1.0 °C after 15 min of exercise to 1.9 °C after 45 min of exercise. There were no intercondition differences among the exercise ThVD (∼0.36 °C above baseline) or postexercise plateau values for Tes (∼0.40 °C above baseline). Thus the relationship between the ThVD during exercise and the postexercise Tes did not appear to be dependent on changes in whole-body heat content as produced by endogenous heating during exercise of different duration. Key words: cutaneous vasodilation threshold, exercise hyperthermia. temperature elevation

Whether nitric oxide (NO) is involved in cutaneous active vasodilation during hyperthermia in humans is unclear. We tested for a role of NO in this process during heat stress (water-perfused suits) in seven healthy subjects. Two forearm sites were instrumented with intradermal microdialysis probes. One site was perfused with the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) dissolved in Ringer solution to abolish NO production. The other site was perfused with Ringer solution only. At those sites, skin blood flow (laser-Doppler flowmetry) and sweat rate were simultaneously and continuously monitored. Cutaneous vascular conductance, calculated from laser-Doppler flowmetry and mean arterial pressure, was normalized to maximal levels as achieved by perfusion with the NO donor nitroprusside through the microdialysis probes. Under normothermic conditions,l-NAME did not significantly reduce cutaneous vascular conductance. During hyperthermia, with skin temperature held at 38–38.5°C, internal temperature rose from 36.66 ± 0.10 to 37.34 ± 0.06°C ( P < 0.01). Cutaneous vascular conductance at untreated sites increased from 12 ± 2 to 44 ± 5% of maximum, but only rose from 13 ± 2 to 30 ± 5% of maximum at l-NAME-treated sites ( P < 0.05 between sites) during heat stress. l-NAME had no effect on sweat rate ( P > 0.05). Thus cutaneous active vasodilation requires functional NO synthase to achieve full expression.

Menopausal hot flashes can seriously disrupt the lives of symptomatic women. The physiological mechanisms of the hot flash efferent responses, particularly in the cutaneous circulation, are not completely understood. The aim of this study was to examine the mechanisms of increases in skin blood flow during the postmenopausal hot flash in symptomatic women.Healthy postmenopausal women rested in a temperature-controlled laboratory while responses before and during hot flashes were recorded for three unique protocols. In protocols 1 and 2, women were locally pretreated with an intradermal injection of botulinum toxin A (BTX; blocks the release of neurotransmitters from sympathetic cholinergic nerves) in the forearm (protocol 1) and in the glabellar region (protocol 2). In protocol 3, skin sympathetic nerve activity from the peroneal nerve was recorded, along with skin blood flow and sweating within the region innervated by that neural signal. Skin blood flow was indexed using laser-Doppler flowmetry at the BTX-treated and adjacent untreated control sites. The onset of a hot flash was objectively identified as a transient and pronounced increase in sternal sweat rate.The increases in forearm (protocol 1) and glabellar skin (protocol 2) blood flow during hot flashes were attenuated at the BTX sites relative to the adjacent untreated sites (P0.05 for both protocols). In protocol 3, skin sympathetic nerve activity significantly increased during hot flashes and returned to pre-hot flash levels after the hot flashes.Increases in skin blood flow during postmenopausal hot flashes are neurally mediated primarily through BTX-sensitive nerves, presumably sympathetic cholinergic.