Endothelial nitric oxide synthase mediates the nitric oxide component of reflex cutaneous vasodilatation during dynamic exercise in humans

McNamara, Tanner C.; Keen, Jeremy T.; Simmons, Grant H.; Alexander, Lacy M.; Wong, Brett J.

doi:10.1113/jphysiol.2014.272898

Cited by 63 publications

(65 citation statements)

References 31 publications

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“…were the first to report that cutaneous vasodilation during exercise is of reflex origin 87 ; however, studies investigating mechanisms of cutaneous vasodilation during dynamic exercise are sparse. A recent study from our laboratory suggests cutaneous vasodilation during dynamic exercise contains a significant NO component that is similar in magnitude as that observed with passive heat stress 46 (Fig. 4).…”

Section: Early Studies Of Human Temperature Regulation and Skin Bloodsupporting

confidence: 80%

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Current concepts of active vasodilation in human skin

Wong

Hollowed

2016

Temperature

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In humans, an increase in internal core temperature elicits large increases in skin blood flow and sweating. The increase in skin blood flow serves to transfer heat via convection from the body core to the skin surface while sweating results in evaporative cooling of the skin. Cutaneous vasodilation and sudomotor activity are controlled by a sympathetic cholinergic active vasodilator system that is hypothesized to operate through a co-transmission mechanism. To date, mechanisms of cutaneous active vasodilation remain equivocal despite many years of research by several productive laboratory groups. The purpose of this review is to highlight recent advancements in the field of cutaneous active vasodilation framed in the context of some of the historical findings that laid the groundwork for our current understanding of cutaneous active vasodilation.

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Section: Early Studies Of Human Temperature Regulation and Skin Bloodsupporting

confidence: 80%

“…3). In contrast, recent data from our laboratory indicates eNOS contributes to reflex cutaneous vasodilation during dynamic exercise 46 (see below). Whether the NO derived from nNOS is released from sympathetic cholinergic nerves, nitroxidergic nerves, or some other source remains unknown.…”

Section: Early Studies Of Human Temperature Regulation and Skin Bloodmentioning

confidence: 63%

Current concepts of active vasodilation in human skin

Wong

Hollowed

2016

Temperature

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“…; McNamara et al . ), despite the fact that elevated levels of circulating malondialdehyde have been reported at this exercise intensity, although to a lesser extent than exercise at 75%

{\dot{V}}_{O_{2} peak}

(Seifi‐Skishahr et al . ).…”

Section: Discussionmentioning

confidence: 99%

Local infusion of ascorbate augments NO‐dependent cutaneous vasodilatation during intense exercise in the heat

Meade

Fujii

Alexander

et al. 2015

The Journal of Physiology

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Key pointsr Recent work demonstrates that nitric oxide (NO) contributes to cutaneous vasodilatation during moderate (400 W of metabolic heat production) but not high (700 W of metabolic heat production) intensity exercise bouts performed in the heat (35°C).r The present study evaluated whether the impairment in NO-dependent cutaneous vasodilatation was the result of a greater accumulation of reactive oxygen species during high (700 W of metabolic heat production) relative to moderate (500 W of metabolic heat production) intensity exercise.r It was shown that local infusion of ascorbate (an anti-oxidant) improves NO-dependent forearm cutaneous vasodilatation during high intensity exercise in the heat.r These findings provide novel insight into the physiological mechanisms governing cutaneous blood flow during exercise-induced heat stress and provide direction for future research exploring whether oxidative stress underlies the impairments in heat dissipation that may occur in older adults, as well as in individuals with pathophysiological conditions such as type 2 diabetes.Abstract Nitric oxide (NO)-dependent cutaneous vasodilatation is reportedly diminished during exercise performed at a high (700 W) relative to moderate (400 W) rate of metabolic heat production. The present study evaluated whether this impairment results from increased oxidative stress associated with an accumuluation of reactive oxygen species (ROS) during high intensity exercise. On two separate days, 11 young (mean ± SD, 24 ± 4 years) males cycled in the heat (35°C) at a moderate (500 W) or high (700 W) rate of metabolic heat production. Each session included two 30 min exercise bouts followed by 20 and 40 min of recovery, respectively. Cutaneous vascular conductance (CVC) was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control); (2) 10 mM ascorbate (Ascorbate); (3) 10 mM L-NAME; or (4) 10 mM ascorbate + 10 mM L-NAME (Ascorbate + L-NAME). At the end of each 500 W exercise bout, CVC was attenuated with L-NAME (ß35% CVC max ) and Ascorbate + L-NAME (ß43% CVC max ) compared to Control (ß60% CVC max ; all P < 0.04); however, Ascorbate did not modulate CVC during exercise (ß60% CVC max ; both P > 0.87). Conversely, CVC was elevated with Ascorbate (ß72% CVC max ; both P < 0.03) but remained similar to Control (ß59% CVC max ) with L-NAME (ß50% CVC max ) and Ascorbate + L-NAME (ß47% CVC max ; all P > 0.05) at the end of both 700 W exercise bouts. We conclude that oxidative stress associated with an accumulation of ascorbate-sensitive ROS impairs NO-dependent cutaneous vasodilatation during intense exercise.

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“…Nitric oxide synthase (NOS) and cyclo-oxygenase (COX) are two key enzymes that can modulate cutaneous vascular tone (Holowatz et al 2005;Kellogg et al 2005;McCord et al 2006;Lenasi & Strucl, 2008;McNamara et al 2014;Cavka et al 2015) as well as sweating (Lee & Mack, 2006;Welch et al 2009;Fujii et al 2014;Stapleton et al 2014). To the best of our knowledge, no study has investigated whether these enzymes contribute to cutaneous vasodilatation and sweating in response to PAR2 activation.…”

Section: Introductionmentioning

confidence: 99%

Activation of protease‐activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo‐oxygenase

Fujii

McNeely

Zhang

et al. 2017

Experimental Physiology

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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 -nitro-l-arginine (NOS inhibitor); (iii) 10 mm ketorolac (COX inhibitor); or (iv) a combination of both inhibitors. At all sites, a PAR2 agonist (SLIGKV-NH ) was co-administered in a dose-dependent fashion (0.06, 0.18, 0.55, 1.66 and 5 mm, each for 25 min). The highest dose of SLIGKV-NH (5 mm) increased CVC from baseline at the control site (P ≤ 0.05). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition regardless of the presence or absence of simultaneous COX inhibition (both P ≤ 0.05). However, COX inhibition alone did not affect the PAR2-mediated increase in CVC (P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV-NH (all P > 0.05). We show that in normothermic resting humans in vivo, PAR2 activation does not increase sweat rate, whereas it does modulate cutaneous vasodilatation through NOS-dependent mechanisms.

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Endothelial nitric oxide synthase mediates the nitric oxide component of reflex cutaneous vasodilatation during dynamic exercise in humans

Cited by 63 publications

References 31 publications

Current concepts of active vasodilation in human skin

Current concepts of active vasodilation in human skin

Local infusion of ascorbate augments NO‐dependent cutaneous vasodilatation during intense exercise in the heat

Activation of protease‐activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo‐oxygenase

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