The initial, rapid increase in skin blood flow in response to direct application of heat is thought to be mediated by an axon reflex, which is dependent on intact cutaneous sensory nerves. We tested the hypothesis that inhibition of transient receptor potential vanilloid type 1 (TRPV-1) channels, which are putative channels located on sensory nerves, would attenuate the skin blood flow response to local heating in humans. Ten subjects were equipped with four microdialysis fibres which were randomly assigned one of four treatments: (1) vehicle control (90% propylene glycol + 10% lactated Ringer solution); (2) 20 mm capsazepine to inhibit TRPV-1 channels; (3) 10 mm l-NAME to inhibit NO synthase; and (4) combined 20 mm capsazepine + 10 mm l-NAME. Following baseline measurements, the temperature of skin heaters was increased from 33• C to 42• C at a rate of 1.0 • C every 10 s and local temperature was held at 42• C for 20-30 min until a stable plateau in skin blood flow was achieved. An index of skin blood flow was measured directly over each microdialysis site via laser-Doppler flowmetry (LDF). Beat-by-beat blood pressure was measured via photoplethysmography and verified via automated brachial auscultation. At the end of the local heating protocol, temperature of the heaters was increased to 43• C and 28 mm nitroprusside was infused to achieve maximal vasodilatation. Cutaneous vascular conductance (CVC) was calculated as LDF/mean arterial pressure and normalized to maximal values (%CVC max ). Initial peak in capsazepine (44 ± 4%CVC max ), l-NAME (56 ± 4%CVC max ) and capsazepine + l-NAME (32 ± 6%CVC max ) sites was significantly attenuated compared to control (87 ± 5%CVC max ; P < 0.001 for all conditions). The plateau phase of thermal hyperaemia was significantly attenuated in capsazepine (73 ± 6%CVC max ), l-NAME (47 ± 5%CVC max ) and capsazepine + l-NAME (31 ± 7%CVC max ) sites compared to control (92 ± 5%CVC max ; P < 0.001 for all conditions). These data suggest TRPV-1 channels contribute substantially to the initial peak and modestly to the plateau phases of thermal hyperaemia. These data further suggest a portion of the NO component of thermal hyperaemia may be due to activation of TRPV-1 channels.

Mechanisms underlying the robust cutaneous vasodilatation in response to local heating of human skin remain unresolved. Adenosine receptor activation has been shown to induce vasodilatation via nitric oxide, and a substantial portion of the plateau phase to local heating of human skin has been shown to be dependent on nitric oxide. The purpose of this study was to investigate a potential role for adenosine receptor activation in cutaneous thermal hyperaemia in humans. Six subjects were equipped with four microdialysis fibres on the ventral forearm. Sites were randomly assigned to receive one of the following four treatments: (1) lactated Ringer solution to serve as a control; (2) 4 mm theophylline, a competitive, non-selective A 1 /A 2 adenosine receptor antagonist; (3) 10 mm N ω -nitro-l-arginine methyl ester (l-NAME) to inhibit NO synthase; or (4) combined 4 mm theophylline + 10 mm l-NAME. Following baseline measurements, each site was locally heated from a baseline temperature of 33• C to 42• C at a rate of 1 • C (10 s) −1 , and skin blood flow was monitored via laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF divided by mean arterial pressure and normalized to maximal values (CVC max ) via local heating to 43• C and infusion of 28 mm sodium nitroprusside. The initial peak was significantly reduced in theophylline (68 ± 2% CVC max ) and l-NAME sites (54 ± 5% CVC max ) compared with control sites (81 ± 2% CVC max ; P < 0.01 and P < 0.001, respectively). Combined theophylline + l-NAME (52 ± 5% CVC max ) reduced the initial peak compared with control and theophylline sites, but was not significantly different compared with l-NAME sites. The secondary plateau was attenuated in theophylline (77 ± 2% CVC max ), l-NAME (60 ± 2% CVC max ) and theophylline + l-NAME (53 ± 1% CVC max ) compared with control sites (94 ± 2% CVC max ; P < 0.001 for all conditions). The secondary plateau was reduced in l-NAME compared with theophylline sites (P < 0.001), and combined theophylline + l-NAME further reduced the secondary plateau compared with theophylline-(P < 0.001) and l-NAME-only sites (P < 0.05). These data suggest that adenosine receptor activation directly contributes to cutaneous thermal hyperaemia, as evidenced by the reduced initial peak and secondary plateau in theophylline sites. These data further suggest that a portion of the NO response may be explained by adenosine receptor activation; however, a substantial portion of the NO response is independent of adenosine receptor activation.

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 CO(2) 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 CO(2) 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.

Wong BJ, Fieger SM. Transient receptor potential vanilloid type 1 channels contribute to reflex cutaneous vasodilation in humans. J Appl Physiol 112: 2037-2042, 2012. First published April 19, 2012 doi:10.1152/japplphysiol.00209.2012.-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 ϩ 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 ϩ 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 (%CVC max). Capsazepine sites were significantly reduced compared with control (50 Ϯ 4%CVC max vs. 67 Ϯ 5%CVC max, respectively; P Ͻ 0.05). L-NAME (33 Ϯ 3%CVCmax) and L-NAME ϩ capsazepine (30 Ϯ 4%CVCmax) sites were attenuated compared with control (P Ͻ 0.01) and capsazepine (P Ͻ 0.05); however, there was no difference between L-NAME and combined L-NAME ϩ 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. microdialysis; heat stress; nitric oxide INCREASES IN SKIN BLOOD FLOW and sweating represent humans' primary physiological defense against an increase in core temperature. The initial increase in skin blood flow during hyperthermia is driven primarily by withdrawal of tonic sympathetic vasoconstrictor tone, which results in approximate doubling of resting thermoneutral skin blood flow(8, 23). Further increases in skin blood flow, concomitant with the onset of sweating, are mediated by reflex sympathetic cholinergic nerve activity (8). This reflex cutaneous active vasodilation accounts for 85-95% of the increase in skin blood flow during hyperthermia and can result in nearly 8 liters/min of cardiac output directed to the cutaneous vasculature(24).The co-transmission theory of cutaneous active vasodilation suggests acetylcholine and one or more unknown vasodilators are co-released from sympathetic cholinergic nerves, where acetylcholine is primarily responsible for the sweat response and the unknown vasodilator(s) are responsible for the refle...

These data suggest A1/A2 adenosine receptor activation does not directly contribute to cutaneous active vasodilatation; however, a role for A1/A2 adenosine receptor activation is unmasked when NO synthase is inhibited.

We conclude that post-junctional α-adrenergic vasoconstrictor responsiveness is not affected by hypoxia in non-acral skin.

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