Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin

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Abstract
Local cooling of nonglabrous skin without functional sympathetic nerves causes an initial vasodilation followed by vasoconstriction. To further characterize these responses to local cooling, we examined the importance of the rate of local cooling and the effect of nitric oxide synthase (NOS) inhibition in intact skin and in skin with vasoconstrictor function inhibited. Release of norepinephrine was blocked locally (iontophoresis) with bretylium tosylate (BT). Skin blood flow was monitored from the forearm by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as the ratio of LDF to blood pressure. Local temperature was controlled over 6.3 cm2 around the sites of LDF measurement. Local cooling was applied at −0.33 or −4°C/min. At −4°C/min, CVC increased (P < 0.05) at BT sites in the early phase. At −0.33°C/min, there was no early vasodilator response, but there was a delay in the onset of vasoconstriction relative to intact skin. The NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME) (intradermal microdialysis) decreased (P < 0.05) CVC by 28.3 ± 3.8% at untreated sites and by 46.9 ± 6.3% at BT-treated sites from the value before infusion. Rapid local cooling (−4°C/min) to 24°C decreased (P < 0.05) CVC at both untreated (saline) sites and l-NAME only sites from the precooling levels, but it transiently increased (P < 0.05) CVC at both BT + saline sites and BT + l-NAME sites in the early phase. After 35–45 min of local cooling, CVC decreased at BT + saline sites relative to the precooling levels (P < 0.05), but at BT + l-NAME sites CVC was not reduced below the precooling level (P = 0.29). These findings suggest that the rate of local cooling, but not functional NOS, is an important determinant of the early non-adrenergic vasodilator response to local cooling and that functional NOS, adrenergic nerves, as well as other mechanisms play roles in vasoconstriction during prolonged local cooling of skin.