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

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 degrees C/min. At -4 degrees C/min, CVC increased (P < 0.05) at BT sites in the early phase. At -0.33 degrees 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 N(G)-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 degrees C/min) to 24 degrees 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.

Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling

“…We do not know the origin of this variance, although preliminary data from our laboratory show the rate of cooling to be an important determinant of the level of vasodilation in those areas (42). Although the vasodilator response was statistically significant at sites pretreated with Emla, bretylium, or yohimbine-propranolol, the degree of vasodilation was not statistically significantly different among sites (P Ͼ 0.06), despite the difference in the mean response.…”

The effect of microdialysis needle trauma on cutaneous vascular responses in humans

“…Local temperature control at the sites of blood flow measurement was achieved with custom-designed metal Peltier cooling-heating probe holders (e.g., Refs. 1,8,10,15,35). These controlled surface temperature within 0.05°C over an area of 6.3 cm 2 with the exception of a small aperture (0.28 cm 2 ) in the center of the holder to enable placement of the laser-Doppler probe.…”

Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin

“…During the early phase of localized cooling (0 -10 min), cold-induced VC is mediated by norepinephrine released from sympathetic axon terminals in the absence of a reflex stimulus. However, during prolonged localized cooling (Ͼ10 min), cold-induced VC is driven primarily by nonsympathetic mechanisms (24,34) that include a putative downregulation of the nitric oxide synthase (NOS) pathway (19,44) but that still remain largely unclear.…”