The nitric oxide dependence of cutaneous microvascular function to independent and combined hypoxic cold exposure

Hypoxic modulation of nitric oxide (NO) production pathways in the cutaneous microvasculature and its interaction with cold-induced reflex vasoconstriction, independent of local cooling, have yet to be identified. This study assessed the contribution of NO to nonglabrous microvasculature perfusion during hypoxia and whole body cooling with concomitant inhibition of NO synthase [NOS; via N ^G-nitro-L-arginine methyl ester (L-NAME)] and the nitrite reductase, xanthine oxidase (via allopurinol), two primary sources of NO production. Thirteen volunteers were exposed to independent and combined cooling via water-perfused suit (5°C) and normobaric hypoxia (FI _O2, 0.109 + 0.002). Cutaneous vascular conductance (CVC) was assessed across four sites with intradermal microdialysis perfusion of 1) lactated Ringers solution (control), 2) 20 mmol L-NAME, 3) 10 mol allopurinol, or 4) combined L-NAME/allopurinol. Effects and interactions were assessed via four-way repeated measures ANOVA. Independently, L-NAME reduced CVC (43%, P < 0.001), whereas allopurinol did not alter CVC (P = 0.5). Cooling decreased CVC (P = 0.001), and the reduction in CVC was consistent across perfusates (~30%, P = 0.9). Hypoxia increased CVC (16%, P = 0.01), with this effect abolished by L-NAME infusion (P = 0.04). Cold-induced vasoconstriction was blunted by hypoxia, but importantly, hypoxia increased CVC to a similar extent (39% at the Ringer site) irrespective of environmental temperature; thus, no interaction was observed between cold and hypoxia (P = 0.1). L-NAME restored vasoconstriction during combined cold-hypoxia (P = 0.01). This investigation suggests that reflex cold-induced cutaneous vasoconstriction acts independently of NO suppression, whereas hypoxia-induced cutaneous vasodilatation is dependent on NOS-derived NO production.