Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans.

Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole + L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial Po2 ~37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole + L-NMMA reduced (P < 0.05) forearm vascular conductance (FVC) by ~10% and ~18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 ± 0.37 and 0.95 ± 0.35 units in control and experimental forearms, respectively (P < 0.05). During hypoxia and fluconazole + L-NMMA (trial 2), FVC increased by 2.32 ± 0.51 and 0.72 ± 0.22 units in control and experimental forearms, respectively (P < 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n = 8) FVC increased by 1.51 ± 0.46 and 0.45 ± 0.32 units in control and experimental forearms, respectively (P < 0.05). These effects were not due to altered skin blood flow. We conclude that endothelium-derived hyperpolarizing factor contributes to basal vascular tone and to hypoxia-induced skeletal muscle vasodilation and could be particularly relevant when other vasodilator systems are impaired.