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.