title: Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans.
abstract: 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.
authors.affiliation: Penn State Hershey Heart and Vascular Institute, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: Samson
authors.initials: S
authors.lastname: Spilk
authors.forename: Michael D
authors.initials: MD
authors.lastname: Herr
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Sinoway
authors.forename: Urs A
authors.initials: UA
authors.lastname: Leuenberger
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001685:Biological Factors / Q000378:metabolism*; D001783:Blood Flow Velocity; D001794:Blood Pressure; D065729:Cytochrome P-450 CYP2C9; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage; D005542:Forearm; D006339:Heart Rate; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012123:Pulmonary Ventilation; D012039:Regional Blood Flow; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D001685:Biological Factors; D004791:Enzyme Inhibitors; C067410:endothelium-dependent hyperpolarization factor; D019323:omega-N-Methylarginine; D015725:Fluconazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019001:Nitric Oxide Synthase; D001189:Aryl Hydrocarbon Hydroxylases
keywords: endothelium-derived hyperpolarizing factor; fluconazole; hypoxia; nitric oxide; vasodilation
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