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

Abstract

Spilk S, Herr MD, Sinoway LI, Leuenberger UA. Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans. Am J Physiol Heart Circ Physiol 305: H1639 -H1645, 2013. First published September 16, 2013 doi:10.1152/ajpheart.00073.2013.-Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O 2 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 ϩ L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial PO 2 ϳ37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole ϩ L-NMMA reduced (P Ͻ 0.05) forearm vascular conductance (FVC) by ϳ10% and ϳ18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 Ϯ 0.37 and 0.95 Ϯ 0.35 units in control and experimental forearms, respectively (P Ͻ 0.05). During hypoxia and fluconazole ϩ L-NMMA (trial 2), FVC increased by 2.32 Ϯ 0.51 and 0.72 Ϯ 0.22 units in control and experimental forearms, respectively (P Ͻ 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n ϭ 8) FVC increased by 1.51 Ϯ 0.46 and 0.45 Ϯ 0.32 units in control and experimental forearms, respectively (P Ͻ 0.05). These effects were not due to altered skin blood flow. We conclude that endotheliumderived 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.hypoxia; vasodilation; endothelium-derived hyperpolarizing factor; fluconazole; nitric oxide UNDER BASAL CONDITIONS and during physiological stress, skeletal muscle blood flow is closely matched to metabolic demand. Accordingly, in healthy humans, systemic hypoxia is accompanied by skeletal muscle vasodilation, which serves to maintain O 2 homeostasis (20,27,29). Because hypoxia raises sympathetic vasoconstrictor nerve traffic and norepinephrine spillover (14, 31), vasodilation results from release of systemic or local vasodilator factors. In agreement with studies in rodents (22,24,26), it has been reported that nitric oxide (NO) (7,9,16,35) and adenosine (15, 18) contribute to hypoxiainduced vasodilation in humans. In addition, some reports (6, 35), but not others (27), support a role for an increase in circulating epinephrine, and one recent report (19) suggests that vasodilator prostaglandins also contribute to the skeletal muscle vasodilation elicited by systemic hypoxia. Thus multiple endogenous vasodilator mechanisms ...

Interactions between local dilator and sympathetic vasoconstrictor influences in skeletal muscle in acute and chronic hypoxia

“…Inhibition of EET synthesis attenuated hypoxic dilatation in the forearm (Spilk et al . ). Furthermore, dilatation induced by graded hypoxia in muscle arteries and arterioles was inhibited by antagonists of EET, HETE synthesis, K Ca or K ATP channels and accompanied by graded release of EETs, but decreased production of vasoconstrictor HETE (see Frisbee et al .…”

Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone

“…Additionally, bone nodule formation by osteoblasts was reduced (−10-fold) and almost completely inhibited as a result of moderate (1–2% O 2 ) and severe (0.2% O 2 ) hypoxia, respectively (Utting et al 2006). Reduced pO 2 is a powerful stimulator for vasodilation in other vascular beds (Spilk et al 2013) and no doubt produces similar responses in the bone vascular system. In order to rapidly restore bone pO 2 , vasodilation of bone blood vessels would be the foremost response.…”

Inhibition of Na+/K+‐ATPase and KIR channels abolishes hypoxic hyperaemia in resting but not contracting skeletal muscle of humans

“…) and cytochrome P‐450 inhibition (∼50%: Spilk et al . ), have all been demonstrated to significantly reduce forearm vasodilatation during hypoxia. We propose that during systemic hypoxia when is reduced to ∼80%, inhibiting the normal vasodilator and hyperaemic response (typically by the order of ∼20–30%) results in a fairly small absolute change in forearm blood flow (Fig.…”

“…, ), Spilk et al . () found that regional infusion of fluconazole (an inhibitor of cytochrome P450 2C9) in the human forearm significantly attenuates hypoxia‐induced dilatation. There is also evidence in humans that EETs can compensate for the loss of NO at rest and during exercise in humans, thus indicating potential cross‐talk between these two pathways (Hillig et al .…”