Role of Glycolysis and Myoendothelial Gap Junctions in the Development of Hypoxic Pulmonary Vasoconstriction

Abstract

1 Institute of Pharmacology and Toxicology, Academy of Medical Sciences of Ukraine, Kyiv, Ukraine. Correspondence should be addressed to A. I. Soloviev (e-mail: s.a.pharm@naverex.kiev.ua). It is well known that hypoxia causes constriction of the pulmonary artery (PA) in contrast to vasodilation in the systemic vessels. The mechanisms responsible for sensing hypoxia and initiating hypoxic pulmonary vasoconstriction (HPV) are not yet fully understood. We therefore examined the roles of glycolysis and myoendothelial gap junctions in HPV of the rat PA. The effects of glycolysis blockade on the contractile activity of the PA and aorta (A) of rats were studied under hypoxic conditions in isolated intact and denuded vascular rings, as well as in those with blocked myoendothelial electrical coupling. Hypoxia (Po 2 = 30-35 mm Hg) elicited a twophase contractile response of the intact PA consisting of transient constriction followed by dilatation. The denuded PA responded to hypoxia by dilatation. After preincubation with 20 μМ 18-glycyrrhetinic acid, a gap junction blocker, the hypoxia-induced transient constriction in intact PA rings was significantly reduced. Hypoxia elicited dilatation of intact A rings, and this effect was not changed after the removal of the endothelium. Preincubation with 18-glycyrrhetinic acid induced transient constriction in the A under hypoxic conditions. Selective blockade of glycolysis (10 μM iodoacetic acid in combination with 1 mM pyruvate) abolished hypoxic constriction in intact PA and promoted dilatation. However, selective blockade of glycolysis had no effect on the PA hypoxic responses after denudation or blockade of myoendothelial gap junctions with 18-glycyrrhetinic acid. Selective glycolysis blockade had no effect on contractile responses to hypoxia of the intact, denuded, and 18-glycyrrhetinic acidtreated A. We conclude that hypoxic constriction of the PA is an endothelium-dependent phenomenon in contrast to hypoxic dilatation of the A. It is likely that glycolysis in endothelial cells contributes, via myoendothelial gap junctions, to hypoxic pulmonary vasoconstriction and, after conduction of depolarizing electrical signals from endothelial cells to underlying smooth muscle cells, causes contraction of the latter under hypoxia.