Acidosis-Induced Coronary Arteriolar Dilation Is Mediated by ATP-Sensitive Potassium Channels in Vascular Smooth Muscle

Abstract

Abstract Although a decrease in extravascular pH has been suggested to be involved in coronary flow regulation during hypoxia, ischemia, and increased metabolic demand of the heart, its vasomotor control mechanism has not been elucidated. To examine the effect of acidosis on vasomotor tone, porcine coronary arterioles (40 to 110 μm) were isolated, cannulated, and pressurized to 60 cm H 2 O intraluminal pressure without flow for in vitro study. Acidosis (pH 7.4 to 7.0) was produced by adding HCl to the extravascular solution. The involvement of potassium channels in the vasomotor response to acidosis was evaluated by using BaCl 2 (100 μmol/L, nonspecific potassium channel inhibitor), glibenclamide (5 μmol/L, ATP-sensitive potassium channel inhibitor), and iberiotoxin (100 nmol/L, calcium-activated potassium channel inhibitor). To determine whether endothelial hyperpolarization contributes to the acidosis-induced dilation, the pH-diameter relation of the vessel was examined under a high intraluminal concentration of KCl (40 mmol/L). The involvement of nitric oxide and prostaglandins was assessed by using N G -monomethyl- l -arginine (L-NMMA, 10 μmol/L) and indomethacin (10 μmol/L), respectively. To evaluate the role of endothelium in the acidosis-induced dilation, the pH-diameter relation was studied after endothelial removal. All vessels developed a similar level of spontaneous tone (internal diameter, 75±4 μm [≈69±1% of maximum diameter]) and dilated to HCl in a dose-dependent manner. Glibenclamide completely abolished vasodilation to a mild level of acidosis (pH 7.2 to 7.3) and attenuated the vasodilation by 70% at pH 7.0. Acidosis-induced dilation was also inhibited by BaCl 2 but not by iberiotoxin. L-NMMA, indomethacin, and intraluminal KCl did not alter the pH-diameter relation. Vasodilation to acidosis of the endothelium-denuded vessels was identical to that of the endothelium-intact vessels. In addition, glibenclamide attenuated the acidosis-induced arteriolar dilation of endothelium-denuded vessels in a manner similar to that of endothelium-intact vessels. These results suggest that the opening of ATP-sensitive potassium channels in vascular smooth muscle mediates the coronary arteriolar dilation during acidosis.