Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Abstract

Hypoxic contraction of pulmonary arterial smooth muscle is thought to require increases in both intracellular Ca2+concentration ([Ca2+]i) and myofilament Ca2+sensitivity, which may or may not be endothelium-dependent. To examine the effects of hypoxia and endothelium on Ca2+sensitivity in pulmonary arterial smooth muscle, we measured the relation between [Ca2+]iand isometric force at 37°C during normoxia (21% O2-5% CO2) and after 30 min of hypoxia (1% O2-5% CO2) in endothelium-intact (E+) and -denuded (E−) rat distal intrapulmonary arteries (IPA) permeabilized with staphylococcal α-toxin. Endothelial denudation enhanced Ca2+sensitivity during normoxia but did not alter the effects of hypoxia, which shifted the [Ca2+]i-force relation to higher force in E+ and E− IPA. Neither hypoxia nor endothelial denudation altered Ca2+sensitivity in mesenteric arteries. In E+ and E− IPA, hypoxic enhancement of Ca2+sensitivity was abolished by the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (30 μM), which shifted normoxic [Ca2+]i-force relations to higher force. In E− IPA, the Rho kinase antagonist Y-27632 (10 μM) shifted the normoxic [Ca2+]i-force relation to lower force but did not alter the effects of hypoxia. These results suggest that acute hypoxia enhanced myofilament Ca2+sensitivity in rat IPA by decreasing nitric oxide production and/or activity in smooth muscle, thereby revealing a high basal level of Ca2+sensitivity, due in part to Rho kinase, which otherwise did not contribute to Ca2+sensitization by hypoxia.