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

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⁺]_i and 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 N^ω-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.