Enhanced ETA-receptor-mediated inhibition of Kv channels in hypoxic hypertensive rat pulmonary artery myocytes

Abstract

Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K+(Kv) channels and release of intracellular Ca2+, were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K+ current [ I K(v)], with maximum inhibition of 12–18% seen at a concentration of 0.1–1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I K(v) inhibition, a switch in coupling between ET-1 and I K(v) from ETB to ETA receptors occurred. This switch in receptor coupling, combined with reduced I K(v) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ETA-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.