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Departments of 1 Medicine and 2 Physiology and Biophysics, Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Science Center, Denver, Colorado 80262
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 [IK(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 IK(v) inhibition, a switch in coupling between ET-1 and IK(v) from ETB to ETA receptors occurred. This switch in receptor coupling, combined with reduced IK(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.
pulmonary hypertension; ion channel; potassium channel; cytosolic calcium; vascular smooth muscle cell
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