Original Research: Role of phosphodiesterases in modulation of BK Ca channels in hypertensive pulmonary arterial smooth muscle

Abstract

BK_Ca channels regulate pulmonary arterial pressure, and protein kinase C (PKC) inhibits BK_Ca channels, but little is known about PKC-mediated modulation of BK_Ca channel activity in pulmonary arterial smooth muscle. Studies were carried out to determine mechanisms of PKC modulation of BK_Ca channel activity in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), an animal model of pulmonary hypertension. Forskolin opened BK_Ca channels in FHR PASMC, which was blocked by PKC activation, and reversed by the phosphodiesterase (PDE) inhibitors IBMX, milrinone, and zaprinast. PDE inhibition also blocked the vasoconstrictor response to PKC activation in FHR pulmonary arteries. These results indicate that PKC inhibits cAMP-induced activation of BK_Ca channels and causes pulmonary vasoconstriction in hypertensive pulmonary arterial smooth muscle via PDE, which further suggests PDE inhibitors for treatment of pulmonary hypertension.

Keywords

phosphodiesterase BKCa channels PKC cAMP pulmonary

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