NITRIC-OXIDE INHIBITS SEROTONIN-INDUCED CALCIUM-RELEASE IN PULMONARY-ARTERY SMOOTH-MUSCLE CELLS

Nitric oxide (NO) is a potent endothelium-derived pulmonary vasodilato r. Serotonin (5-HT; 10-50 mu M) constricts pulmonary artery (PA) by re leasing Ca2+ from intracellular stores and promoting Ca2+ influx throu gh Ca2+ channels in PA smooth muscle cells (PASMC). The effect of NO o n 5-HT-induced increase in cytosolic free Ca2+ concentration ([Ca2+](i )) in rat PASMC was investigated to elucidate whether inhibition of ag onist-mediated Ca2+ rise is involved in the NO-mediated pulmonary vaso dilation. The 5-HT-induced increase in [Ca2+](i) was characterized by a transient (because of Ca2+ release from intracellular stores) follow ed by a plateau (because of Ca2+ influx). Removal of extracellular Ca2 + eliminated the 5-HT-induced [Ca2+](i) plateau, but insignificantly a ffected the [Ca2+](i) transient. In some of the PASMC bathed in the Ca 2+-containing or Ca2+-free solution, 5-HT also induced Ca2+ oscillatio ns. Pretreatment of the cells with 10 mu M cyclopiazonic acid (CPA) ab olished, whereas 10 mM caffeine negligibly affected, the 5-HT-induced [Ca2+](i) transients in the absence of external Ca2+. Authentic NO (si milar to 0.3 mu M) reversibly diminished 5-HT-induced [Ca2+](i) transi ents but augmented CPA-induced Ca2+ release in the absence of extracel lular Ca2+. NO also significantly inhibited 5-HT-induced [Ca2+](i) pla teau in PASMC bathed in Ca2+-containing solution, suggesting that NO i nhibits both agonist-induced Ca2+ release from the CPA-sensitive Ca2stores and Ca2+ influx from extracellular fluid. These data suggest th at NO-induced inhibition of the evoked increases in [Ca2+](i) and augm entation of Ca2+ sequestration into intracellular stores in PASMC are involved in the mechanisms by which NO causes pulmonary vasodilation.