Nitric oxide inhibits serotonin-induced calcium release in pulmonary artery smooth muscle cells.

Abstract

Nitric oxide (NO) is a potent endothelium-derived pulmonary vasodilator. Serotonin (5-HT; 10-50 microM) constricts pulmonary artery (PA) by releasing Ca2+ from intracellular stores and promoting Ca2+ influx through Ca2+ channels in PA smooth muscle cells (PASMC). The effect of NO on 5-HT-induced increase in cytosolic free Ca2+ concentration ([Ca2+]i) in rat PASMC was investigated to elucidate whether inhibition of agonist-mediated Ca2+ rise is involved in the NO-mediated pulmonary vasodilation. The 5-HT-induced increase in [Ca2+]i was characterized by a transient (because of Ca2+ release from intracellular stores) followed by a plateau (because of Ca2+ influx). Removal of extracellular Ca2+ eliminated the 5-HT-induced [Ca2+]i plateau, but insignificantly affected the [Ca2+]i transient. In some of the PASMC bathed in the Ca(2+)-containing or Ca(2+)-free solution, 5-HT also induced Ca2+ oscillations. Pretreatment of the cells with 10 microM cyclopiazonic acid (CPA) abolished, whereas 10 mM caffeine negligibly affected, the 5-HT-induced [Ca2+]i transients in the absence of external Ca2+. Authentic NO (approximately 0.3 microM) reversibly diminished 5-HT-induced [Ca2+]i transients but augmented CPA-induced Ca2+ release in the absence of extracellular Ca2+. NO also significantly inhibited 5-HT-induced [Ca2+]i plateau in PASMC bathed in Ca(2+)-containing solution, suggesting that NO inhibits both agonist-induced Ca2+ release from the CPA-sensitive Ca2+ stores and Ca2+ influx from extracellular fluid. These data suggest that NO-induced inhibition of the evoked increases in [Ca2+]i and augmentation of Ca2+ sequestration into intracellular stores in PASMC are involved in the mechanisms by which NO causes pulmonary vasodilation.