These results indicate that KV channel function in PPH-PASMCs is inhibited compared with SPH-PASMCs. The resulting membrane depolarization and increase in [Ca2+]cyt lead to pulmonary vasoconstriction and PASMC proliferation. Our data suggest that defects in PASMC KV channels in PPH patients may be a unique mechanism involved in initiating and maintaining pulmonary vasoconstriction and appear to play a role in the pathogenesis of PPH.
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.
Effective attenuation of pulmonary vasoconstriction is essential during early postnatal development when increased pulmonary vascular resistance (PVR) may lead to a resumption of right-to-left shunting across fetal channels. In addition, modulation of venous resistance contributes to normal lung fluid balance. This study was designed to identify the relative modulating effects of endothelium-derived nitric oxide (EDNO) and dilator prostaglandins (PG) on normoxic and hypoxic pulmonary vasomotor tone in young newborns. Total and segmental PVR were measured using inflow-outflow and double occlusion techniques in isolated lungs of 6-h-old lambs studied under control conditions or after blocking PG and/or EDNO synthesis with indomethacin and/or N omega-nitro-L-arginine, respectively. During normoxia, both indomethacin and N omega-nitro-L-arginine were required to increase total PVR, but EDNO appeared to have the greater modulating effect. Indomethacin markedly enhanced hypoxic pulmonary vasoconstriction of large and small arteries and small veins, whereas N omega-nitro-L-arginine caused a lesser, but significant, increase in hypoxic pulmonary vasoconstriction of small arteries and veins, suggesting that dilator PG played the dominant modulating role during hypoxia. In addition, PG synthesis appeared to be enhanced after inhibition of EDNO synthesis. In contrast, indomethacin caused a decrease in venous resistance, suggesting that constrictor prostanoids had a greater effect than dilator PG on this segment. EDNO had a modest modulating effect on venous resistance in these lungs. These data suggest that dilator PG and EDNO exert complementary effects in attenuating total and segmental PVR during normoxia and hypoxia in 6-hold lamb lungs.
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