NO causes perinatal pulmonary vasodilation through K+-channel activation and intracellular Ca2+ release

Evidence suggests that nitric oxide (NO) causes perinatal pulmonary vasodil ation through K+-channel activation. We hypothesized that this effect worke d through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ ch annel that requires release of intracellular Ca2+ from a ryanodine-sensitiv e store. We studied the effects of 1) K+-channel blockade with tetraethylam monium, 4-aminopyridine, a voltage-dependent K+-channel blocker, or glibenc lamide, an ATP-sensitive K+-channel blocker; 2) cyclic nucleotide-sensitive kinase blockade with either KT-5823, a guanylate-sensitive kinase blocker, or H-89, an adenylate-sensitive kinase blocker; and 3) blockade of intrace llular Ca2+ release with ryanodine on NO-induced pulmonary vasodilation in acutely prepared late-gestation fetal lambs. N-nitro-L-arginine, a competit ive inhibitor of endothelium-derived NO synthase, was infused into the left pulmonary artery, and tracheotomy was placed. The animals were ventilated with 100% oxygen for 20 min, followed by ventilation with 100% oxygen and i nhaled NO at 20 parts/million (ppm) for 20 min. This represents the control period. In separate protocols, the animals received an intrapulmonary infu sion of the different blockers and were ventilated as above. Tetraethylammo nium (n = 6 animals) and KT-5823 (n = 4 animals) attenuated the response, w hereas ryanodine (n = 5 animals) blocked NO-induced perinatal pulmonary vas odilation. 4-Aminopyridine (n = 5 animals), glibenclamide (n = 5 animals), and H-89 (n = 4 animals) did not affect NO-induced pulmonary vasodilation. We conclude that NO causes perinatal pulmonary vasodilation through cGMP-de pendent kinase-mediated activation of Ca2+-activated K+ channels and releas e of Ca2+ from ryanodine-sensitive stores.