ALUNG June 20/6

Saqueton, Connie B., Robert B. Miller, Valerie A. Porter, Carlos E. Milla, and David N. Cornfield. NO causes perinatal pulmonary vasodilation through K1-channel activation and intracellular Ca21 release. Am. J. Physiol. 276 (Lung Cell. Mol. Physiol. 20): L925–L932, 1999.—Evidence suggests that nitric oxide (NO) causes perinatal pulmonary vasodilation through K1-channel activation. We hypothesized that this effect worked through cGMP-dependent kinase-mediated activation of Ca21-activated K1 channel that requires release of intracellular Ca21 from a ryanodinesensitive store. We studied the effects of 1) K1-channel blockade with tetraethylammonium, 4-aminopyridine, a voltage-dependent K1-channel blocker, or glibenclamide, an ATPsensitive K1-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 intracellular Ca21 release with ryanodine on NO-induced pulmonary vasodilation in acutely prepared late-gestation fetal lambs. N-nitro-L-arginine, a competitive 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 inhaled NO at 20 parts/million (ppm) for 20 min. This represents the control period. In separate protocols, the animals received an intrapulmonary infusion of the different blockers and were ventilated as above. Tetraethylammonium (n 5 6 animals) and KT-5823 (n 5 4 animals) attenuated the response, whereas ryanodine (n 5 5 animals) blocked NO-induced perinatal pulmonary vasodilation. 4-Aminopyridine (n 5 5 animals), glibenclamide (n 5 5 animals), and H-89 (n 5 4 animals) did not affect NO-induced pulmonary vasodilation. We conclude that NO causes perinatal pulmonary vasodilation through cGMP-dependent kinase-mediated activation of Ca21-activated K1 channels and release of Ca21 from ryanodinesensitive stores.