Evidence suggests that nitric oxide (NO) causes perinatal pulmonary vasodilation through K⁺-channel activation. We hypothesized that this effect worked through cGMP-dependent kinase-mediated activation of Ca²⁺-activated K⁺ channel that requires release of intracellular Ca²⁺ from a ryanodine-sensitive store. We studied the effects of 1) K⁺-channel blockade with tetraethylammonium, 4-aminopyridine, a voltage-dependent K⁺-channel blocker, or glibenclamide, 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 intracellular Ca²⁺ 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 = 6 animals) and KT-5823 (n = 4 animals) attenuated the response, whereas ryanodine (n = 5 animals) blocked NO-induced perinatal pulmonary vasodilation. 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-dependent kinase-mediated activation of Ca²⁺-activated K⁺ channels and release of Ca²⁺ from ryanodine-sensitive stores.

nitric oxide; potassium channel; newborn; pulmonary hypertension; smooth muscle cells; oxygen sensing

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