NO causes perinatal pulmonary vasodilation through K+-channel activation and intracellular Ca2+ release.
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.
Saqueton
C B
CB
Division of Pediatric Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Miller
R B
RB
Porter
V A
VA
Milla
C E
CE
Cornfield
D N
DN
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus / Q000187:drug effects*; D007425:Intracellular Membranes / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D009712:Nucleotides, Cyclic / Q000502:physiology; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology; D012756:Sheep / Q000196:embryology; D014664:Vasodilation / Q000502:physiology*
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D009712:Nucleotides, Cyclic; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012433:Ryanodine; D009569:Nitric Oxide; D010770:Phosphotransferases; D002118:Calcium