Oxygen Causes Fetal Pulmonary Vasodilation through Activation of a Calcium-Dependent Potassium Channel

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-07, Vol.93 (15), p.8089-8094
• Main Authors: Cornfield, David N., Reeve, Helen L., Tolarova, Simona, Weir, E. Kenneth, Archer, Stephen
• Format: Article
• Language: English
• Subjects: Alkaloids - pharmacology; Aminoquinolines - pharmacology; Anaerobic conditions; Anatomy & physiology; Animals; Blood flow; Blood gases; Carbazoles; Charybdotoxin - pharmacology; Electric current; Endothelium, Vascular - physiology; Enzyme Inhibitors - pharmacology; Female; Fetus; Fetuses; Glyburide - pharmacology; Guanylate Cyclase - antagonists & inhibitors; Hypoxia; Indoles; Isoquinolines - pharmacology; Lungs; Membrane Potentials - drug effects; Models, Cardiovascular; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - embryology; Muscle, Smooth, Vascular - physiology; Nitric Oxide - pharmacology; Nitric Oxide Synthase - metabolism; Oxygen; Oxygen - pharmacology; Patch-Clamp Techniques; Peptides - pharmacology; Potassium; Potassium Channel Blockers; Potassium Channels - physiology; Pregnancy; Protein Kinase Inhibitors; Pulmonary artery; Pulmonary Artery - drug effects; Pulmonary Artery - embryology; Pulmonary Artery - physiology; Sheep; Smooth muscle myocytes; Sulfonamides; Tetraethylammonium; Tetraethylammonium Compounds - pharmacology; Vasodilation; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.15.8089

At birth, pulmonary vasodilation occurs as air-breathing life begins. The mechanism of O2-induced pulmonary vasodilation is unknown. We proposed that O2 causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel (KCa) via a cyclic nucleotide-dependent kinase. We tested this hypothesis in hemodynamic studies in acutely prepared fetal lambs and in patch-clamp studies on resistance fetal pulmonary artery smooth muscle cells. Fetal O2 tension (PaO2) was increased by ventilating the ewe with 100% O2, causing fetal total pulmonary resistance to decrease from 1.18 ± 0.14 to 0.41 ± 0.03 mmHg per ml per min. Tetraethylammonium and iberiotoxin, preferential KCa-channel inhibitors, attenuated O2-induced fetal pulmonary vasodilation, while glibenclamide, an ATP-sensitive K+-channel antagonist, had no effect. Treatment with either a guanylate cyclase antagonist (LY83583) or cyclic nucleotide-dependent kinase inhibitors (H-89 and KT 5823) significantly attenuated O2-induced fetal pulmonary vasodilation. Under hypoxic conditions (PaO2 = 25 mmHg), whole-cell K+-channel currents (Ik) were small and were inhibited by 1 mM tetra-ethylammonium or 100 nM charybdotoxin (CTX; a specific KCa-channel blocker). Normoxia (PaO2 = 120 mmHg) increased Ik by more than 300%, and this was reversed by 100 nM CTX. Nitric oxide also increased Ik. Resting membrane potential was -37.2 ± 1.9 mV and cells depolarized on exposure to CTX, while hyperpolarizing in normoxia. We conclude that O2 causes fetal pulmonary vasodilation by stimulating a cyclic nucleotide-dependent kinase, resulting in KCa-channel activation, membrane hyperpolarization, and vasodilation.