Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel

At birth, pulmonary vasodilation occurs as air-breathing life begins, The mechanism of O-2-induced pulmonary vasodilation is unknown. We proposed that O-2 causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel (K-Ca) 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 O-2 tension (Pa-O2) was increased by ventilating the ewe with 100% O-2, causing fetal total pulmonary resistance to decrease from 1.18 +/- 0.14 to 0.41 +/- 0.03 mmHg per mi per min, Tetraethylammonium and iberiotoxin, preferential K-Ca-channel inhibitors, attenuated O-2-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 O-2-induced fetal pulmonary vasodilation. Under hypoxic conditions (Pa-O2 = 25 mmHg), whole-cell K+-channel currents (I-k) were small and were inhibited by 1 mM tetraethylmmonium or 100 nM charybdotoxin (CTX; a specific K-Ca-channel blocker). Normoxia (Pa-O2 = 120 mmHg) increased I-k by more than 300%, and this was reversed by 100 nM CTX, Nitric oxide also increased I-k. Resting membrane potential was -37.2 +/- 1.9 mV and cells depolarized on exposure to CTX, while hyperpolarizing in normoxia. We conclude that O-2 causes fetal pulmonary vasodilation by stimulating a cyclic nucleotide-dependent kinase, resulting in K-Ca-channel activation, membrane hyperpolarization, and vasodilation.