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 O₂-induced pulmonary vasodilation is unknown. We proposed that O₂ 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 O₂ tension (Pa(O₂)) 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 K(Ca)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 (Pa(O₂) = 25 mmHg), whole-cell K⁺- channel currents (I(k)) were small and were inhibited by 1 mM tetraethylammonium 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 O₂ causes fetal pulmonary vasodilation by stimulating a cyclic nucleotide-dependent kinase, resulting in K(Ca)-channel activation, membrane hyperpolarization, and vasodilation.