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

David N. Cornfield, Helen L. Reeve, Simona Tolarova, Edward K Weir, Stephen Archer

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8089-8094
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number15
DOIs
StatePublished - Jul 23 1996

Keywords

  • K channels
  • O-sensing
  • fetus
  • nitric oxide
  • protein kinase
  • pulmonary vasculature

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