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Subacute Hypoxia Decreases Voltage-Activated Potassium Channel Expression and Function in Pulmonary Artery Myocytes

VA Medical Center, University of Minnesota, Minneapolis, Minnesota; and Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Justus-Liebig-University, Giessen, Germany

Address correspondence to: Andrea Olschewski, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Justus-Liebig-University, D-35392 Giessen, Germany. E-mail: andrea.j.olschewski{at}physiologie.med.uni-giessen.de

Chronic hypoxia results in both structural changes in the pulmonary artery and a sustained increase in pulmonary vascular tone. This study investigated the effects of subacute moderate hypoxia on expression and function of potassium (K⁺) channels in rat pulmonary artery myocytes (PASMCs). The rats were kept at 0.67 atmospheres for 6, 12, or 24 h. We found that the expression of mRNA for voltage-activated K⁺ channels (Kv)1.2, Kv1.5, and Kv2.1 is reduced after less than 24 h of this moderate hypoxia. K⁺ current (Ik) is significantly inhibited in PASMCs from rats hypoxic for 24 h, resting membrane potential is depolarized and cytosolic [Ca²⁺] is increased in these cells. In addition, antibodies to Kv1.2, Kv1.5, and Kv2.1 inhibit Ik, cause membrane depolarization and attenuate both hypoxia- and 4-AP–induced elevation in [Ca²⁺]_i in PASMCs from normoxic rats but not from 24 h hypoxic rats. Subacute hypoxia does not completely remove the mRNA for Kv1.2, Kv1.5, and Kv2.1, but antibodies against these channels no longer alter Ik or cytosolic calcium, suggesting that subacute hypoxia may inactivate the channels as well as reduce expression. As the expression of mRNA for Kv1.2, Kv1.5, and Kv2.1 is sensitive to subacute hypoxia and decreased expression/function of these channels has physiologic effects on membrane potential and cytosolic calcium, it seems likely that these Kv channels may also be involved in the mechanism of high-altitude pulmonary edema and possibly in the signaling of chronic hypoxic pulmonary hypertension.

Abbreviations: 4-aminopiridine, 4-AP • ethylene glycol-bis(ß-aminoethyl ether) N,N,N',N'-tetraacetic acid, EGTA • resting membrane potential, E_m • high-altitude pulmonary edema, HAPE • N-(2-hydroxyethyl)-piperazine-N'-(2-ethane sulfonic acid), HEPES • hypoxic pulmonary vasoconstriction, HPV • potassium current, Ik • inward-rectifier potassium channel, Kir • voltage-activated potassium channels, Kv • optical density, OD • pulmonary artery, PA • rat pulmonary artery myocytes, PASMCs • polymerase chain reaction, PCR • reverse transcriptase, RT

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