Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: a Ca(2+)-activated K(+)-channel opener.
In the present study, we investigated the effects of the naturally occurring hormone dehydroepiandrosterone (DHEA) on hypoxic pulmonary vasoconstriction (HPVC) in isolated ferret lungs and on K+ currents in isolated and cultured ferret pulmonary arterial smooth muscle cells (FPSMCs). Severe alveolar hypoxia (3% O2-5% CO2-92% N2) caused an initial increase in pulmonary arterial pressure (Ppa) that was followed by a reversal in pulmonary hypertension. Maintaining alveolar hypoxia caused a sustained secondary increase in Ppa. Pretreating the lungs with the K(+)-channel inhibitor tetraethylammonium (TEA) caused a small increase in baseline Ppa, potentiated HPVC, and prevented the reversal of HPVC during the sustained alveolar hypoxia. Treating the lungs with DHEA caused a near-complete reversal of HPVC in control lungs and in lungs that were pretreated with TEA. DHEA also reversed the KCl-induced increase in Ppa. In FPSMCs, DHEA caused an adenosine 3',5'-cyclic monophosphate- and guanosine 3',5'-cyclic monophosphate-independent increase in activity of the Ca(2+)-activated K+ (KCa) current. In a cell-attached configuration, DHEA caused a mean shift of -22 mV in the voltage-dependent activation of the KCa channel. We conclude that DHEA is a novel KCa-channel opener of the pulmonary vasculature.
Farrukh
I S
IS
Department of Internal Medicine, University of Utah Health Science Center, Salt Lake City 84132, USA.
Peng
W
W
Orlinska
U
U
Hoidal
J R
JR
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D005289:Ferrets; D015640:Ion Channel Gating / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D011650:Pulmonary Alveoli / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D003687:Dehydroepiandrosterone; D019789:Tetraethylammonium; D000242:Cyclic AMP; D006152:Cyclic GMP