Am. J. Respir. Cell Mol. Biol., Volume 20, Number 4, April, 1999 737-745

Role of a Novel K_Ca Opener in Regulating K⁺ Channels of Hypoxic Human Pulmonary Vascular Cells

Wei Peng, John R. Hoidal, and Imad S. Farrukh

Division of Respiratory, Critical Care and Occupational Medicine, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah

Hypoxic pulmonary vasoconstriction (HPVC) is mediated, in part, via membrane depolarization and inhibition of K⁺ channels. We recently observed that the naturally occurring steroid dehydroepiandrosterone (DHEA) reversed and prevented HPVC in isolated perfused and ventilated ferret lungs. In the current study, we investigated the effects of DHEA on the major K⁺ channels of chronically hypoxic human pulmonary smooth-muscle cells (HPSMC). K⁺ channels were recorded by using the patch-clamp technique in whole-cell and single-channel configurations. Single-channel recordings were performed in inside-out and outside-out excised patches, and in intact HPSMC in cell-attached configuration. Using whole-cell current recording, chronic hypoxia decreased the high-amplitude, high-noise, and charybdotoxin-sensitive Ca²⁺-dependent K⁺ channels (K_Ca). DHEA reversed the effect of chronic hypoxia on K_Ca, but had no effect on the low-amplitude, low-noise, and 4-aminopyridine-sensitive delayed rectifying K⁺ channels. In the cell-attached configuration, chronic hypoxia caused a decrease in K_Ca sensitivity to membrane potential (E_m). DHEA reversed the effect of hypoxia on K_Ca sensitivity to E_m and caused a mean of 40-mV left shift in voltage-dependent activation of K_Ca. DHEA increased K_Ca activation from both sides of membrane patches of hypoxic HPSMC via a cyclic adenosine monophosphate- and cyclic guanosine monophosphate-independent pathway. We concluded that DHEA is a novel K_Ca opener of the human pulmonary vasculature.

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