Role of a novel K-Ca opener in regulating K+ channels of hypoxic human pulmonary vascular cells

Hypoxic pulmonary vasoconstriction (HPVC) is mediated, in part, via membran e depolarization and inhibition of K+ channels. We recently observed that t he naturally occurring steroid dehydroepiandrosterone (DHEA) reversed and p revented HPVC in isolated perfused and ventilated ferret lungs. In the curr ent study, we investigated the effects of DHEA on the major K+ channels of chronically hypoxic human pulmonary smooth-muscle cells (HPSMC). K+ channel s 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 decrease d the high-amplitude, high-noise, and charybdotoxin-sensitive Ca2+-dependen t K+ channels (K-Ca). DHEA reversed the effect of chronic hypoxia on K-Ca b ut had no effect on the low-amplitude, low-noise, and 4-aminopyridine-sensi tive delayed rectifying K+ channels. In the cell-attached configuration, ch ronic 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 c aused a mean of 40-mV left shift in voltage-dependent activation of K-Ca DH EA increased K-Ca activation from both sides of membrane patches of hypoxic HPSMC via a cyclic adenosine monophosphate- and cyclic guanosine monophosp hate-independent pathway. We concluded that DHEA is a novel K-Ca opener of the human pulmonary vasculature.