Role of a novel KCa opener in regulating K+ channels of hypoxic human pulmonary vascular cells.

Abstract

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 (KCa). DHEA reversed the effect of chronic hypoxia on KCa, 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 KCa sensitivity to membrane potential (Em). DHEA reversed the effect of hypoxia on KCa sensitivity to Em and caused a mean of 40-mV left shift in voltage-dependent activation of KCa. DHEA increased KCa 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 KCa opener of the human pulmonary vasculature.

• Authors: W Peng, J R Hoidal, I S Farrukh
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 20 Issue 4 Pg. 737-45 (Apr 1999) ISSN: 1044-1549 [Print] United States
• PMID: 10101006 (Publication Type: Journal Article)

Chemical References

• 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
• Enzyme Inhibitors
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• Potassium Channels, Voltage-Gated
• Protein Kinase Inhibitors
• Thionucleotides
• potassium channel protein I(sk)
• Charybdotoxin
• adenosine-3',5'-cyclic phosphorothioate
• Dehydroepiandrosterone
• Egtazic Acid
• 4-Aminopyridine
• Cyclic AMP
• Cyclic GMP

Topics

• 4-Aminopyridine (pharmacology)
• Cell Hypoxia (physiology)
• Cells, Cultured
• Charybdotoxin (pharmacology)
• Cyclic AMP (analogs & derivatives, pharmacology)
• Cyclic GMP (analogs & derivatives, pharmacology)
• Dehydroepiandrosterone (pharmacology)
• Egtazic Acid (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Membrane Potentials (drug effects, physiology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Patch-Clamp Techniques
• Potassium Channels (drug effects, physiology)
• Potassium Channels, Inwardly Rectifying
• Potassium Channels, Voltage-Gated
• Protein Kinase Inhibitors
• Pulmonary Circulation (physiology)
• Thionucleotides (pharmacology)