Diazepam, gamma-aminobutyric acid, and progesterone open K(+) channels in myocytes from coronary arteries.
Benzodiazepines enhance coronary blood flow and lower blood pressure, but the cellular basis of this action remains unclear. The present study now demonstrates a direct effect of diazepam, gamma-aminobutyric acid (GABA), and progesterone on the large conductance, Ca(2+)- and voltage-activated K(+) channel (BK(Ca)) in single myocytes isolated from porcine coronary arteries. These GABA receptor agonists significantly increased whole-cell (perforated patch) K(+) currents and stimulated the activity of single BK(Ca) channels in cell-attached patches dramatically. This effect is not mediated via cyclic AMP or cyclic GMP, but involves stimulation of Ca(2+) influx in response to activation of a bicuculline-sensitive GABA(A)-like receptor. We propose that localized, subsarcolemmal increases in Ca(2+) levels open BK(Ca) channels, thereby promoting K(+) efflux, membrane repolarization, and coronary relaxation. This transduction pathway can now account, at least in part, for the direct vasodilatory effects of diazepam, progesterone, and GABA.
Jacob
M K
MK
Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, OH 45435, USA.
White
R E
RE
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011374:Progesterone / Q000494:pharmacology*; D013552:Swine; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018756:GABA Antagonists; D018757:GABA Modulators; D015221:Potassium Channels; D011374:Progesterone; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D003975:Diazepam; D002118:Calcium; D001640:Bicuculline