Diazepam, γ-aminobutyric acid, and progesterone open K + channels in myocytes from coronary arteries

Abstract

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, γ-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.