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, y-aminobutyric acid (GABA), and progesterone on the large conductance, Ca2+- 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 Ca2+ influx in response to activation of a bicuculline-sensitive GABA(A)-like receptor. We propose that localized, subsarcolemmal increases in Ca2+ 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.