VOLTAGE-SENSITIVE ion channels play fundamental roles in the regulation of cardiac function by various neurotransmitters(1,2). Endothelins(3) have strong positive inotropic(4) and chronotropic(5) effects, for,which recent studies have implicated various intracellular mechanisms(6,7). However, very little is known about the underlying ion-channel regulation by the peptide. We report here that endothelin-1 consistently hyperpolarizes the membrane and shortens the duration of the action potential in mammalian atrial myocytes, leading to suppression of electrical excitability of the heart. Endothelin-1, but not endothelin(3), inhibited the L-type calcium current by decreasing cyclic AMP accumulation and activated the muscarinic potassium current by stimulating a pertussis toxin-sensitive GTP-binding protein. Consistent with these results, endothelin-1 strongly reduced the heart rate when it was increased by beta-adrenoceptor stimulation. These effects were blocked by an ET(A) (endothelin-1-selective) receptor-selective antagonist, BQ123 (refs 8-11). The ET(A) receptor-mediated regulation of cardiac ion channels gives new insight into our understanding of the physiological and pathophysiological roles of endothelins in the control of cardiac function.