Antiadrenergic effects of endothelin-1 on the L-type Ca2+ current in dog ventricular myocytes

The effect of endothelin-1 (ET-1) on L-type Ca2+ current (I-Ca) and the interaction of ET-I with beta-adrenergic stimulation were studied in dog ventricular myocytes by means of a whole-cell patch-clamp technique. ET-1 (10(-8) M) had no effect on the baseline I-Ca, but at 10(-9)-10(-7) M, it inhibited the isoproterenol (ISO)-induced increase in I-Ca. The maximal inhibition induced by ET-I at 3 x 10(-8) M was similar to 30%. and the median inhibitory (IC50) value of ET-1 was 1.1 x 10(-9) M. The inhibitory action of ET-I (10(-8) M) on the ISO-induced increase in I-Ca was markedly attenuated by the ETA antagonist FR139317 (10(-6) M) and was partially inhibited by the ETB antagonist BQ-788 (10(-6) M). The inhibitory action of ET-1 was totally inhibited by the nonselective ET-receptor antagonist, TAK-044 (10-(6) 1). These results indicate that ET-1 exerts an antiadrenergic effect on the ISO-induced increase in I-Ca, which is mediated mainly by ETA, but activation of ETB receptors might contribute to the effect of ET-I to a lesser extent.