ENDOTHELIN-1 INHIBITS L-TYPE CA CURRENTS ENHANCED BY ISOPROTERENOL INGUINEA-PIG VENTRICULAR MYOCYTES

To investigate the action of endothelin-1 (ET-1) on L-type Ca currents (I-Ca,I-L in guinea-pig ventricular cells, whole-cell currents were r ecorded at approximate to 36-37 degrees C in enzymatically isolated my ocytes. ET-1 (greater than or equal to 10 nM) suppressed the basal I(C a,L) to 79 +/- 8% of control at 20 nM. Bath application of isoproteren ol (ISO; 10 nM) enhanced I-Ca,I-L to 192 +/- 28% with about a -10-mV s hift of its relationship with membrane potential. ET-1 concentration d ependently inhibited this ISO-enhanced I-Ca,I-L, with a half-maximally inhibitory concentration (IC50) of 168 pM. The inhibitory actions of ET-1 were antagonised by BQ-123 (300 nM), cyclo(D-Asp-L-Pro-D-Val-L-Le u-D-Trp), a specific ETA receptor antagonist. Histamine-enhanced rca,L was also suppressed by ET-1, but I-Ca,I-L potentiated by internal ade nosine 3',5'-cyclic monophosphate (cAMP) was unaffected. Preincubation of myocytes with pertussis toxin (PTX, at 5 mu g/ml for >60 min at 36 degrees C) completely occluded the ET-1 action. Thus, stimulation of ETA receptors by subnanomolar ET-1 inhibits I-Ca,I-L via PTX-sensitive G-proteins.