Endothelin-1 inhibitsl-type Ca currents enhanced by isoproterenol in guinea-pig ventricular myocytes

To investigate the action of Endothelin-1 (ET-1) on L-type Ca currents (I_Ca,L) in guinea-pig ventricular cells, whole-cell currents were recorded at 36-37° C in enzymatically isolated myocytes. ET-1 ( 10 nM) suppressed the basal I_ca,L to 79 ± 8% of control at 20 nM. Bath application of isoproterenol (ISO; 10 nM) enhanced I_Ca,L to 192±28% with about a – 10-mV shift of its relationship with membrane potential. ET-1 concentration dependently inhibited this ISO-enhanced I_Ca,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-Leu-d-Trp), a specific ETA receptor antagonist. Histamine-enhancedI_Ca,L was also suppressed by ET-1, butI_Ca,L potentiated by internal adenosine 3,5-cyclic monophosphate (cAMP) was unaffected. Preincubation of myocytes with pertussis toxin (PTX, at 5 g/ml for >60 min at 36° C) completely occluded the ET-1 action. Thus, stimulation of ET_A receptors by subnanomolar ET-1 inhibitsI_Ca,L via PTX-sensitive G-proteins.