ETA RECEPTORS MEDIATE INHIBITION OF THE CARDIAC PKA-DEPENDENT CL- CURRENT VIA A PERTUSSIS-TOXIN-SENSITIVE MECHANISM

The effects of endothelin-1 (ET-1) on whole-cell cardiac PKA-dependent Cl- currents (I-Cl) were investigated using patch clamp techniques. E T-1 inhibited the isoproterenol-induced I-Cl with a half-maximally eff ective concentration of similar to 1nM. Similar concentrations of ET-1 also inhibited the forskolin- and histamine-induced currents. In cont rast, ET-1 did not inhibit the I-Cl induced by internal dialysis with cyclic AMP. The effects of ET-1 were abolished by pretreatment with pe rtussis toxin. Binding assays revealed both ET(A) (similar to 75%) and ET(B) (similar to 25%) receptors in ventricular membranes. The inhibi tory action of ET-1 was almost completely prevented by the ET(A)-selec tive antagonist, BQ-123 (3 mu M). On the other hand the ET(B)-selectiv e agonist, sarafotoxin S6c, did not inhibit I-Cl.