REVERSAL OF ESTABLISHED RESPONSES TO ENDOTHELIN-1 IN-VIVO AND IN-VITRO BY THE ENDOTHELIN RECEPTOR ANTAGONISTS, BQ-123 AND PD-145065

1 Endothelin-1 binds almost irreversibly to its receptors and causes prolonged vasoconstrictions. Here we have studied the reversal of established responses to ET-1 in vivo and in vitro by BQ-123, an ET(A) receptor-selective antagonist, and/or PD 145065, an ET(A)/ET(B) receptor non-selective antagonist. 2 In anaesthetized rats pretreated with hexamethonium, infusion of ET-1 (10(-11) mol kg(-1) min(-1)) increased the mean arterial pressure (MAP) from 93 +/- 1.5 mmHg to 137 +/- 2.4 mmHg after 70 min (n = 29). While the ET-1 infusion was continued an additional infusion of BQ-123 caused a gradual dose-dependent reduction in the presser effect of ET-1. For instance, after a 60 min infusion of BQ-123 (10(-8) mol kg(-1) min(-1)) the MAP was decreased by 29.3 +/- 4.3 mmHg (n = 4). 3 PD 145065 was a much weaker antagonist of the established pressor effects of ET-1. At 10(-8) mol kg(-1) min(-1) it had no significant effect and even at 10(-7) mol kg(-1) min(-1) the elevated blood pressure was only reduced by 11.8 +/- 8.0 mmHg (n = 5) after 60 min. Co-infusion of BQ-123 and PD 145065 caused smaller reductions in the established response to ET-1 than infusion of BQ-123 alone. 4 Sustained contractions of rat aortic rings induced by ET-1 (3 x 10(-9) M) and mediated by ET(A) receptors were slowly reversed by addition of BQ-123 (10(-5) M) or PD 145065 (10(-5) M). For instance, after 40 min the elevated tone was reduced 85.8 +/- 5.6% (n = 6) by PD 145065, and 77.1 +/- 6.7% (n = 6) by BQ-I23. Thus, on the rat aortic rings in vitro both antagonists were equally effective against established responses to ET-1. 5 ET-1 increased the perfusion pressure of the rat isolated perfused kidney by 138.1 +/- 7.6 mmHg (n = 14). Subsequent co-infusion of BQ-123 or PD 145065 reversed this increase with PD 145065 being more active. For instance, PD 145065 (10(-6) M) reversed the increase in perfusion pressure by 56.9 +/- 8.8% (n = 5) and BQ-123 (10(-6) M) reversed it by 22.8 +/- 8.0% (n = 5). This fits well with the vasoconstriction induced by ET-1 in the rat kidney being mediated by ET(A) and ET(B) receptors. 6 Thus, sustained vasoconstrictions to ET-1 in vitro, mediated by either ET(A) or ET(B) receptors, may be reversed slowly by the subsequent application of receptor antagonists. Similarly, endothelin antagonists reverse the presser effects of ET-1 in vivo although co-antagonism of ET(A) and ET(B) receptors or the co-administration of an ET(A) receptor antagonist, BQ-123, and a mixed antagonist, PD 145065 produces less reversal than the application of an ETA receptor-selective antagonist. This may be because PD 145065 also reduces vasodilatations induced by ET-1 in vivo, or could suggest that because of its peptide structure PD 145065 affects the elimination of ET-1.