British journal of pharmacology

Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065.

PMID 8032643


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 ETA receptor-selective antagonist, and/or PD 145065, an ETA/ETB 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 pressor 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 ETA 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-123. 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 ETA and ETB receptors.6. Thus, sustained vasoconstrictions to ET-1 in vitro, mediated by either ETA or ETB receptors, may be reversed slowly by the subsequent application of receptor antagonists. Similarly, endothelin antagonists reverse the pressor effects of ET-1 in vivo although co-antagonism of ETA and ETB receptors or the co-administration of an ETA 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.

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BQ-123, ≥99%, lyophilized powder