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 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).(ABSTRACT TRUNCATED AT 250 WORDS)[1]References
- Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065. Warner, T.D., Allcock, G.H., Vane, J.R. Br. J. Pharmacol. (1994) [Pubmed]
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