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Reversal of established responses to endothelin‐1 in vivo and in vitro by the endothelin receptor antagonists, BQ‐123 and PD 145065
Author(s) -
Warner Timothy D.,
Allcock Graham H.,
Vane John R.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13053.x
Subject(s) - endothelin receptor , in vivo , endothelin 1 , pharmacology , in vitro , endothelin 3 , receptor , endothelins , endocrinology , medicine , chemistry , biology , biochemistry , microbiology and biotechnology
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 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 × 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‐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 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 pressor 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 ET A 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.