Activation of endothelin ET A receptors masks the constrictor role of endothelin ET B receptors in rat isolated small mesenteric arteries

Endothelin‐1 (ET‐1) produces constriction of the rat mesenteric vascular bed in vivo via ET A and ET B receptor subtypes. The aim of this study was to investigate the relative roles of these receptor subtypes in rat isolated, endothelium‐denuded, small mesenteric arteries, under pressure, by use of ET‐1; the ET A receptor antagonist, BQ‐123; the ET B receptor selective agonist, sarafotoxin S6c (SRTX S6c); the ET B receptor selective antagonist, BQ‐788; and the ET A /ET B antagonist, TAK‐044. In 3rd generation mesenteric arteries, ET‐1 (10 −13 10 −7 m ) produced concentration‐dependent contractions (pD 2 9.86). SRTX S6c (10 −12 10 −7 m ) also induced concentration‐dependent contractions in 53% of arteries studied, although the E max was much less than that obtained with ET‐1 (10.7±2.9% vs 101.9±2.6% of the 60 m m KCl‐induced contraction). Neither ET B receptor desensitization, by a supra‐maximal concentration of SRTX S6c (10 −7 m ), nor incubation with BQ‐788 (3×10 −8 m ), had any significant effect on the ET‐1 concentration‐response curve, although both treatments tended to enhance rather than inhibit responses to ET‐1. In the presence of BQ‐123 (10 −6 m ), responses to low concentrations of ET‐1 (up to 10 −10 m ) were unaffected but responses to concentrations of ET‐1 above 10 −10 m were significantly inhibited. SRTX S6c desensitization followed by incubation with BQ‐123 (10 −6 m ) or co‐incubation with BQ‐788 (3×10 −8 m ) and BQ‐123 caused inhibition of responses to all concentrations of ET‐1, resulting in a rightward shift of the ET‐1 concentration‐response curve. The same effect was obtained by incubation with TAK‐044 (10 −8 m and 3×10 −7 m ). Thus, responses of rat small mesenteric arteries to ET‐1 are mediated by both ET A and ET B receptors. The relative role of ET B receptors is greater than that predicted by the small responses to SRTX S6c or by resistance of ET‐1‐induced contraction to ET B receptor desensitization or BQ‐788. The effect of ET B receptor desensitization or blockade is only revealed in the presence of ET A receptor blockade, suggesting the presence of a ‘crosstalk’ mechanism between the receptors. These results support the concept that dual receptor antagonists, like TAK‐044, may be required to inhibit completely constrictor responses to ET‐1.British Journal of Pharmacology (1997) 120 , 1376–1382; doi: 10.1038/sj.bjp.0701036