Influence of endothelin ETA and ETB receptor antagonists on endothelin-induced contractions of the guinea pig isolated gall bladder

The receptors mediating guinea pig gall bladder (GPGB) contractions induced by endothelin-l (ET-I) and related peptides were characterized using various ET receptor antagonists. As all ET-receptor agonists used, except sarafotoxin S6c (SRTX), failed to induce a clear-cut maximal response at the highest concentration tested (i.e. 100 nM), their potencies are expressed in terms of a CK50 (i.e. the concentration causing 50% of the response to 80 mM KCl). ET-1 (CK50 0.8 mM) was equipotent to ET-2 and SRTX (selective ETB receptor agonist), but more potent than ET-3 (5-fold) or IRL 1620 (selective ETA receptor agonist). BQ-123 (0.3 mu M, peptidic ETB receptor antagonist) did not alter responses to ET-1, ET-3 or SRTX. BQ-788 (1 mu M, peptidic ETB receptor antagonist) reduced the potency of ET-3 (9-fold at the CK50, level) and SRTX ( > 20-fold), but not ET-1. SRTX responses were unaffected by RES-701-1 (3 mu M, peptidic ET, receptor antagonist). The combination BQ-123 (0.3 mu M) plus BQ-788 (1 mu M) did not modify responses to ET-1, inhibited SRTX responses similarly to BQ-788 alone and abolished ET-3 responses. Bosentan (1 mu M, non-peptidic ETA/ETB receptor antagonist) reduced the potency of ET-1 (9-fold), ET-3 (9-fold) and SRTX (4-fold). In rat aorta, the antagonists blocked ET-1-induced contractions (BQ-123 and bosentan) or SRTX-induced endothelium-dependent relaxations (BQ-788, RES-701-1 and bosentan). Thus, the GPGB expresses both ETA and ETB receptors. As BQ-123 only blocked responses to ET-3 in the presence of BQ-788, there appears to be cross-talk between both receptor types. Also, the binding sites of ET-1 and ET-3 on the ETA receptor may not coincide entirely, as BQ-123, even in presence of BQ-788, did not affect ET-1-induced contractions. Copyright (C) 1997 Elsevier Science B.V.