title: Influence of endothelin ET(A) and ET(B) receptor antagonists on endothelin-induced contractions of the guinea pig isolated gall bladder.
abstract: The receptors mediating guinea pig gall bladder (GPGB) contractions induced by endothelin-1 (ET-1) 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 nM) was equipotent to ET-2 and SRTX (selective ET(B) receptor agonist), but more potent than ET-3 (5-fold) or IRL 1620 (selective ET(B) receptor agonist). BQ-123 (0.3 microM, peptidic ET(A) receptor antagonist) did not alter responses to ET-1, ET-3 or SRTX. BQ-788 (1 microM, peptidic ET(B) 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 microM, peptidic ET(B) receptor antagonist). The combination BQ-123 (0.3 microM) plus BQ-788 (1 microM) did not modify responses to ET-1, inhibited SRTX responses similarly to BQ-788 alone and abolished ET-3 responses. Bosentan (1 microM, non-peptidic ET(A)/ET(B) receptor antagonist) reduced the potency of ET-1 (15-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 ET(A) and ET(B) 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 ET(A) receptor may not coincide entirely, as BQ-123, even in presence of BQ-788, did not affect ET-1-induced contractions.
authors.affiliation: Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, Rua Ferreira Lima, Florianopolis, SC, Brazil.
authors.forename: A M
authors.initials: AM
authors.lastname: Cardozo
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.forename: M
authors.initials: M
authors.lastname: Yano
authors.forename: P A
authors.initials: PA
authors.lastname: Frank
authors.forename: G A
authors.initials: GA
authors.lastname: Rae
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*
chemical_list: C097273:BMS 184696; C097274:BMS 184697; D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C087120:RES 701-1; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)