title: Nonpeptide endothelin receptor antagonists. IX. Characterization of endothelin receptors in guinea pig bronchus with SB 209670 and other endothelin receptor antagonists.
abstract: In this study the endothelin (ET) receptors mediating contractions produced by ET-1, ET-3 and the selective ET(B) ligands sarafotoxin 6c (S6c) and BQ-3020 in guinea pig bronchus were investigated using SB 209670, a nonpeptide, mixed ET(A)/ET(B) receptor antagonist, and the peptide ET receptor antagonists BQ-123 (ET(A) receptor-selective), BQ-788 (ET(B) receptor-selective) and RES-701 (ET(B) receptor-selective). SB 209670 (10 microM) antagonized concentrations induced by ET-1 (pK(B) = 6.1). In contrast, BQ-788 (10 microM) and BQ-123 (10 microM), either alone or in combination, were without significant effect on ET-1 concentration-response curves. SB 209670 (10 microM) and BQ-788 (10 microM) antagonized S6c concentration-response curves with pKB values of 6.6 and 5.5, respectively, whereas RES-701 (10 microM) and BQ-123 (10 microM) were without effect. SB 209670 (10 microM) was about a 10-fold less potent antagonist of contractions produced by ET-3 (pK(B) = 5.4) than of those elicited by S6c. BQ-788 (10 microM), RES-701 (10 microM) and BQ-123 (10 microM) were without effect on ET-3 concentration-response curves. BQ-788 (10 microM) had similar potencies for inhibition of contractions induced by S6c (pK(B) = 5.8) and BQ-3020 (pK(B) = 6.25). These data indicate that contractions induced by ET-1, ET-3, S6c and BQ-3020 in guinea pig bronchus appear to be mediated predominantly via stimulation of ET(B) receptors. However, these receptors are not very sensitive to the standard ET(B) receptor antagonists BQ-788 and RES-701, which suggests that responses produced by these ligands in this tissue involve activation not of the classical ET(B) receptor, but rather of an atypical ET receptor population. The results also provide additional evidence that the potencies of ET receptor antagonists depend upon the specific ET agonist.
authors.affiliation: Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: M A
authors.initials: MA
authors.lastname: Luttmann
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D007189:Indans; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; C087120:RES 701-1; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)