title: BQ-788, a selective endothelin ET(B) receptor antagonist.
abstract: We describe characteristics of a selective endothelin (ET) ET(B) receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETs in vitro and in vivo. In vitro, BQ-788 potently and competitively inhibited (125)I-labeled ET-1 binding to ET(B) receptors in human Girrardi heart cells (hGH) with an IC(50) of 1.2 nM, but only poorly inhibited the binding to ET A receptors in human neuroblastoma cell line SK-N-MC cells (IC(50), 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 showed no agonistic activity up to 10 microM and competitively inhibited the vasoconstriction induced by an ET(B)-selective agonist (pA(2), 8.4). BQ-788 also inhibited several bioactivities of ET-1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET-1. Thus, it is confirmed that BQ-788 is a potent, selective ET(B) receptor antagonist. In vivo, in conscious rats, BQ-788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET-1- or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)-induced ET(B) receptor-mediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concentration of ET-1, which is considered an index of potential ET(B) receptor blockade in vivo. In Dahl salt-sensitive hypertensive (DS) rats, BQ-788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ-788 also inhibited ET-1-induced bronchoconstriction, tumor growth and lipopolysaccharide-induced organ failure. These data suggest that BQ-788 is a good tool for demonstrating the role of ET-1 and ET(B) receptor subtypes in physiological and/or pathophysiological conditions.
authors.affiliation: Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan. okadamg@banyu.co.jp.
authors.forename: Megumu
authors.initials: M
authors.lastname: Okada
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D044023:Receptor, Endothelin B
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; C086539:BQ 788