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BQ-788, A Selective Endothelin ETB Receptor Antagonist

     We describe characteristics of a selective endothelin (ET) ETB receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-?-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

    125I-labeled ET-1 binding to ETB receptors in human Girrardi heart cells (hGH) with an

    IC50 of 1.2 nM, but only poorly inhibited the binding to ETA receptors in human neuroblastoma cell line SK-N-MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries,BQ-788 showed no agonistic activity up to 10 M and competitively inhibited the

    vasoconstriction induced by an ETB-selective agonist (pA2, 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 ETB 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 ETB receptormediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concentration of ET-1, which is considered an index of potential ETB 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 ETB receptor subtypes in physiological and_or pathophysiological conditions.