BQ-788, a selective endothelin ET(B) receptor antagonist

Cardiovasc Drug Rev. Winter 2002;20(1):53-66. doi: 10.1111/j.1527-3466.2002.tb00082.x.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology*
  • Antihypertensive Agents / therapeutic use
  • Endothelin Receptor Antagonists*
  • Endothelins / blood
  • Endothelins / physiology
  • Hemodynamics / drug effects
  • Humans
  • Hypertension / drug therapy
  • Muscle, Smooth, Vascular / drug effects
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Oligopeptides / therapeutic use
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Receptor, Endothelin B

Substances

  • Antihypertensive Agents
  • Endothelin Receptor Antagonists
  • Endothelins
  • Oligopeptides
  • Piperidines
  • Receptor, Endothelin B
  • BQ 788