Detail of "156161-89-6"

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Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor-Mediated and Nitric Oxide-Dependent Mechanism

Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor-Mediated and Nitric Oxide-Dependent Mechanism. Goddard, Jane; Eckhart, Corine; Johnston, Neil R.Several substances are used for example 156161-89-6 and 9015-82-1 which are their cas registry numbers.; Cumming, Allan D.; Rankin, Andrew J.; Webb, David J. (Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK). Journal of the American Society of Nephrology, 15(10), 2601-2610 (English) 2004 Lippincott Williams & Wilkins. CODEN: JASNEU. ISSN: 1046-6673. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve ± SEM; BQ-123, -2.3 ± 1.8%; BQ-123+E, -5.1 ± 1.1%; P < 0.05 vs. placebo). BQ-123 increased effective renal blood flow (BQ-123, -0.1 ± 2.4%; BQ-123+E, 10.9 ± 4.2%; P < 0.01 vs. BQ-123), reduced effective renal vascular resistance (BQ-123, -1.2 ± 3.1%; BQ-123+E, -12.8 ± 3.0%; P < 0.01 vs. placebo and vs. BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 ± 12.8%; BQ-123+E, 25.2 ± 12.6%; P < 0.05 vs. BQ-123, P < 0.01 vs. placebo and vs. E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptor-mediated, NO-dependent, COX-independent mechanism. The redn. of BP and renal vascular resistance and assocd. substantial natriuresis make this a potentially attractive therapeutic combination in renal disease. .

BQ-788, a selective endothelin ETB receptor antagonist

BQ-788, a selective endothelin ETB receptor antagonist. Okada, Megumu; Nishikibe, Masaru (Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan). Cardiovascular Drug Reviews, 20(1), 53-66 (English) 2002 Neva Press. CODEN: CDREEA. ISSN: 0897-5957. DOCUMENT TYPE: Journal; General Review CA Section: 1 (Pharmacology) A review. 156161-89-6 and 123626-67-5 are cas registry numbers. These chemicals are also mentioned in this article. We describe characteristics of a selective endothelin (ET) ETB receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-g-methylleucyl-D-1-methoxycar bonyltryptophanyl-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 mM 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 pharmacol. dose of ET-1- or sarafotoxin 6C (S6c) (0.5 nmol/kg, i.v.)-inducted ETB receptor-mediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concn. 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 physiol. and/or pathophysiol. conditions. .