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Omapatrilat decreased macrophage oxidative status and atherosclerosis progression in atherosclerotic apolipoprotein E-deficient mice.

Abstract：

UNLABELLED:Oxidative stress is an important risk factor in the pathogenesis of atherosclerosis. Angiotensin-converting enzyme (ACE) inhibitors attenuate atherosclerosis and oxidative stress in animal models. Omapatrilat, a VasoPeptidase-inhibitor, selectively inhibits both Neutral-Endo-Peptidase (NEP) and ACE. OBJECTIVE:In this study, we analyzed the effect of Omapatrilat administration (1, 4, or 20mg/kg/d, for 12 weeks) to atherosclerotic apolipoprotein E-deficient (E0) mice on their blood pressure (BP), serum and macrophage oxidative status, and atherosclerotic lesion area. RESULTS:Following administration of Omapatrilat (4 mg/kg/d and 20 mg/kg/d), the mice systolic and diastolic BP significantly decreased by up to 33% and 25% respectively, compared with placebo-treated mice. However, administration of Omapatrilat at 1mg/kg/d did not affect the mice BP. The Omapatrilat-treated mice serum susceptibility to lipid peroxidation was reduced by up to 21%, and their serum paraoxonase activity was increased by up to 24%, compared with placebo-treated mice. Peritoneal macrophages from Omapatrilat-treated (20 mg/kg/d) mice exhibited a reduced oxidative stress, evidenced by a reduction in macrophage lipid peroxide content (by 45%), cholesteryl-linoleate hydroperoxide content (by 48%), and oxidized glutathione levels (by 40%). Finally, the area of the mice atherosclerotic lesion was dose-dependently reduced, by 50%, 67%, and 82%, following Omapatrilat administration at 1mg/kg/d, 4 mg/kg/d, and 20 mg/kg/d respectively, compared with placebo-treated mice. CONCLUSION:Omapatrilat has a substantial anti-atherosclerotic effect, which can be related not only to BP reduction but also to its ability to reduce oxidative stress in atherosclerotic E0 mice.

journal_name

J Cardiovasc Pharmacol

journal_title

Journal of cardiovascular pharmacology

authors

Hayek T,Hamoud S,Keidar S,Pavlotzky E,Coleman R,Aviram M,Kaplan M

doi

10.1097/00005344-200401000-00021

subject

Has Abstract

pub_date

2004-01-01 00:00:00

pages

140-7

issue

eissn

0160-2446

issn

1533-4023

journal_volume

pub_type

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Omapatrilat decreased macrophage oxidative status and atherosclerosis progression in atherosclerotic apolipoprotein E-deficient mice.