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Effect of chronic treatment with the vasopeptidase inhibitor AVE 7688 and ramipril on endothelial function in atherogenic diet rabbits

Aventis Pharma, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany

Daniela Leitzbach

Aventis Pharma, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany

Leszek Kalinowski

Ohio University, Department of Chemistry and Biochemistry, Athens, OH 45701-2979, USA

Tadeusz Malinski

Ohio University, Department of Chemistry and Biochemistry, Athens, OH 45701-2979, USA

Andreas E Busch

Aventis Pharma, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany

Wolfgang Linz

Aventis Pharma, DG Cardiovascular Diseases, D-65926 Frankfurt/Main, Germany, Wolfgang.Linz{at}aventis.com

Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis.

This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O₂ ) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet.

At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73±2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%.

Six weeks' feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food subsequently being changed to a normal chow. All measured parameters indicated a significant favourable effect on endothelial dysfunction as a result of the two treatment regimens. Endothelial function measured in the organ chamber showed somewhat greater improvement in the ACE-NEP treated group than in the ACE-I treated group. The treatment with ramipril, as well as with AVE 7688, restored endothelial function by increasing the ratio of NO to O₂- concentration and bioavailability of NO. In this study, a similar protective effect on endothelial function was shown by ACE-NEP inhibition as already seen with ACE inhibitors in an animal model of atherosclerosis.

Key Words: ACE-NEP inhibition • rabbits • hypercholesterolaemia • endothelial dysfunction

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 4, No. 3, 191-196 (2003)
DOI: 10.3317/jraas.2003.031


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Weckler, N. Articles by Linz, W. Search for Related Content PubMed PubMed Citation Articles by Weckler, N. Articles by Linz, W. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cholesterol Social Bookmarking                         What's this?