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Vasopeptidase Inhibition Prevents Target Organ Damage and Improves Survival in Spontaneously Hypertensive Rats

Therapeutic Department Cardiovascular Diseases, wolfgang.linz{at}sanofi-aventis.com

Stefan Schäfer

Therapeutic Department Cardiovascular Diseases

Freni Afkham

LASW (Laboratory Animal Science and Welfare) Sanofi Aventis Deutschland GmbH, Frankfurt am Main, Germany

Martin Gerl

Biomarkers

Hans-Ludwig Schmidts

LASW (Laboratory Animal Science and Welfare) Sanofi Aventis Deutschland GmbH, Frankfurt am Main, Germany

Hartmut Rütten

Therapeutic Department Cardiovascular Diseases

Background. Vasopeptidase inhibition has been shown to be an effective antihypertensive principle but its long-term effects on hypertensive target organ damage are not known. We investigated the myocardial, vascular and renal effects of chronic vasopeptidase inhibition in arterial hypertension.

Methods and Results. One hundred and thirty-nine male spontaneously hypertensive rats aged 15 months were treated chronically with either the pure angiotensin-converting enzyme (ACE) inhibitor, ramipril (1 mg/kg/d in drinking water, n=46), or the vasopeptidase inhibitor AVE7688 (30 mg/kg/d in chow, n=46), or placebo (n=47) and followed up until they died. After six months, both ramipril and AVE7688 had markedly reduced plasma ACE activity, normalised blood pressure (BP), reduced left ventricular mass and improved systolic function to similar extents. Acetylcholine mediated relaxation of aortic rings was improved by both ramipril and AVE7688. There was substantial albuminuria in the placebo group (albumin-to-creatinine ratio 107±54 µg/mg), which was significantly reduced by ramipril to 57±34 µg/mg, and practically abolished in the AVE7688 group (22±12 µg/mg, p<0.05 vs. placebo and ramipril).Tubulointerstitial damage (semi-quantitative score) was significantly reduced by AVE7688 and ramipril. significantly reduced byAVE7688 and ramipril. Overall mortality was markedly reduced in the ramipril and AVE7688 groups (13% and 16% at six months, respectively), both p<0.05 vs. placebo (71%).

Conclusions. Vasopeptidase inhibition effectively controls BP and reduces myocardial, vascular and renal target organ damage, resulting in a markedly prolonged survival.At similar degrees of plasma ACE inhibition, AVE7688 compared to ramipril offers superior protection against hypertensive kidney damage.

Key Words: Spontaneously hypertensive rat • Target organ damage • Hypertensive nephropathy • Angiotensin-converting enzyme inhibition • Vasopeptidase inhibition

Journal of Renin-Angiotensin-Aldosterone System, Vol. 7, No. 3, 155-161 (2006)
DOI: 10.3317/jraas.2006.025


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