Vasopeptidase inhibition prevents target organ damage and improves survival in spontaneously hypertensive rats.
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.


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 microg/mg), which was significantly reduced by ramipril to 57+/-34 microg/mg, and practically abolished in the AVE7688 group (22+/-12 microg/mg, p<0.05 vs. placebo and ramipril). Tubulo-interstitial damage (semi-quantitative score) was significantly reduced by AVE7688 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.
Linz
Wolfgang
W
Therapeutic Department Cardiovascular Diseases, Sanofi Aventis Deutschland GmbH, Frankfurt am Main, Germany. wolfgang.linz@sanofi-aventis.com
Schäfer
Stefan
S
Afkham
Freni
F
Gerl
Martin
M
Schmidts
Hans-Ludwig
HL
Rütten
Hartmut
H
D000419:Albuminuria / Q000175:diagnosis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D005355:Fibrosis / Q000517:prevention & control; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006973:Hypertension / Q000201:enzymology*; D006977:Hypertension, Renal / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D010447:Peptide Hydrolases / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D010919:Placebos / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D016277:Ventricular Function, Left / Q000187:drug effects
C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010919:Placebos; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril