|
Sign In to gain access to subscriptions and/or personal tools.
|
Vasopeptidase Inhibition Prevents Target Organ Damage and Improves Survival in Spontaneously Hypertensive Rats
Wolfgang Linz
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
References
- Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-72.[Abstract/Free Full Text]
- Trippodo NC, Robl JA, Asaad MM et al. Effects of omapatrilat in low, normal, and high renin experimental hypertension. Am J Hypertens 1998;11:363-72.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Intengan HD, Schiffrin EL Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. Hypertension 2000;35:1221.[Abstract/Free Full Text]
- Graham D., Hamilton C., Beattle E., Spiers A., Dominiczak AF Comparison of the effects of omapatrilat and irbesartan/hydrochlorothiazide on endothelial function and cardiac hypertrophy in the stroke-prone spontaneously hypertensive rat: sex differences. J Hypertens 2004;22:329-37.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kostis JB, Packer M., Black HR et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103-11.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Quaschning T., d'Uscio LV, Shaw S. et al. Vasopeptidase inhibition restores renovascular endothelial dysfunction in salt-induced hypertension. J Am Soc Nephrol 2001;12:2280-7.[Abstract/Free Full Text]
- Aguilar-Salinas CA, Arellano SA, Villanueva-Sanchez O. et al. Effects of omapatrilat on blood pressure and insulin sensitivity in an animal model of insulin resistance. Blood Press 2001;10:164-9.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Schäfer S., Steioff K., Linz W. et al. Chronic vasopeptidase inhibition normalizes diabetic endothelial dysfunction. Eur J Pharmacol 2004;484:361-2.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Weckler N., Leitzbach D., Kalinowski L. et al. Effect of chronic treatment with the vasopeptidase inhibitor AVE 7688 and ramipril on endothelial function in atherogenic diet rabbits. JRAAS 2003;4:191-6.[Medline]
[Order article via Infotrieve]
- Hayek T., Hamoud S., Keidar S. et al. Omapatrilat decreased macrophage oxidative status and atherosclerosis progression in atherosclerotic apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 2004;43:140-7.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Taal MW, Nenov VD, Wong W. et al. Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting enzyme inhibition alone. J Am Soc Nephrol 2001; 12:2051-9.[Abstract/Free Full Text]
- Davis BJ, Johnston CI, Burrell LM et al. Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy. Diabetologia 2003;46:961-71.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Schäfer S., Linz W., Bube A. et al. Vasopeptidase inhibition prevents nephropathy in Zucker diabetic fatty rats. Cardiovasc Res 2003;60:447-54.[Abstract/Free Full Text]
- Linz W., Jessen T., Becker RH et al. Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation 1997;96:3164-72.[Abstract/Free Full Text]
- Unger T., Mattfeldt T., Lamberty V. et al. Effect of early onset angiotensin converting enzyme inhibition on myocardial capillaries. Hypertension 1992;20:478-82.[Abstract/Free Full Text]
- Linz W., Wohlfart P., Schoelkens BA et al. Late treatment with ramipril increases survival in old spontaneously hypertensive rats. Hypertension 1999;34:291-5.[Abstract/Free Full Text]
- Palmerini CA, Fini C., Floridi A. et al. High-performance liquid chromatographic analysis of free hydroxyproline and proline in blood plasma and of free and peptide-bound hydroxyproline in urine. J Chromatogr 1985;339:285-92.[Web of Science][Medline]
[Order article via Infotrieve]
- Bickel M., Baringhaus KH, Gerl M. et al. Selective inhibition of hepatic collagen accumulation in experimental liver fibrosis in rats by a new prolyl 4-hydroxylase inhibitor. Hepatology 1998;28:404-11.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Opie LH, Parving HH Diabetic nephropathy: can renoprotection be extrapolated to cardiovascular protection? Circulation 2002;106:643-5.[Free Full Text]
- Schäfer S., Linz W., Vollert H. et al. The vasopeptidase inhibitor AVE7688 ameliorates Type 2 diabetic nephropathy. Diabetologia 2004;47:98-103.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Benigni A., Zoja C., Zatelli C. et al. Vasopeptidase inhibitor restores the balance of vasoactive hormones in progressive nephropathy. Kidney Int 2004;66:1959-65.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Azizi M., Bissery A., Peyrard S., Guyene TT, Ozoux M.-L. Floch A., Menard J. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans. Clin Pharmacol Ther 2006;79:49-61.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Blais C., Jr., Lapointe N., Rouleau JL et al. Effects of the vasopeptidase inhibitor omapatrilat on cardiac endogenous kinins in rats with acute myocardial infarction. Peptides 2001;22:953-62.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Marin-Castano ME, Schanstra JP, Neau E. et al. Induction of functional bradykinin b(1)-receptors in normotensive rats and mice under chronic Angiotensin-converting enzyme inhibitor treatment. Circulation 2002;105:627-32.[Abstract/Free Full Text]
- Agata J., Miao RQ, Yayama K. et al. Bradykinin B(1) receptor mediates inhibition of neointima formation in rat artery after balloon angioplasty. Hypertension 2000;36:364-70.[Abstract/Free Full Text]
Journal of Renin-Angiotensin-Aldosterone System, Vol. 7, No. 3,
155-161 (2006)
DOI: 10.3317/jraas.2006.025
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
|
|
