Attenuation of cardiovascular remodeling in DOCA-salt rats by the vasopeptidase inhibitor, omapatrilat.

Abstract

Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and angiotensin-converting enzyme with similar potency. The aim of this study was to investigate whether omapatrilat prevents or reverses cardiovascular remodeling and hypertension in deoxycorticosterone acetate (DOCA)-salt rats. Male Wistar rats (313 +/- 2 g, n = 114) were uninephrectomized (UNX) with or without further treatment with DOCA and 1% NaCl in the drinking water. Compared with UNX control rats, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, perivascular and interstitial cardiac fibrosis and inflammation, endothelial dysfunction, and the prolongation of ventricular action potential duration within four weeks. The administration of omapatrilat (40 mg/kg/day po) for two weeks commencing two weeks after surgery attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation. In contrast, omapatrilat treatment did not lower systolic blood pressure nor improve endothelial dysfunction. This study concludes that the renin-angiotensin-aldosterone, natriuretic peptide, and bradykinin systems are directly involved in the pathogenesis of cardiovascular remodeling in the DOCA-salt model of hypertension in rats, which may be independent of their effects on blood pressure.

• Authors: David Loch, Andrew Hoey, Lindsay Brown
• Journal: Clinical and experimental hypertension (New York, N.Y. : 1993) (Clin Exp Hypertens) Vol. 28 Issue 5 Pg. 475-88 (Jul 2006) ISSN: 1064-1963 [Print] England
• PMID: 16820344 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antihypertensive Agents
• Pyridines
• Sodium Chloride, Dietary
• Thiazepines
• omapatrilat
• Desoxycorticosterone
• Metalloendopeptidases

Topics

• Action Potentials (drug effects)
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Aorta, Thoracic (drug effects)
• Blood Pressure (drug effects)
• Desoxycorticosterone
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects)
• Fibrosis (drug therapy)
• Heart Ventricles (drug effects)
• Hypertension (chemically induced, drug therapy, physiopathology)
• Hypertrophy (drug therapy)
• Inflammation (drug therapy)
• Male
• Membrane Potentials (drug effects)
• Metalloendopeptidases (antagonists & inhibitors)
• Myocardial Contraction (drug effects)
• Papillary Muscles (drug effects)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• Sodium Chloride, Dietary
• Thiazepines (pharmacology)
• Ventricular Remodeling (drug effects)