omapatrilat and Hypertrophy

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.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Fibrosis; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Male; Membrane Potentials; Metalloendopeptidases; Myocardial Contraction; Papillary Muscles; Pyridines; Rats; Rats, Wistar; Sodium Chloride, Dietary; Thiazepines; Ventricular Remodeling

Renovascular hemodynamics plays a pivotal role in the regulation of BP. The effect of the vasopeptidase inhibitor omapatrilat (O) and the ACE-inhibitor captopril (C) on endothelial function in the renal circulation in salt-induced hypertension were investigated. Dahl salt-sensitive rats (n = 6 per group) on standard or salt-enriched chow were treated for 8 wk with O (36 +/- 4 mg/kg per d), C (94 +/- 2 mg/kg per d), or placebo. Renal arteries were suspended in organ chambers for isometric tension recording. Vascular hypertrophy was assessed by determination of standardized heart weight and aortic weight, and morphologic analysis of glomerular injury was performed. Systolic BP of salt-fed, placebo-treated animals increased to 196 +/- 6 mmHg, which was reduced by O (162 +/- 5 mmHg; P < 0.05) and C (164 +/- 7 mmHg; P < 0.05) to a comparable degree. In salt-induced hypertension, endothelium-dependent relaxations in renal arteries (56 +/- 6 versus 100 +/- 6%; P < 0.05) as well as contractions to endothelin-1 (ET-1) (98 +/- 5% versus 128 +/- 5%; P < 0.05) and big ET-1 (47 +/- 6% versus 116 +/- 7%; P < 0.05) were markedly reduced as compared with control animals, whereas standardized aortic weight and heart weight (4.9 +/- 0.4 versus 3.2 +/- 0.3 g/kg; P < 0.05) increased. Treatment with O restored endothelium-dependent relaxations (88 +/- 6%; P < 0.05 versus C) and contractions to ET-1 (120 +/- 6%) and big ET-1 (98 +/- 9%). O prevented vascular hypertrophy (0.23 +/- 0.019 mg/mm(2) versus 0.31 +/- 0.018 mg/mm(2) in high-salt diet; P < 0.05), but, in contrast to C, it only had a modest effect on glomerular injury. In conclusion, O restored renovascular endothelial function and prevented vascular hypertrophy in salt-induced hypertension and therefore may advance as a beneficial approach in the therapy of various forms of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Vessels; Captopril; Cardiomegaly; Endothelium, Vascular; Hypertension; Hypertrophy; Kidney Glomerulus; Male; Myocardium; Neprilysin; Protease Inhibitors; Pyridines; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride; Thiazepines; Vasoconstriction; Vasodilation