Abstract 21085: Direct Renin Inhibition with Aliskiren Enhances Beneficial Effects of Angiotensin II Receptor Blocker on Cardiovascular and Renal Injury in eNOS Deficient Mice
Objective: This work was undertaken to compare the protective effects of aliskiren and valsartan, an angiotensin II receptor blocker (ARB) against cardiovascular and renal injury in endothelial nitric oxide synthase (eNOS)-deficient mice and also to examine the significance of their combination for cardiovascular and renal protection.
Methods: We developed a model of vascular remodeling by placing a polyethylene cuff around the femoral artery of eNOS deficient mice (eNOS−/− mice), and administered (1) vehicle, (2) hydralazine, (3) valsartan (8mg/kg/day), (4) aliskiren (25mg/kg/day), and (5) combined valsartan (4mg/kg/day) and aliskiren (12.5mg/kg/day) to eNOS−/− mice for 4 weeks.
Results: Each drug treatment exerted similar blood pressure lowering in eNOS−/− mice. Aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; prevented cuff injury-induced arterial intimal thickening; and reduced urinary albumin excretion, glomerular inflammation, and glomerulosclerosis in endothelial NO synthase-deficient mice. These beneficial effects of aliskiren and valsartan were associated with the significant attenuation of oxidative stress in these tissues. Hence, aliskiren and valsartan markedly exert the protective effects against cardiovascular and renal injury through the reduction of oxidative stress. Furthermore, compared with monotherapy with aliskiren or valsartan, the combination of a half dose of these drugs more greatly improved the above-mentioned cardiovascular and renal injuries of endothelial NO synthase-deficient mice, which were associated with greater attenuation of tissue oxidative stress by the combination therapy.
Conclusions: Renin is involved in the progression of cardiac hypertrophy and remodeling, and vascular neointimal formation in eNOS−/− mice. Our present work provides the first evidence that direct renin inhibition enhances the beneficial effects of ARB on cardiovascular injuries, independently of eNOS pathway. Thus, the combination of aliskiren and valsartan seems to be a promising therapeutic strategy for hypertensive organ injury caused by endothelial NO synthase dysfunction.
- © 2010 by American Heart Association, Inc.