ISH NIA PS 01-05 Cardioprotection by aliskiren, valsartan and their combination in rats with chronic myocardial infarction

Abstract

Objective: Aliskiren is a renin inhibitor approved for the treatment of hypertension. Aliskiren increases cardiac tissue kallikrein and bradykinin levels, both of which are important for cardioprotection. We showed previously that aliskiren reduces myocardial ischemia-reperfusion injury via a bradykinin B2 and angiotensin AT2 receptor-mediated mechanism. In the present study, we investigated the effects of aliskiren on cardiac remodeling and hemodynamics post myocardial infarction (MI). Design and Method: Female Sprague-Dawley rats were subjected to either sham MI or MI produced by permanent ligation of the left anterior descending coronary artery. MI rats were then divided into 4 treatment groups at 2 days post-MI: vehicle, aliskiren (10 mg/kg/day s.c.), valsartan (30 mg/kg/day p.o.), or the combination of aliskiren and valsartan. Cardiac function was assessed by echocardiography and in vivo pressure-volume loop analysis of hemodynamics at 28 days post-MI. Results: Vehicle-treated MI rats developed left ventricular dilation, with higher end-diastolic volumes (530 ± 60 μl c.f. 370 ± 30 μl) and end-systolic volumes (300 ± 50 μl c.f. 120 ± 10 μl) when compared with sham MI rats. Compared to sham MI rats, vehicle-treated MI rats had reduced ejection fraction (EF; 47 ± 4% c.f. 69 ± 2%), fractional area change (FAC; 35 ± 4% c.f. 59 ± 5%) and fractional shortening (FS; 21 ± 2% c.f. 43 ± 3%). Treatment with valsartan or the combination of aliskiren and valsartan improved EF to 58 ± 3% or 55 ± 3%, respectively, and a similar trend was observed in aliskiren-treated rats (56 ± 3%; P = 0.056). FAC was improved in valsartan-treated rats (44 ± 3%) but not in aliskiren- (39 ± 3%) or combination-treated (37 ± 3%) rats. FS improved significantly with aliskiren (to 31 ± 3%), valsartan (to 31 ± 3%) and with the combination of aliskiren and valsartan (to 26 ± 2%). Apart from a lowering of systolic blood pressure with valsartan and the combination of aliskiren and valsartan, there were no effects of treatment on hemodynamics. Conclusions: In rats with chronic myocardial infarction, aliskiren and valsartan were similarly cardioprotective with no additional benefit from their combination.