Aliskiren in combination with valsartan exerts synergistic protective effects against ventricular remodeling after myocardial infarction in mice

Abstract

The efficacy of aliskiren, a direct renin inhibitor, in ventricular remodeling after myocardial infarction (MI) compared with conventional renin-angiotensin system (RAS) inhibitors remains to be defined. This study was performed to examine the protective effects of aliskiren and its addition to valsartan, an angiotensin-II receptor blocker, against ventricular remodeling after MI. MI was induced in 8-to 12-week-old C57BL/6 mice by ligating the left anterior descending artery. At 3 days after MI, mice were divided into five groups and were treated with the following: (1) phosphate-buffered saline (PBS); (2) hydralazine (10 mg kg -1 day -1 ); (3) valsartan (8 mg kg -1 day -1 ); (4) aliskiren (25 mg kg -1 day -1 ); and (5) combined aliskiren (25 mg kg -1 day -1 ) and valsartan (8 mg kg -1 day -1 ). With these doses of drugs, blood pressure-lowering effects compared with the PBS group were similar among the treated groups in sham-operated mice. At 28 days after MI, echocardiographic, hemodynamic and histological assessments demonstrated that monotherapy with valsartan or aliskiren alone significantly and similarly ameliorated ventricular remodeling after MI compared with the PBS and the hydralazine groups. Combination therapy of valsartan and aliskiren more greatly improved ventricular remodeling after MI with enhancement of angiogenesis and greater attenuation of tissue oxidative stress and inflammation. Our results indicate that aliskiren can be an alternative to conventional RAS inhibitors in the treatment of post-MI patients. Moreover, the dual therapy of valsartan and aliskiren may be more beneficial than either monotherapy. Further clinical trials will be warranted to sufficiently assess the safety and the efficacy of the use of aliskiren in post-MI patients.

Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects

“…Gervais and colleagues showed that treatment with valsartan at 50 mg/kg/day, given from day 7 post-MI for 6 weeks, limited the development of cardiac hypertrophy in Wistar rats [24]. Higashikuni et al showed that, in mice, valsartan at 25 mg/kg/day, given from 3–28 days post MI, ameliorated ventricular remodeling [25]. The previous studies and our own data suggest that the dosage and the timing of treatment have significant and differential effect on LV remodeling.…”

Direct Renin Inhibition Exerts an Anti-hypertrophic Effect Associated with Improved Mitochondrial Function in Post-infarction Heart Failure in Diabetic Rats

“…Aliskiren could be involved in inhibition of the rennin receptor internalization and, as a consequence, prevent AngII-independent signaling pathway and its deleterious consequences. Most recent studies demonstrated that in combination with the inhibitor of angiotensin converting enzyme or AngII receptor blocker, aliskiren exerted additional synergistic protective effects against ventricular remodeling following myocardial infarction in rodents [32, 33] although clinical trials demonstrated no additional benefit of RAS blockade with aliskiren in post-infarcted patients [34]. The beneficial effects of combined therapy could indicate existence of AngII-independent pathways through which aliskiren would affect cell metabolism.…”

Neuropathic pain-attenuating potential of aliskiren in chronic constriction injury model in rats

“…There have been studies documenting the potent anti-inflammatory potential of aliskiren through inhibiting leukocyte adhesion, preventing oxidative stress and decreasing the production of inflammatory cytokines including TNF-a. 13,33,34 Furthermore, aliskiren has also been shown to attenuate TNF-a mediated deleterious effects on different body systems including the coagulation pathway in human umbilical vein endothelial cells. 34 An aliskiren-induced decrease in inflammatory mediators in the present study may possibly be due to a decrease in angiotensin II levels as this has been well documented to modulate several steps of the inflammatory response including vascular permeability, leukocyte infiltration, production of reactive oxygen species and inflammatory cytokines.…”