METHODS: The influence of chronic administration of low doses of aliskiren (5 mg/kg/day, i.p.) for a period of eight weeks on cardiac electrophysiological and structural remodeling was investigated in transgenic (TGR)(mRen-2)27 rats. Cardiac and plasma angiotensin II (Ang II) levels were determined by ELISA before and after administration of the drug. Moreover, histological, electrophysiological and echocardiographic studies were performed in controls and at the end of eight weeks of aliskiren administration. RESULTS: 1) The cardiac Ang II levels were significantly reduced while the plasma Ang II levels were not significantly decreased in rats treated with low doses of aliskiren; 2) echocardographic studies showed a decrease of left ventricle diameter (LVD), left ventricle posterior wall thickness (LVPW), left ventricle end diastolic volume (LVEDV) and increased ejection fraction (EF); 3) aliskiren improved the impulse propagation, increased the cardiac refractoriness and reduced the incidence of triggered activity; 4) perivascular and interstitial fibrosis were greatly reduced, which explains the increase in conduction velocity. All these effects of aliskiren were found independently of blood pressure, suggesting that the beneficial effect of aliskiren was related to an inhibition of the local cardiac renin angiotensin system; and 5) the effect of mechanical stretch on action potential duration, conduction velocity and spontaneous rhythmicity was changed by aliskiren, supporting the hypothesis presented here that the beneficial effect of the drug on cardiac remodeling is related to a decreased sensitivity of cardiac muscle to mechanical stress.
METHODS: The influence of chronic administration of low doses of aliskiren (5 mg/kg/day, i.p.) for a period of eight weeks on cardiac electrophysiological and structural remodeling was investigated in transgenic (TGR)(mRen-2)27 rats. Cardiac and plasma angiotensin II (Ang II) levels were determined by ELISA before and after administration of the drug. Moreover, histological, electrophysiological and echocardiographic studies were performed in controls and at the end of eight weeks of aliskiren administration. RESULTS: 1) The cardiac Ang II levels were significantly reduced while the plasma Ang II levels were not significantly decreased in rats treated with low doses of aliskiren; 2) echocardographic studies showed a decrease of left ventricle diameter (LVD), left ventricle posterior wall thickness (LVPW), left ventricle end diastolic volume (LVEDV) and increased ejection fraction (EF); 3) aliskiren improved the impulse propagation, increased the cardiac refractoriness and reduced the incidence of triggered activity; 4) perivascular and interstitial fibrosis were greatly reduced, which explains the increase in conduction velocity. All these effects of aliskiren were found independently of blood pressure, suggesting that the beneficial effect of aliskiren was related to an inhibition of the local cardiac renin angiotensin system; and 5) the effect of mechanical stretch on action potential duration, conduction velocity and spontaneous rhythmicity was changed by aliskiren, supporting the hypothesis presented here that the beneficial effect of the drug on cardiac remodeling is related to a decreased sensitivity of cardiac muscle to mechanical stress.