Effects of ranolazine on cardiac function in rats with heart failure.

To investigate the effects of ranolazine on the cardiac function and myocardial apoptosis in rats with heart failure and its possible mechanisms. Thirty Wistar rats were randomly divided into sham operation (negative control; NC), chronic heart failure (CHF), and ranolazine groups. Suprarenal abdominal aortic coarctation was used to induce CHF in rats. Five weeks later, rats in the ranolazine group received ranolazine (50 mg/kg) daily, whereas those in the CHF group received normal saline. After 4 weeks, changes in hemodynamic parameters, cardiac structure and pathology, myocardial apoptosis, and protein expression were assessed. The left ventricular end-diastolic pressure (LVEDP) significantly increased in the CHF group; whereas the maximal rate of left ventricular pressure rise and fall (±dp/dtmax) decreased, compared to those in the NC group. Ranolazine significantly reduced LVEDP and increased ±dp/dtmax (p<0.01), compared to those in the CHF group. Severe impairment of cardiomyocytes was observed in the CHF group with evident inflammation; however, ranolazine reversed these deficits. Rats in the CHF group exhibited an increase in TUNEL-positive cells, which was inhibited by ranolazine, where the apoptotic index significantly decreased in ranolazine-treated rats (p<0.01). Also, ranolazine downregulated caspase-9 expression and upregulated pAKT and Bcl-2 expression in rat cardiomyocytes. Moreover, ranolazine significantly inhibited myocardial apoptosis and caspase-9 expression, promoted AKT phosphorylation, and upregulated pAKT and Bcl-2 expression in vitro, compared to those in the control group (p<0.001). LY294002 inhibited ranolazine-induced suppression of myocardial apoptosis (p<0.001). Ranolazine improved cardiac function and inhibited myocardial apoptosis in rats with CHF, which could be attributed to the regulation of AKT phosphorylation.