Long-acting calcium channel antagonist pranidipine prevents ventricular remodeling after myocardial infarction in rats.

Abstract

The purpose of this study was to examine the effects of the long-acting calcium channel antagonist pranidipine on ventricular remodeling, systolic and diastolic cardiac function, circulating humoral factors, and cardiac mRNA expression in myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was randomly administered to the infarcted rats. Hemodynamic measurements, Doppler echocardiographic examinations, analyses of the plasma levels of humoral factors, and myocardial mRNA expression were performed at 4 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 24.2 +/- 1.2mmHg and 5.4 +/- 0.6 mmHg. Pranidipine reduced LVEDP and CVP to 13.6 +/- 1.4mmHg (P < 0.01) and 2.5 +/- 0.4mmHg (P < 0.01). The weight of the left and right ventricles in MI was significantly higher than in the sham-operated rats (sham, 2.02 +/- 0.04 and 0.47 +/- 0.02g/kg; MI, 2.18 +/- 0.05 and 0.79 +/- 0.04g/ kg; P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 +/- 0.3mm (P < 0.01) (sham, 6.4 +/- 0.3mm). Pranidipine prevented an increase in the weight of the left and right ventricles (2.02 +/- 0.04 and 0.6 +/- 0.03g/kg, P < 0.01) and LVDd (7.9 +/-0.2mm, P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine, norepinephrine, and dopamine concentrations in MI were higher than those of the sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels of the myocardial infarcted rats to the level of the sham-operated rats. Moreover, the rats in MI showed systolic dysfunction, shown by decreased fractional shortening (sham, 31 +/- 2% vs MI, 15 +/- 1%; P < 0.01) and diastolic dysfunction shown by the E-wave deceleration rate (sham, 12.8 +/- 1.1 m/s2; MI, 32.6 +/- 2.1 m/s2; P < 0.01). Pranidipine significantly prevented systolic and diastolic dysfunction. The increases in beta-myosin heavy chain (MHC), alpha-skeletal actin, and atrial natriuretic polypeptide mRNAs in the noninfarcted left ventricle and right ventricle at 4 weeks after the myocardial infarction were significantly suppressed by the treatment with pranidipine. On the other hand, depressed alpha-MHC was restored to normal levels by pranidipine in both regions. In conclusion, pranidipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.