Takeuchi K, Omura T, Yoshiyama M, Yoshida K, Otsuka R, Shimada Y, Ujino K, Yoshikawa J
First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
Heart Vessels. 1999;14(3):111-9. doi: 10.1007/BF02482294.
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.
本研究旨在探讨长效钙通道拮抗剂普拉地平对心肌梗死大鼠心室重构、心脏收缩和舒张功能、循环体液因子以及心脏mRNA表达的影响。通过结扎Wistar大鼠冠状动脉制备心肌梗死（MI）模型。将3mg/kg/天的普拉地平随机给予梗死大鼠。在心肌梗死后4周进行血流动力学测量、多普勒超声心动图检查、体液因子血浆水平分析以及心肌mRNA表达检测。左心室舒张末期压力（LVEDP）和中心静脉压（CVP）分别升至24.2±1.2mmHg和5.4±0.6mmHg。普拉地平将LVEDP和CVP分别降至13.6±1.4mmHg（P<0.01）和2.5±0.4mmHg（P<0.01）。MI组左、右心室重量显著高于假手术大鼠（假手术组，2.02±0.04和0.47±0.02g/kg；MI组，2.18±0.05和0.79±0.04g/kg；P<0.01）。MI组左心室舒张末期内径（LVDd）增至10.3±0.3mm（P<0.01）（假手术组，6.4±0.3mm）。普拉地平可防止左、右心室重量增加（2.02±0.04和0.6±0.03g/kg，P<0.01）以及LVDd增加（7.9±0.2mm，与MI组相比P<0.01）。MI组血浆肾素活性（PRA）以及血浆肾上腺素、去甲肾上腺素和多巴胺浓度高于假手术大鼠。普拉地平将心肌梗死大鼠的PRA和血浆儿茶酚胺水平降至假手术大鼠水平。此外，MI组大鼠表现出收缩功能障碍，表现为缩短分数降低（假手术组，31±2% vs MI组，15±1%；P<0.01），以及舒张功能障碍，表现为E波减速速率增加（假手术组，12.8±1.1m/s²；MI组，32.6±2.1m/s²；P<0.01）。普拉地平显著预防了收缩和舒张功能障碍。心肌梗死后4周，非梗死左心室和右心室中β-肌球蛋白重链（MHC）、α-骨骼肌肌动蛋白和心钠素mRNA的增加被普拉地平治疗显著抑制。另一方面，普拉地平使两个区域中降低的α-MHC恢复到正常水平。总之，普拉地平可预防伴有收缩和舒张功能障碍的左心室重构过程，并抑制心肌梗死后心脏基因的异常表达。
