论文标题:缬沙坦对心力衰竭大鼠心肌细胞凋亡与心室重构作用的实验研究
Experimental Study on Role of Valsartan to Cardiomyocyte Apoptosis and Ventricular Remodeling in Rats with Congestive Heart Failure
论文作者 王立宏
论文导师 蔡智荣,论文学位 硕士,论文专业 心血管内科
论文单位 青岛大学,点击次数 77,论文页数 60页File Size3041k
2003-03-01论文网 http://www.lw23.com/lunwen_364249387/ 心力衰竭;心室重构;细胞凋亡;缬沙坦;大鼠
Congestive heart failure;Ventricular remodel;Apoptosis;Valsartan;Rats
目的 应用大鼠心力衰竭模型观察心肌细胞凋亡和心室重构在心力衰竭发生发展中的作用，以及缬沙坦对心力衰竭时心肌细胞凋亡与心室重构的影响，探讨血管紧张素Ⅱ1型受体(AT_1)拮抗剂对心力衰竭的治疗机制及其临床应用价值。 方法 缩窄Wistar-Kyoto(WKY)大鼠的腹主动脉建立充血性心力衰竭(CHF)模型，手术后将已缩窄了腹主动脉的WKY大鼠随机分为缬沙坦治疗组和心力衰竭组，每组10只，另设同源WKY大鼠做为假手术组，即只开腹而不缩窄血管。缬沙坦治疗组的大鼠于手术后第10周之后开始每日给予灌喂缬沙坦15mg／kg，而其他两组的大鼠则灌服以等量的蒸馏水。6周后，处死三组动物，分别①测量大鼠的体重、左心室质量以计算左心室质量指数；②计算心肌羟脯氨酸的量并以此推算出心肌的胶原含量；③取心肌组织进行苏木精-伊红染色和胶原V．G法染色，进行普通光学显微镜检查，比较心肌细胞的变化和心肌间质纤维化程度，来评价心室的重构；④此外，另取心肌组织进行心肌细胞凋亡的脱氧核糖核酸(DNA)琼脂糖凝胶电泳，观察心肌脱氧核糖核酸电泳梯带的变化，作为检测心肌细胞凋亡的方法。 结果 ①左心室质量指数：心力衰竭组大鼠的左心室质量指数(4.08±0.21)较假手术组(2.32±0.14 p＜0.01)与缬沙坦治疗组的左心室质量指数(2.91±0.32p＜0.01)显著增大；缬沙坦治疗组的左心室质量指数虽较心力衰竭组的明显减小但与假手术组相比，仍存在差异(p＜0.05)。②左心室心肌胶原的含量：心力衰竭组大鼠的左心室心肌胶原含量(7.91±0.21ug／mg)较假手术组(5.37±0.13ug／mgp＜0.01)与缬沙坦治疗组的心肌胶原含量(5.89±0.18ug／mg p＜0.01)显著增高，具有统计学意义；缬沙坦治疗组胶原含量虽较心力衰竭组降低，但与假手术组相比仍有差别(p＜0.05)。③苏木精-伊红及胶原染色示：心力衰竭组大鼠心肌重构，心肌细胞肥大，粗大的胶原纤维；缬沙坦治疗组大鼠心肌重构较心力衰竭组明显改善，但仍未达到假手术组的水平。④琼脂糖凝胶电泳：心力衰竭组和缬沙坦治疗组大鼠心肌组织均出现细胞凋亡的典型“DNA Ladder”，且缬沙坦治疗组的DNA梯带亮度较心力衰竭组减轻。 结论 ①心肌细胞凋亡和心室重构在心力衰竭的发生发展中起着重要的作用;②缘沙坦具有降低心肌细胞凋亡和逆转心室重构的作用;③血管紧张素nl型受体拮抗剂对心力衰竭具有较好的疗效，并且能改善心力衰竭的预后，其机理可能与减少心肌细胞的凋亡、逆转心室重构有关。
Objective (1) To investigate the role of cardiomyocyte apoptosis andventricular remodeling in the progress of heart failure by experiments of heart failure model in rats. (2) To explore the mechanism and evaluate the therapeutic effects of angiotensin II type 1 receptor (AT1) antagonism on rats with congestive heart failure by observing the changes of cardiomyocyte apoptosis and ventricular remodeling induced by using of valsartan.Methods Pathological models of congestive heart failure (CHF) wereestablished by constriction of abdominal aorta of rats partly. Then they were divided randomly into 2 groups and each group had 10 rats. One was valsartan treated group, the other was named as heart failure group. Another 10 corresponding Wistar-Kyoto rats were recruited as sham-operated. That is, they were operated as these two groups except abdominal aortic banding. The rats hi valsartan group began to be treated with daily 15mg/kg valsartan by gavage at the end of 10th week after operation, while the other rats were administered equal volume of distilled water respectively by the same way. Six weeks later, all the rats were killed, and (1) all the left ventricular muscle weight (LVW) were measured respectively to calculate the left ventricular weight index (LVMT). (2) It was performed to analyze the collagen concentration by measuring left ventricular hydroxyproline content. (3) Observed the pathological morphological change of cardiac myocyte and the degree of myocardial interstitial fibrosis with light microscopy after cardiac tissue were handled by H.E or collagen V.G staining. (4)Compared the difference of electrophoresis pattern of myocardial apoptosis among the three groups as the method of assessing apoptosis in myocardium.Result (1) The left ventricular weight index (LVWI): the left ventricular weightindex of heart failure group (4.08±0.21 ) increased significantly contrast to sham-operated group (2.32±0.14 p<0.01 ) or valsartan treating group (2.91±0.32p<0.01) . While the difference between valsartan treating group and sham-operated group still existed (p<0.05). (2) The left ventricular collagen content (LVCC) : the left ventricular collagen content of heart failure group (7.91±0.21 ug/mg) is more than the sham-operated group (5.37±0.13 ug/mg p<0.01) or valsartan treating group (5.89± 0.18 ug/mg p<0.01) . There is still obviously difference between valsartan treated and sham-operated group (p<0.05), although the item was clearly decreased in the treating group contrast to heart failure group. (3) After H.E or collagen staining, the pathomorphology photos showed ventricular remodeling including myocardial cells hypertrophy and myocardial interstitial fibrosis with rearrangement and slippage of muscle fibers in the heart failure group. Otherwise in the rats of valsartan treating group, the situation was significantly improved, there was less myofibrillae and less collagen fibrillae, but still didn"t recover to the level of the sham-operated rats.(4)There appeared typical "DNA Ladder" in heart failure and valsartan treating groups by agarose gel electrophoresis but the sham-operated group didn"t show the phenomenon. And the "DNA Ladder" in valsartan treating group was dimmer and fainter than the heart failure group.Conclusion (1) The results suggest that cardiomyocyte apoptosis andventricular remodeling take an important role in the development of heart failure. (2) The results also indicate that valsartan can effectively decrease myocardial apoptosis and regress ventricular remodeling at the same time. (3) It is suggested that angiotensin II receptor antagonism are effective in treatment of heart failure and have a good prognosis. The mechanism may be related to decrease myocardial apoptosis and reverse ventricular remodeling.
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