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[摘要] 目的 探讨阿折地平对自发性高血压大鼠心肌细胞凋亡的影响。方法 将自发性高血压大鼠随机分为治疗组[阿折地平3mg/(kg・d)溶于生理盐水中灌胃]、SHR组,另选WKY大鼠为正常对照组,每组10只。分别每周测大鼠血压,10周后处死测其左心室肥厚指数,计数细胞凋亡数,ELISA法检测心肌细胞TNF-α的表达。结果 SHR组与WKY组血压无明显改变,治疗前后比较亦无明显差异(P>0.05),治疗组的血压较治疗前显著降低(P0.05)。结论 阿折地平能有效的控制血压,能有效的抑制高血压所致的左心室肥厚、细胞凋亡及心肌TNF-α的表达。
[关键词] 阿折地平;细胞凋亡;大鼠
[中图分类号] R972[文献标识码] A [文章编号] 1673-9701(2010)04-29-03
Effects of Azelnidipine on Cardiomyocyte Apoptosis of Spontaneously Hypertensive Rats
HU LianfenLIU Guangde
Department of Cardiology,Zhuhai Municipal People’s Hospital,Zhuhai 519000,China
[Abstract] Objective To explore the effect of Azelnidipine on cardiomyocyte apoptosis of spontaneously hypertensive rats(SHR). Methods Twenty SHRs were randomly divided into 2 groups(treatment group and SHR group,with 10 rats in each) and treated with Azelnidipine for 10 weeks and control group(10 WKY rats) was treated with 0.9% sodium chloride solution.The rat blood pressure was measured every week. The rats were sacrificed after 10 weeks,the left ventricular hypertrophy index was measured,the number of cell apoptosis was counted,and the expression of myocardial cell TNF-αwas detected by ELISA. Results Compared with the control group,Azelnidipine could significantly reduce the 1eft ventricular hypertrophic index,cardiomyocyte apoptosis and TNF-α(P0.05),但阿折地平治疗组的血压较治疗前显著降低(P0.05)。
2.3凋亡细胞计数
治疗10周后治疗组、SHR组、WKY组的心肌细胞凋亡指数分别为(104.34±35.38)‰、(502.13±54.84)‰和(23.13±12.25)‰。治疗组和SHR组心肌细胞凋亡指数明显地高于WKY组(P 2.4阿折地平对高血压大鼠TNF-α表达的影响
治疗10周后治疗组TNF-α的表达显著小于SHR组(P0.05)。
3讨论
阿折地平(Azelnidipin)是2003年日本Sankyo公司与Ube公司联合开发的一种新型二氢吡啶类钙拮抗药,选择性作用于L-型钙通道,在日本已被批准用于治疗高血压,其降压疗效与肾上腺素β受体阻断剂和血管紧张素(angiotensin,AngⅡ)转换酶抑制剂相当。阿折地平对自发性高血压大鼠的肾脏和心肌缺血狗具有明显的器官保护作用[1,2]。阿折地平具有抗氧化特性,通过减弱局部氧化应激和抑制单核细胞趋化蛋白-1的过度表达,抑制动脉粥样硬化的形成[3,4];在体外,阿折地平也能减弱单核细胞趋化蛋白-1诱发的血管平滑肌细胞增殖和转移[4];在人类脐静脉上皮细胞,阿折地平通过降低NADPH氧化酶介导的活性氧簇抑制肿瘤坏死因子(TNF-α)活性和白细胞介素-8(IL-8)的表达[5,6]及内皮细胞炎症反应[7];在糖尿病大鼠,阿折地平通过抑制氧化应激而改善大鼠对葡萄糖的耐受性[8];在卒中型自发性高血压大鼠中,阿折地平治疗能够减弱交感神经反射,使脑、心脏和大动脉的内皮型氧化亚氮(eNOS)的生成增加[9-11]。
实验表明,高血压病心肌肥厚除了与间质增生,还与心肌细胞个体增大和凋亡的失衡有密切的关系。在血压升高早期心肌细胞以个体增大为主,凋亡相对不足[12]。新的研究发现,SHR的心脏由高血压发展为左心室肥厚(LVH),再发展到心力衰竭(CHF)的过程中,其心肌细胞增殖与凋亡存在明显的“时间窗”:1月内与5～17月以心肌细胞增大为主;1～4月与18月以后以凋亡为主。SHR出现LVH而尚未进展为CHF时,其心肌细胞凋亡指数与左心室心肌肥厚指数呈显著负相关,出现CHF后则心肌细胞凋亡明显增多[13]。
细胞凋亡又称细胞程序性死亡[14],是由遗传决定的生理性死亡。近年来的研究[15,16]表明,心肌细胞的凋亡参与高血压LVH的病理生理过程。高血压时,心肌和内皮、平滑肌细胞异常凋亡,一些散在的、选择性心肌细胞首先凋亡,释放ATP,又进一步刺激邻近的心肌细胞凋亡,形成恶性循环。凋亡心肌被胶原纤维取代,产生心肌纤维化、心肌肥厚。本实验表明阿折地平能显著的减少高血压时心肌细胞的凋亡数。
肿瘤坏死因子(TNF-α)是一种主要由单核-巨噬细胞分泌的具有多种生物学效应的细胞因子,已知TNF-α能诱导心肌细胞凋亡[17],虽然正常心肌很少或不表达TNF-α,但在高血压时,由于RAS系统激活,AngⅡ可以促使培养的心肌细胞在蛋白水平和mRNA水平表达TNF-α显著增高[18]。
本实验表明新型二氢吡啶类钙拮抗药阿折地平能有效的控制血压,能有效的抑制高血压所致的左心室肥厚、心肌细胞凋亡和心肌TNF-α的表达。但其具体机制仍有待进一步研究。
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(收稿日期:2009-10-28)
