【作者】 黄艳；

【导师】 季勇； 肖继皋；

【作者基本信息】 南京医科大学 ， 心血管药理学， 2002， 硕士

【摘要】 左室肥厚(left ventricular hypertrophy，LVH)是心血管系统常见的并发症，高血压患者中约60％合并LVH。心肌肥厚主要表现为心肌细胞增大、间质细胞增生、胶原异常堆积以及冠脉微循环改变，即心血管系统的“重构”(Remodeling)。心肌肥厚常伴发心律失常、心衰、猝死，因此研究心肌肥厚发生机制以及药物逆转心肌肥厚一直是心血管疾病研究领域的热点。目前发现一些抗高血压药物，如血管紧张素Ⅱ转化酶抑制剂(ACEI)、部分钙拮抗济剂、β受体阻断剂及血管紧张素Ⅱ(AT-Ⅱ)受体阻滞剂等对心肌肥厚有一定的逆转作用。 心肌负荷增加是引起心肌肥厚的最主要原因，交感神经、儿茶酚胺、局部肾素血管紧张素系统和生长因子等在心肌肥厚的发生过程中也起着重要作用。心肌肥厚的机制至今仍不明确，但是大量研究表明心肌肥厚的发生涉及细胞内信号系统改变以及基因表达的异常。越来越多的研究发现心肌肥厚时，心血管系统的细胞内钙代谢发生异常，并且与心肌肥厚的发生、发展密切相关。近年的研究发现Na~+/H~+交换体(NHE)与心肌肥厚关系也很密切。作为哺乳动物心脏中主要的细胞内pH(pH_i)调节机制，NHE在调节pH_i，细胞容积及细胞内Na~+浓度方面起重要作用，而且NHE可能介导了血管紧张素Ⅱ(AngⅡ)、内皮素-1(ET-1)、佛波酯和许多生长因子的细胞生长和增殖反应。 Amiloride是Na~+/H~+交换抑制剂。以往的研究已证实：amiloride具有保护缺血重灌损伤心肌；抗心律失常；阻止心肌梗塞后的心室重构；抑制心肌对各种刺激的肥厚反应等作用。这些研究提示amiloride可能具有抑制心肌肥厚的作用。但 南京医科人学颀十学位论文 Aniloride对成年 SHR j艰y几。c功能、。仰屿d8内游g寺和 州值的影响矾系统晰 晚本一2月龄洲R大鼠 以血 管紧糖11车 澜。喇剂ena laPril为郴，赂amiloride对 SHR在体C功能、。y朋妮飨以及C室月旭邮包内Ca“、pH值的 影响。旨硼寸SHR。y朋瞬的湘IJ，kX及 ami loride对SHR月巴 厚。u）ljL6勺影响拄讳心哩。 本实验内容包拓〔户盼，现拒出o。下： 实马全共分 5 M SH月娜蜘（潮良同－鳅水X 高 Sdeamiloride组（潮a7．sing．kg‘．d‘X ］MIJ量amiloride 组 （潮民sins．ks‘．d‘），enalanril治疗－（椰良ms．ks‘．d”X SD oh铡蜘（潮良同体积生理盐水）。FX帧删 8周后进 行以下实验。 lAs if or i de 7djikze自发 大鼠n朋膨删炯瞄勺 影响 减赂D娜tSHR聊成q）Jju：l醇。本sjlfrlot 大胁C湿 重4，iNN比（W／驯）、左室湿重6’iNN比几 VWWVWW／W）敝邯朋巴 刷敝结跟示：S皿的驯／驯及w侧／驯轨晾洲组均明显 升高（P＜0．01）。与S皿刎B士；高、寸 uam门orMe颐 ena april组65WBW，拥怦 均倒氏17．61％，14．88％，23．48？ （P＜0．01）；L VWWVWW／驯则拥怀阶24．05％，12．一％，＊上0％ （P＜0．01）。 以翱一j躺上 JSHR左、右。Gi6t翱…。 结服示：SHR的左室翱一比正常SD大鼠明显升高 （P＜0．01），高、4MIJ量am门orme鹏洲R剃目上，左呈翱敞 酸含量无明硼（P＞0．05），而 enalapril 则明显俐氏SHR白 左室翱一叩功．05）。糊间大肪室翱… 音隧异（P＞0．05）。 在大鼠的胁。u功能锁中，以左室d灶宿压（LVSP），＋da／dt删 川锄侧 站宿压3BP）作为脓。。恻饰功制淋以左室舒张 期末压（LwDP）及dP／d t皿作为腴册铂桃动s时g标。结驭 见与SD iM盯匕SHR组的－dP／dtn队平均下降38．29％（P＜0．01 L呸DP平均升高 227％（P＜0．01）。SHR组的 LVSP与赈孤组无显 4 南京医科人学颀士学位论文 著隧异；十dp／dt删平均下降了 26．58％（P＜0．01）；SBP则平均上 升了旭．90％（P＜0．01）。与Sin 刎目卜，高齐量am门orme和 enalapril组的－dp／dt删olJ平均J％h。29．53％，50．45％；LVEDP 则elJ下降45．60％，63．17％，但高剂量ami loride与艄SD组 椭郡11；高剂量am门orme明淑。＊R白川P／dt删，而其它 嫩刎洲R的＋dp／dt删无明媳响；与洲R红时t匕，ami loride 及 enalapril 白 SBP slJ平均下降 27．60％，24．83％，33．90％， ami loride组与N常SD婶踞隧异。 上上违洁?更多还原

【Abstract】 Left ventricular hypertrophy (LVH), an increase in cardiac cell size without cell division, is induced by mechanical overload, neural and humoral factors such as angiotensin II(Angll), endothelin (ET)-l, a ,-adrenergic agonists and peptide growth factors. Cardiac hypertrophy has a prevalence approaching 60% in patients with hypertension, and it is the single most important contributor to cardiovascular morbidity and mortality. Antihypertensive therapy with certain drugs may prevent or reverse the cardiac hypertrophy, including angiotensin converting enzyme inhibitors (ACEI), P -adrenergic antagonists, calcium antagonists and angiotensin II receptor blockers.The molecular mechanisms including intracellular signaling pathways in cardiac hypertrophy have not been well understood. Increased intracellular calcium concentration ([Ca +]\) is known to be an important signal for cellular growth. Various experimental results demonstrated that the [Ca2+]j was higher in hypertrophic myocardial cells than in normal myocardial cells, which indicates that Ca2+ is one of the important factors in the initiation and progression of LVH. In recent years, increased sodium-hydrogen exchanger (NHE) activity related to LVH has been the subject of extensive investigation. NHE is a major regulator of pHj in the mammalian myocardium. It can also play additional roles, such as the regulation of cell volume, initiation of cell growth and proliferation, the cellular response to certain hormones and the regulation of cellular Na+ uptake. Somereports demonstrate that the NHE is activated in hypertrophic cardiac myocytes. This activation leads to a cytoplasmic alkalinization.There is a growing body of evidence that amiloride, a NHE blocker, exerts protective effects on ischemia and reperfusion injury. It also can treat arrhythmias, prevent ventricular remodeling after myocardial infarction, and reduce the hypertrophic reaction of myocardium to various factors. These data indicate that amiloride may prevent cardiac hypertrophy. Our previous investigations have reported that amiloride can prevent or reverse the cardiac hypertrophy induced by partial ligation of abdominal aorta. The present study was designed to investigate the effect of amiloride on hypertrophic myocardium, collagen content, cardiac function, intracellular [Ca2+j] and pH in adult SHR. We also wished to study further the mechanism of cardiac hypertrophy.This study was in three parts:1. The ratio of heart wet weight (HW)/body weight (BW) and the ratio of left ventricular wet weight (LVWW) / body weight (BW) of SHR were both higher than that of Sprague-Dawley (SD) rat group. In the high (7.5 mg/kg) and low (5mg/kg) dose amiloride and enalapril groups, HW/BW was decreased by 17.61%, 14.88%, 23.48% respectively, and LVWW/BW was decreased by 24.05%, 12.46%, 34.20% respectively, compared with the SHR group, and enalapril showed a more marked inhibitory effect on HW/BW and LVWW/BW than than of amiloride.In order to analyse the collagen content in myocardium, the hydroxyproline content was measured in all groups. It was 5.72 + 0.59 u g/g dry weight in the left ventricular myocardial tissue from SHR group, which was higher than that from SD group(3.73+0.78u g/g dry weight, P<0.01). The hydroxyproline content in the amiloride group was not significantly different to the SHR group (P>0.05). Bycontrast, in the enalapril group,it was 4.62 + 0.84 u g/g dry weight, which was significantly lower than SHR (P<0.05). The hydroxyproline content in the right ventricular myocardial tissue was similar in all groups. From the results above, we concluded that the collagen content in the left ventricular myocardial tissue from SHR increased markedly, which indicated that cardiac hypertrophy in SHR was characterized by left ventricular hypertrophy. Amiloride was less effective in preventing the increase in collagen content in ventricular myocardium of SHR than enalapril, which indicated that the NHE might not be responsible for the collagen accumulation of ventricular remodeling.F更多还原