丹参酮ⅡA对腹主动脉缩窄高血压大鼠心肌肥厚的作用及分子生物学机制
|
摘要
心肌肥厚是心脏对多种疾病包括高血压、机械压力负荷、心肌梗塞、心律失常、内分泌机能紊乱以及心肌收缩蛋白基因突变而产生的适应性病理反应。在疾病早期,因心脏作功增加可引起代偿性心肌肥厚反应。持续性的心肌肥厚能够引起扩张性心肌病、心律失常、心力衰竭甚至猝死。心肌肥厚是引起心血管疾病发病率和病死率的独立危险因素。
研究发现在心肌肥厚时左心室重量普遍增高,心血管事件发生率是无心肌肥厚者的2-4倍。心肌肥厚不仅是一个病理生理过程,而更是一个影响其短期和长期预后的失代偿性变化。它的不可逆性进展可以直接导致心力衰竭。目前临床上用于治疗心肌肥厚的治疗药物主要有血管紧张素转化酶抑制剂、血管紧张素受体拮抗剂和钙离子通道阻滞剂,但皆因存在不同程度的副作用而使其临床应用受到一定限制。而心肌肥厚的治疗是一个长期的过程,因此寻找一些疗效好而毒副作用低的药物显得十分必要。丹参酮ⅡA是中药丹参的主要脂溶性成分。目前已发现丹参酮ⅡA可以减轻、逆转高血压左心室肥厚,但其具体作用机制尚未阐明。
本研究拟在腹主动脉缩窄的高血压大鼠上构建心肌肥厚模型,将丹参酮ⅡA与经典的抗心肌肥厚药物血管紧张素1型受体拮抗剂――缬沙坦比较,以探讨丹参酮ⅡA逆转心肌肥厚的分子生物学机制。
第一部分丹参酮ⅡA对腹主动脉缩窄高血压大鼠心肌肥厚超声影像学及病理形态学的影响
目的:研究丹参酮ⅡA对腹主动脉缩窄术后大鼠左室心肌肥厚的作用。
方法:40只健康SD大鼠,行腹主动脉缩窄术建立高血压左室心肌肥厚模型,另取8只大鼠行假手术。术后4周将手术大鼠随机分为心肌肥厚组、丹参酮低剂量组(10mg/Kg/d腹腔注射)、丹参酮高剂量组(20mg/Kg/d腹腔注射)及缬沙坦组(10mg/Kg/d灌胃)。用药8周后通过超声心动图测定左室后壁、室间隔的厚度及左室射血分数(EF);取左心室组织检测左心室质量指数(left ventricular mass index,LVMI)、病理切片HE染色测量心肌纤维直径(myocardial fiber dimension,MFD)。
结果:
1.心肌肥厚组、丹参酮组(高、低剂量)的血压显著高于假手术组及缬沙坦组(p﹤0.01),丹参酮高、低剂量组及心肌肥厚组之间无统计学差异(p﹥0.05),缬沙坦组的血压值降至正常、但仍明显高于假手术组(p﹤0.05)。
2.丹参酮高、低剂量组和缬沙坦组的室间隔厚度均高于假手术组(p﹤0.05),显著低于心肌肥厚组(p﹤0.01);丹参酮两组的室间隔厚度无差异(p﹥0.05),但高于缬沙坦组(p﹤0.05)。
3.丹参酮低剂量、高剂量组及缬沙坦组之间左室后壁值数据没有显著性差异(P>0.05),此三组左室后壁值均明显低于心肌肥厚组(p﹤0.01),但尚未恢复至正常水平(p﹤0.05)。
4.所有各组的EF值均在正常值范围(>60%),尚未表现出心功能衰竭。但心肌肥厚组的EF值小于其他各组(p﹤0.05),丹参酮组的EF也小于缬沙坦组(p﹤0.05)。
5.丹参酮低剂量和高剂量组间LVMI和MFD没有显著性差异(P>0.05),缬沙坦组和丹参酮各组的LVMI、MFD均高于假手术组(p﹤0.05),显著低于心肌肥厚组(p﹤0.01);丹参酮两组的LVMI、MFD均高于缬沙坦组(p﹤0.05)。
结论:
丹参酮Ⅱ-A对心肌肥厚的逆转作用是非血压依从性的。丹参酮Ⅱ-A与血管紧张素Ⅱ1型受体拮抗剂缬沙坦均可阻止、逆转高血压心肌肥厚的发展,但其作用弱于缬沙坦。
第二部分丹参酮ⅡA对腹主动脉缩窄大鼠肥厚心肌血管紧张素受体的影响
目的:通过研究丹参酮ⅡA对腹主动脉大鼠肥厚心肌血管紧张素受体及细胞内游离钙离子的影响,探讨丹参酮ⅡA逆转高血压左心室肥厚的分子生物学机制。
方法:取各组大鼠的左心室组织,采用逆转录-聚合酶链式反应(RT-PCR)、免疫印记法(Western blotting)分别检测AT1、AT2受体mRNA和蛋白的表达水平。利用激光共聚焦显微镜测定心肌细胞内Ca2+浓度的变化。
结果:
1.心肌肥厚组的AT1 mRNA和蛋白的表达显著高于其他各组(p﹤0.01);丹参酮ⅡA高、低剂量组间无差异(p﹥0.05),丹参酮ⅡA组高于缬沙坦组(P﹤0.05);丹参酮ⅡA组和缬沙坦组的AT1基因表达均未降至假手术组水平(p﹤0.05)。
2.缬沙坦组的AT2 mRNA和蛋白表达水平较其他各组升高(p﹤0.05),其他各组之间无统计学差异(p﹥0.05)。
3.心肌肥厚组细胞内[Ca2+]i明显高于其他各组(p﹤0.01);丹参酮高剂量组与假手术组之间无统计学差异(p﹥0.05);缬沙坦组和丹参酮低剂量组仍高于假手术组和丹参酮高剂量组(p﹤0.05);丹参酮低剂量组细胞内钙浓度与缬沙坦组之间无差异(p﹥0.05)。
结论:
丹参酮ⅡA和缬沙坦均可通过下调AT1基因表达、阻止心肌细胞的钙离子内流发挥逆转心肌肥厚的作用,AT2有可能参与了缬沙坦降低血压、逆转心肌肥厚的作用。
第三部分丹参酮IIA对腹主动脉缩窄高血压大鼠肥厚心肌一氧化氮合酶的影响
目的:通过研究丹参酮ⅡA对腹主动脉缩窄大鼠肥厚心肌一氧化氮合酶的影响,探讨丹参酮ⅡA逆转高血压左心室肥厚的分子生物学机制。
方法:取各组大鼠的左心室组织,利用硝酸还原酶法测定心肌组织的NO含量,采用逆转录-聚合酶链式反应(RT-PCR)、免疫印记法(Western blotting)分别检测eNOS的基因表达水平和蛋白激酶C(PKC)的活性。
结果:
1.假手术组的心肌组织NO含量明显高于其他各组(p﹤0.01);丹参酮高、低剂量组与缬沙坦组之间无统计学差异(p﹥0.05),但此三组的NO含量明显高于心肌肥厚组(p﹤0.01)。
2.心肌肥厚组的eNOS mRNA和蛋白表达水平明显低于其他各组(p﹤0.01),缬沙坦组低于假手术组和丹参酮组(p﹤0.05),丹参酮高、低剂量组与假手术组之间无差异(p﹥0.05)。
3.心肌肥厚组的PKC蛋白水平明显高于其他各组(p﹤0.01),缬沙坦组低于假手术组和丹参酮组(p﹤0.05),丹参酮高、低剂量组与假手术组之间无差异(p﹥0.05)。
结论:心肌局部的NO/NOS系统与心肌肥厚的病理过程密切相关。丹参酮ⅡA可能通过抑制PKC的蛋白活性、促进心肌局部eNOS的基因表达和内源性NO的产生,发挥其逆转心肌肥厚的药理作用。
Cardiac hypertrophy is an adaptive response of the heart to virtually all forms of cardiac diseases, including those arising from hypertension, mechanical load, myocardial infarction ,cardiac arrhythmias, endocrine disorders, and genetic mutations in cardiac contractile protein genes. While the hypertrophic response is initially a compensatory mechanism that augments cardiac output, hypertrophy can lead to dilated cardiomyopathy, heart failure and sudden death. cardiac hypertrophy was an absolute and dangerous factor that affected mortality and morbidity for cardiovascular diseases.
Left ventricular weight rise in patients with cardiac hypertrophy. Cardiac hypertrophy was not only a pathophysiological process, but also a discompensatory change that affected short-term and long-term prognosis. Nowdays drugs for curing cardiac hypertrophy mostly have angiotenesin converting enzyme inhibitors ,angiotensin receptor blocker and calcium channel antagonist. But these drugs have their limit for some adverse reaction. So it is important to look for several drugs which have good therapeutic effect and little side effect in the long-term cure for myocardial hypertrophy.
TanshinoneⅡA is the main lipid soluble component of danshen, a kind of traditional Chinese drug. Now it has been found that tanshinoneⅡA could alleviate and reverse left ventricular hypertrophy causing by hypertension, but its mechanism is still unknown.
In this study, we would construct the model of myocardial hypertrophy in hypertensive rats caused by abdominal aorta constriction and compare tanshinoneⅡA with an angiotensin receptor inhibitor-valsartan, a classical drug for resisting cardiac hypertrophy to explore the molecular biological mechanism for tanshinoneⅡA reversing myocardial hypertrophy.
Part one : the ultrasound imageological and pathomorphological effect of tanshinoneⅡA on hypertrophic myocardium due to abdominal aorta stenosis in rats
Objective: To study the effect of tanshinoneⅡA on hypertrophic myocardium caused by abdominal aorta stenosis in rats.
Methods: Taking 40 rats who were suffered abdominal aorta constriction and 8 rats who were suffered artificial surgery. 4 weeks later, these rats would be divided into 4 groups: myocardial hypertrophy, low dose tanshinoneⅡA treatment (10mg/kg/d peritoneal injection), high dose tanshinoneⅡA treatment (20mg/kg/d peritoneal injection) and valsartan treatment (10mg/kg/d intragastric administration). After accepting therapy for 8 weeks, to measure the thickness of posterior ventricular wall and interventricular septum and left ventricular ejection fraction(EF) by echocardiogram ; then to take the tissue of left ventricle to detect left ventricular mass index ( LVMI) and myocardial fiber dimension (MFD) by pathological section and HE stain.
Results :
1. The blood pressure in the group of myocardial hypertrophy and tanshinoneⅡA treatment (low and high dose) was obviously higher than that in the group of artificial surgery and valsartan treatment (p<0.01). But it was not different between myocardial hypertrophy group and tanshinoneⅡA treatment (low and high dose) groups (p>0.05).
2. The thickness of interventricular septum in the groups of tanshinoneⅡA and valsartan was more than that in artificial surgery (p<0.05), but less than that in myocardial hypertrophy. And two tanshinoneⅡA treatment groups had similar result(p>0.05), but they both were thicker than valsartan treatment group.
3. There were not significant difference about thickness of posterior left ventricle among two tanshinoneⅡA treatment groups and valsartan treatment group(p<0.05). They were all obviously less than that in myocardial hypertrophy group(p<0.01), but did not get to normal lever(p<0.05).
4. The EF value in all groups were in normal range(>60%). Though it was not found heart failure in myocardial hypertrophy group, the EF value in this group were less than that in other groups(p<0.05). And EF value in tanshinoneⅡA groups was less than that in valsartan group(p<0.05).
5. There were not significantly different in LVMI and MFD between two tanshinoneⅡA treatment groups(p>0.05). MFD in valsartan group and two tanshinoneⅡA groups were obviously less than that in myocardial hypertrophy group(p<0.01) and more than that in artificial surgery group(p<0.05); and two tanshinoneⅡA groups more than valsartan group(p<0.05).
Conclusion: The effect of tanshinoneⅡA on myocardial hypertrophy was not dependent on blood pressure. As angiotensinⅡreceptor antagonist-valsartan did , tanshinoneⅡA could block and reverse the development of myocardial hypertrophy, but its was a little weaker .
Part two: The effect of tanshinoneⅡA on angiotensin receptor and free calcium ion in hypertrophic myocardium of rats due to abdominal aorta constriction.
Objective: To explore the molecular biological mechanism about tanshinoneⅡA reversing left ventricular hypertrophy, it would be studied how tanshinoneⅡA gave an impact to angiotensin receptor and free calcium ion in hypertrophic myocardium of rats due to abdominal aorta constriction.
Methods: To detect mRNA and protein’s expression of AT1 and AT2 receptors in left ventricular tissues of all groups by RT-PCR and Western blotting.
Results:
1. The mRNA and protein’s expression of AT1 receptor in myocardial hypertrophy group were obviously more than that in other groups(p<0.01); there were no difference within two tanshinoneⅡA groups(p>0.05), but tanshinoneⅡA groups was higher than valsartan group(p<0.05). The genic expression in these three groups did not recover to normal lever( artificial surgery group)(p<0.05).
2. The mRNA and protein’s expression of AT2 in valsartan group was more than that in other groups(p<0.05), and there were no difference among the other groups(p>0.05).
3. The concentration of calcium ion in myocardial hypertrophy group was highest( VS other groups, p<0.01); and that in the two tanshinoneⅡA groups and artificial surgery group had not statistically different(p>0.05) , but they were lower than that in valsartan group(p<0.05).
Conclusion: TanshinoneⅡA and Valsartan both could resist the myocardial hypertrophy by downregulating the genic expression of AT1 receptor and blocking the inflow of calcium ion in cadiocyte. Moreover, AT2 receptor may participate the effect of lowering blood pressure and reversing hypertrophy as for valsartan.
Part three: the effect of tashinone on the nitric oxide synthase in the hypertrophic cadiocyte of rats suffered abdominal aorta constriction.
Objective: To explore the molecular biological mechanism for tanshinoneⅡA reversing left ventricular hypertrophy, it would be studying the effect of tashinone on the endothelial nitric oxide synthase( eNOS) in the hypertrophic cadiocyte of rats suffered abdominal aorta constriction.
Methods: To detect the nitric oxide content by nitrate reductase, to detect the genic expression of eNOS by RT-PCR and to detect the activity of protein kinase C( PKC) by Western blotting.
Results:
1. The expressive lever of eNOSmRNA and protein in myocardial hypertrophy group was less than that in other groups(p<0.01). And valsartan group was less than tanshinoneⅡA groups and artificial surgery group(p<0.05), but there were no difference among the two tanshinoneⅡA groups and artificial surgery group(p>0.05).
2. The expression of PKC in myocardial hypertrophy group was much more than that in other groups(p<0.01). valsartan group was less than artificial surgery group and tanshinoneⅡA groups(p<0.05), but there were no difference among two tanshinoneⅡA groups and artificial surgery group(p>0.05).
Conclusion: NO/NOS system in local myocardium had close relationship with the pathological process for myocardial hypertrophy. TanshinoneⅡA could produce the pharmacological action to reverse myocardial hypertrophy by inhibiting the activity of PKC and promoting the genic expression of eNOS in local myocardium and the production of endogenous NO.
研究发现在心肌肥厚时左心室重量普遍增高,心血管事件发生率是无心肌肥厚者的2-4倍。心肌肥厚不仅是一个病理生理过程,而更是一个影响其短期和长期预后的失代偿性变化。它的不可逆性进展可以直接导致心力衰竭。目前临床上用于治疗心肌肥厚的治疗药物主要有血管紧张素转化酶抑制剂、血管紧张素受体拮抗剂和钙离子通道阻滞剂,但皆因存在不同程度的副作用而使其临床应用受到一定限制。而心肌肥厚的治疗是一个长期的过程,因此寻找一些疗效好而毒副作用低的药物显得十分必要。丹参酮ⅡA是中药丹参的主要脂溶性成分。目前已发现丹参酮ⅡA可以减轻、逆转高血压左心室肥厚,但其具体作用机制尚未阐明。
本研究拟在腹主动脉缩窄的高血压大鼠上构建心肌肥厚模型,将丹参酮ⅡA与经典的抗心肌肥厚药物血管紧张素1型受体拮抗剂――缬沙坦比较,以探讨丹参酮ⅡA逆转心肌肥厚的分子生物学机制。
第一部分丹参酮ⅡA对腹主动脉缩窄高血压大鼠心肌肥厚超声影像学及病理形态学的影响
目的:研究丹参酮ⅡA对腹主动脉缩窄术后大鼠左室心肌肥厚的作用。
方法:40只健康SD大鼠,行腹主动脉缩窄术建立高血压左室心肌肥厚模型,另取8只大鼠行假手术。术后4周将手术大鼠随机分为心肌肥厚组、丹参酮低剂量组(10mg/Kg/d腹腔注射)、丹参酮高剂量组(20mg/Kg/d腹腔注射)及缬沙坦组(10mg/Kg/d灌胃)。用药8周后通过超声心动图测定左室后壁、室间隔的厚度及左室射血分数(EF);取左心室组织检测左心室质量指数(left ventricular mass index,LVMI)、病理切片HE染色测量心肌纤维直径(myocardial fiber dimension,MFD)。
结果:
1.心肌肥厚组、丹参酮组(高、低剂量)的血压显著高于假手术组及缬沙坦组(p﹤0.01),丹参酮高、低剂量组及心肌肥厚组之间无统计学差异(p﹥0.05),缬沙坦组的血压值降至正常、但仍明显高于假手术组(p﹤0.05)。
2.丹参酮高、低剂量组和缬沙坦组的室间隔厚度均高于假手术组(p﹤0.05),显著低于心肌肥厚组(p﹤0.01);丹参酮两组的室间隔厚度无差异(p﹥0.05),但高于缬沙坦组(p﹤0.05)。
3.丹参酮低剂量、高剂量组及缬沙坦组之间左室后壁值数据没有显著性差异(P>0.05),此三组左室后壁值均明显低于心肌肥厚组(p﹤0.01),但尚未恢复至正常水平(p﹤0.05)。
4.所有各组的EF值均在正常值范围(>60%),尚未表现出心功能衰竭。但心肌肥厚组的EF值小于其他各组(p﹤0.05),丹参酮组的EF也小于缬沙坦组(p﹤0.05)。
5.丹参酮低剂量和高剂量组间LVMI和MFD没有显著性差异(P>0.05),缬沙坦组和丹参酮各组的LVMI、MFD均高于假手术组(p﹤0.05),显著低于心肌肥厚组(p﹤0.01);丹参酮两组的LVMI、MFD均高于缬沙坦组(p﹤0.05)。
结论:
丹参酮Ⅱ-A对心肌肥厚的逆转作用是非血压依从性的。丹参酮Ⅱ-A与血管紧张素Ⅱ1型受体拮抗剂缬沙坦均可阻止、逆转高血压心肌肥厚的发展,但其作用弱于缬沙坦。
第二部分丹参酮ⅡA对腹主动脉缩窄大鼠肥厚心肌血管紧张素受体的影响
目的:通过研究丹参酮ⅡA对腹主动脉大鼠肥厚心肌血管紧张素受体及细胞内游离钙离子的影响,探讨丹参酮ⅡA逆转高血压左心室肥厚的分子生物学机制。
方法:取各组大鼠的左心室组织,采用逆转录-聚合酶链式反应(RT-PCR)、免疫印记法(Western blotting)分别检测AT1、AT2受体mRNA和蛋白的表达水平。利用激光共聚焦显微镜测定心肌细胞内Ca2+浓度的变化。
结果:
1.心肌肥厚组的AT1 mRNA和蛋白的表达显著高于其他各组(p﹤0.01);丹参酮ⅡA高、低剂量组间无差异(p﹥0.05),丹参酮ⅡA组高于缬沙坦组(P﹤0.05);丹参酮ⅡA组和缬沙坦组的AT1基因表达均未降至假手术组水平(p﹤0.05)。
2.缬沙坦组的AT2 mRNA和蛋白表达水平较其他各组升高(p﹤0.05),其他各组之间无统计学差异(p﹥0.05)。
3.心肌肥厚组细胞内[Ca2+]i明显高于其他各组(p﹤0.01);丹参酮高剂量组与假手术组之间无统计学差异(p﹥0.05);缬沙坦组和丹参酮低剂量组仍高于假手术组和丹参酮高剂量组(p﹤0.05);丹参酮低剂量组细胞内钙浓度与缬沙坦组之间无差异(p﹥0.05)。
结论:
丹参酮ⅡA和缬沙坦均可通过下调AT1基因表达、阻止心肌细胞的钙离子内流发挥逆转心肌肥厚的作用,AT2有可能参与了缬沙坦降低血压、逆转心肌肥厚的作用。
第三部分丹参酮IIA对腹主动脉缩窄高血压大鼠肥厚心肌一氧化氮合酶的影响
目的:通过研究丹参酮ⅡA对腹主动脉缩窄大鼠肥厚心肌一氧化氮合酶的影响,探讨丹参酮ⅡA逆转高血压左心室肥厚的分子生物学机制。
方法:取各组大鼠的左心室组织,利用硝酸还原酶法测定心肌组织的NO含量,采用逆转录-聚合酶链式反应(RT-PCR)、免疫印记法(Western blotting)分别检测eNOS的基因表达水平和蛋白激酶C(PKC)的活性。
结果:
1.假手术组的心肌组织NO含量明显高于其他各组(p﹤0.01);丹参酮高、低剂量组与缬沙坦组之间无统计学差异(p﹥0.05),但此三组的NO含量明显高于心肌肥厚组(p﹤0.01)。
2.心肌肥厚组的eNOS mRNA和蛋白表达水平明显低于其他各组(p﹤0.01),缬沙坦组低于假手术组和丹参酮组(p﹤0.05),丹参酮高、低剂量组与假手术组之间无差异(p﹥0.05)。
3.心肌肥厚组的PKC蛋白水平明显高于其他各组(p﹤0.01),缬沙坦组低于假手术组和丹参酮组(p﹤0.05),丹参酮高、低剂量组与假手术组之间无差异(p﹥0.05)。
结论:心肌局部的NO/NOS系统与心肌肥厚的病理过程密切相关。丹参酮ⅡA可能通过抑制PKC的蛋白活性、促进心肌局部eNOS的基因表达和内源性NO的产生,发挥其逆转心肌肥厚的药理作用。
Cardiac hypertrophy is an adaptive response of the heart to virtually all forms of cardiac diseases, including those arising from hypertension, mechanical load, myocardial infarction ,cardiac arrhythmias, endocrine disorders, and genetic mutations in cardiac contractile protein genes. While the hypertrophic response is initially a compensatory mechanism that augments cardiac output, hypertrophy can lead to dilated cardiomyopathy, heart failure and sudden death. cardiac hypertrophy was an absolute and dangerous factor that affected mortality and morbidity for cardiovascular diseases.
Left ventricular weight rise in patients with cardiac hypertrophy. Cardiac hypertrophy was not only a pathophysiological process, but also a discompensatory change that affected short-term and long-term prognosis. Nowdays drugs for curing cardiac hypertrophy mostly have angiotenesin converting enzyme inhibitors ,angiotensin receptor blocker and calcium channel antagonist. But these drugs have their limit for some adverse reaction. So it is important to look for several drugs which have good therapeutic effect and little side effect in the long-term cure for myocardial hypertrophy.
TanshinoneⅡA is the main lipid soluble component of danshen, a kind of traditional Chinese drug. Now it has been found that tanshinoneⅡA could alleviate and reverse left ventricular hypertrophy causing by hypertension, but its mechanism is still unknown.
In this study, we would construct the model of myocardial hypertrophy in hypertensive rats caused by abdominal aorta constriction and compare tanshinoneⅡA with an angiotensin receptor inhibitor-valsartan, a classical drug for resisting cardiac hypertrophy to explore the molecular biological mechanism for tanshinoneⅡA reversing myocardial hypertrophy.
Part one : the ultrasound imageological and pathomorphological effect of tanshinoneⅡA on hypertrophic myocardium due to abdominal aorta stenosis in rats
Objective: To study the effect of tanshinoneⅡA on hypertrophic myocardium caused by abdominal aorta stenosis in rats.
Methods: Taking 40 rats who were suffered abdominal aorta constriction and 8 rats who were suffered artificial surgery. 4 weeks later, these rats would be divided into 4 groups: myocardial hypertrophy, low dose tanshinoneⅡA treatment (10mg/kg/d peritoneal injection), high dose tanshinoneⅡA treatment (20mg/kg/d peritoneal injection) and valsartan treatment (10mg/kg/d intragastric administration). After accepting therapy for 8 weeks, to measure the thickness of posterior ventricular wall and interventricular septum and left ventricular ejection fraction(EF) by echocardiogram ; then to take the tissue of left ventricle to detect left ventricular mass index ( LVMI) and myocardial fiber dimension (MFD) by pathological section and HE stain.
Results :
1. The blood pressure in the group of myocardial hypertrophy and tanshinoneⅡA treatment (low and high dose) was obviously higher than that in the group of artificial surgery and valsartan treatment (p<0.01). But it was not different between myocardial hypertrophy group and tanshinoneⅡA treatment (low and high dose) groups (p>0.05).
2. The thickness of interventricular septum in the groups of tanshinoneⅡA and valsartan was more than that in artificial surgery (p<0.05), but less than that in myocardial hypertrophy. And two tanshinoneⅡA treatment groups had similar result(p>0.05), but they both were thicker than valsartan treatment group.
3. There were not significant difference about thickness of posterior left ventricle among two tanshinoneⅡA treatment groups and valsartan treatment group(p<0.05). They were all obviously less than that in myocardial hypertrophy group(p<0.01), but did not get to normal lever(p<0.05).
4. The EF value in all groups were in normal range(>60%). Though it was not found heart failure in myocardial hypertrophy group, the EF value in this group were less than that in other groups(p<0.05). And EF value in tanshinoneⅡA groups was less than that in valsartan group(p<0.05).
5. There were not significantly different in LVMI and MFD between two tanshinoneⅡA treatment groups(p>0.05). MFD in valsartan group and two tanshinoneⅡA groups were obviously less than that in myocardial hypertrophy group(p<0.01) and more than that in artificial surgery group(p<0.05); and two tanshinoneⅡA groups more than valsartan group(p<0.05).
Conclusion: The effect of tanshinoneⅡA on myocardial hypertrophy was not dependent on blood pressure. As angiotensinⅡreceptor antagonist-valsartan did , tanshinoneⅡA could block and reverse the development of myocardial hypertrophy, but its was a little weaker .
Part two: The effect of tanshinoneⅡA on angiotensin receptor and free calcium ion in hypertrophic myocardium of rats due to abdominal aorta constriction.
Objective: To explore the molecular biological mechanism about tanshinoneⅡA reversing left ventricular hypertrophy, it would be studied how tanshinoneⅡA gave an impact to angiotensin receptor and free calcium ion in hypertrophic myocardium of rats due to abdominal aorta constriction.
Methods: To detect mRNA and protein’s expression of AT1 and AT2 receptors in left ventricular tissues of all groups by RT-PCR and Western blotting.
Results:
1. The mRNA and protein’s expression of AT1 receptor in myocardial hypertrophy group were obviously more than that in other groups(p<0.01); there were no difference within two tanshinoneⅡA groups(p>0.05), but tanshinoneⅡA groups was higher than valsartan group(p<0.05). The genic expression in these three groups did not recover to normal lever( artificial surgery group)(p<0.05).
2. The mRNA and protein’s expression of AT2 in valsartan group was more than that in other groups(p<0.05), and there were no difference among the other groups(p>0.05).
3. The concentration of calcium ion in myocardial hypertrophy group was highest( VS other groups, p<0.01); and that in the two tanshinoneⅡA groups and artificial surgery group had not statistically different(p>0.05) , but they were lower than that in valsartan group(p<0.05).
Conclusion: TanshinoneⅡA and Valsartan both could resist the myocardial hypertrophy by downregulating the genic expression of AT1 receptor and blocking the inflow of calcium ion in cadiocyte. Moreover, AT2 receptor may participate the effect of lowering blood pressure and reversing hypertrophy as for valsartan.
Part three: the effect of tashinone on the nitric oxide synthase in the hypertrophic cadiocyte of rats suffered abdominal aorta constriction.
Objective: To explore the molecular biological mechanism for tanshinoneⅡA reversing left ventricular hypertrophy, it would be studying the effect of tashinone on the endothelial nitric oxide synthase( eNOS) in the hypertrophic cadiocyte of rats suffered abdominal aorta constriction.
Methods: To detect the nitric oxide content by nitrate reductase, to detect the genic expression of eNOS by RT-PCR and to detect the activity of protein kinase C( PKC) by Western blotting.
Results:
1. The expressive lever of eNOSmRNA and protein in myocardial hypertrophy group was less than that in other groups(p<0.01). And valsartan group was less than tanshinoneⅡA groups and artificial surgery group(p<0.05), but there were no difference among the two tanshinoneⅡA groups and artificial surgery group(p>0.05).
2. The expression of PKC in myocardial hypertrophy group was much more than that in other groups(p<0.01). valsartan group was less than artificial surgery group and tanshinoneⅡA groups(p<0.05), but there were no difference among two tanshinoneⅡA groups and artificial surgery group(p>0.05).
Conclusion: NO/NOS system in local myocardium had close relationship with the pathological process for myocardial hypertrophy. TanshinoneⅡA could produce the pharmacological action to reverse myocardial hypertrophy by inhibiting the activity of PKC and promoting the genic expression of eNOS in local myocardium and the production of endogenous NO.
引文
1. Franz HM,Reinhard K.Left ventricular hypertrophy: a pressure-independent cardiovascular risk factor.J Cardiovasc Pharmacol,1993;22(suppl 1):S7-S13.
2.黄熙,藏益民.丹参酮ⅡA磺酸钠的心血管药理.国外医学中医中药分册,1995;17(1):9-12.
3.梁勇,羊裔明,袁淑兰.丹参酮药理作用及临床应用研究进展.中草药,2000;31(4):304-306.
4.钟先阳,罗仁,魏连波,等.丹参酮ⅡA对大鼠出现性休克-再灌注肾损伤的防治作用.中国中西医结合肾病杂志,2002;3(1):13-15.
5.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
6.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
7.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
8.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
1.Baker KM, Chernin MI, Wisson SK, et al. Renin-angiotensin system involvement in pressure overload cardiac hypertrophy in rats. Am J Physiol,1990;259:324-329.
2.彭亚飞,孙明,周宏研,等.亚降压剂量依那普利预防大鼠压力负荷性心肌肥厚的作用.中国现代医学杂志, 1998;8(9):7-10.
3.Takemoto M, Egashila K, Usui M, et al. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats.J Clin Invest,1997,99(2):278-287.
4. Kato H, Hou J, Chobanian AV, et al. Effects of angiotensinⅡinfusion and inhibition of nitric oxide synthase on the rat aorta[J].Hypertens, 1996;28:153-157.
5.胡文养,陈达光,苏津自,等.卡托普利治疗自发性高血压大鼠对循环和局部肾素-血管紧张素系统的长期影响[J].高血压杂志,1998;6(2):83-88.
6.张萍,何国祥,迟路湘,等. Irbesartan和培哚普利对压力超负荷大鼠循环与心脏组织RAS的影响.重庆医学,2000;29(4): 306-308.
7.Yamazaki T, Komuro I, Yazaki Y. Molecular mechanism of cardiac cellular hypertrophy by mechanical stress.J Mole Cell Cardiol,1995;27:133-140.
8. Crozatier B. Stretch-induced modification of myocardial performance:from ventricular function to cellular and molecular mechanisms. Cardiovasc Res, 1996, 32:25-37.
9. Crozatier B. Stretch-induced modification of myocardial performance:from ventricular function to cellular and molecular mechanisms. Cardiovasc Res, 1996, 32:25-37.
10.姜志胜.心肌肥大过程中的信号转导.中国动脉硬化杂志,2005,13(2):125-128.
11.Takeishi Y,Ping P,Bolli R,et al. Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy. Circ Res,2000,86(12):1218-223.
12. Mochly-Rosen D,Wu G,Hahn H,et al. Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKC epsilon translocation. Circ Res,2000,86(11):1173-1179.
13.桂波,曹红,曾因明.丝裂原活化蛋白激酶与高血压所致的心肌肥厚.《国外医学》麻醉学与复苏分册,2004,25(6): 359-361.
14.汪明慧,梁文同. MAP激酶及其在心肌肥厚中作用的研究.医学综述,2003,9(3):146-148.
15.Schmieder RE,Martus P,Klingbeil A.Reversal of left ventricular hypertrophy in essential hypertension: meta-analysis of randomized double-blind studies. JAMA,1996;275:1505-1513.
16.Dahlof B.Left ventricular hypertrophy and angiotensionⅡantagonist.Am J Hypertens,2001;14:174-182.
17.Palmieri V,Devereux RB. Angiotension converting enzyme inhibition and dihydropyridine calcium channel blockade in the treatment of left ventricular hypertrophy in arterial hypertension. Minerva Cardioangiol,2002,50:169-174.
1.朱红,王汐,刘明宇.左心室肥厚及其药物治疗新进展.中国循环杂志,2003,18(2):151-153.
2. Carsten Zobel,kassiri Z,The-Tin T,et al.Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal cardomyocytes.Circulation 2002;106:2385-2391.
3.施新猷.现代医学试验动物学[M].北京人民军医出版社,2000:464-465.
4. Zhang TT,Koichi Takinoto,Alexandre FR,et al.Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensionⅡand phenylephrine.Cire Res,2001,88:476-482.
5. Lin Qing,Li Peng.Effects of chronic stress on blood pressure and heart rate in rats.Chinese Journal of Physiological Sciences,1990,6(2):101-107.
6. Capasso JM,Strobeck JE,Malbotra A.Contractile behavior of rat myocardium after reversal of hypertensive hypertension.Am J Physiol , 1982 ;242:H882-889.
7.彭亚飞,孙明,周宏研,等.亚降压剂量依那普利预防大鼠压力负荷性心肌肥厚的作用.中国现代医学杂志, 1998,8(9):7-10.
8. Takemoto M, Egashila K, Usui M, et al. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest, 1997, 99(2):278-287.
9.张萍,何国祥,迟路湘,等. Irbesartan和培哚普利对压力超负荷大鼠循环与心脏组织RAS的影响.重庆医学, 2000,29(4): 306-308.
10. Kato H, Hou J, Chobanian AV, et al. Effects of angiotensinⅡinfusion and inhibition of nitric oxide synthase on the rat aorta[J]. Hypertens, 1996, 28:153-157.
11.胡文养,陈达光,苏津自,等.卡托普利治疗自发性高血压大鼠对循环和局部肾素-血管紧张素系统的长期影响[J].高血压杂志, 1998, 6(2): 83-88.
12. Baker KM, Chernin MI, Wisson SK, et al. Renin-angiotensin system involvement in pressure overload cardiac hypertrophy in rats. Am J Physiol, 1990, 259:324-329
13. Yamazaki T, Komuro I, Yazaki Y. Molecular mechanism of cardiac cellular hypertrophy by mechanical stress. J Mo Cell Cardiol, 1995, 27:133-140.
14.Crozatier B. Stretch-induced modification of myocardial performance:from ventricular function to cellular and molecular mechanisms. Cardiovasc Res, 1996, 32:25-37.
15.姜志胜.心肌肥大过程中的信号转导.中国动脉硬化杂志,2005,13(2):125-128.
16.Takeishi Y,Ping P,Bolli R,et al. Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy. Circ Res,2000,86(12):1218-223.
17. Mochly-Rosen D,Wu G,Hahn H,et al. Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKC epsilon translocation. Circ Res,2000,86(11):1173-179.
18.桂波,曹红,曾因明.丝裂原活化蛋白激酶与高血压所致的心肌肥厚.《国外医学》麻醉学与复苏分册,2004,25(6): 359-361.
19.汪明慧,梁文同.MAP激酶及其在心肌肥厚中作用的研究.医学综述,2003,9(3):146-148.
20.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
21.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
22.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
23.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
1. Franz HM,Reinhard K.Left ventricular hypertrophy: a pressure-independent cardiovascular risk factor.J Cardiovasc Pharmacol,1993;22(suppl 1):S7-S13.
2.LoreⅡBH.Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and disease[J].Am J Cardiol.1999,83(12A):48H.
3.DellItalia LJ,Meng QC,Balcells E,et al. Compartmentalization of angiotensin II generation in the dog heart.Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest,1997,100:253-258.
4.Paradis P,Daliyoucef N ,Paradis FW,et al. Overexpression of angiotensin Ⅱtype1 receptors in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl, 2000,97:931-936.
5.Metcalfe BL,Huentelman MJ,Parilak LD,et al.Prevention of cardiac hypertrophy by angiotensin II type 2 receptor gene transfer.Hypertension,2004,43:1-6.
6.Senbonmatsu T,Ichihara S,Price EJ,et al.Evidence for angiotensinⅡtype 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload[J].J Clin Invest,2000,106(3):R25-29.
7.曾武涛,马虹,冷秀玉,等.血管紧张素-(1-7)对血管紧张素诱导心肌细胞原癌基因c-fos表达的影响[J].中国心血管杂志,2003,8(1):9-11
8.Harrison-Bernard LM,El-Dahr SS,O.Leary DF,etal.Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension[J].Hypertension,1999,33(1):340-346.
9.何建桂,黄艺仪,马虹,等.血管紧张素-(1-7)对压力负荷增高大鼠血管紧张素及受体的影响.中国医师杂志,2005,7(8):1035-1037.
10.Cheng HF,Burns KD,Harris RC.Reduced proximal tubule angiotensin receptor expression in streptozotocin - induced diabetes mellitus. KidneyInt,1994,46(6):1603-1610.
11.Hou M,Pantev E,Moller S,etal. Angiotensin type 1 receptor atimulate protein synthesis in human cardiac fibrobiasts via a Ca2+ - sensitive: PKC -dependent tyrosine kinase pathway. Acta Physiol Scand, 2000, 168(2): 301-309.
12.Yamada H,Horiuchi M.Regulation if vascular development and differentiation by angiotensin type 2 receptor. Hypertension, 1997, 30: 470-475.
13.Takekoshhi K,Ishii K,Shibuya S,et al. Angiotensin type 2 receptor counterregulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells[J]. Hypertension, 2002, 39(1):142-148.
14.Baker KM, Booz GW, Dostal DE. Cardiac actions of AngiotensinⅡ: role of an intracardiac rennin-angiotensin system [J]. Annu Rev Physiol, 1992,54: 227-241.
15.刘键.心肌肥厚大鼠心肌细胞核三磷酸肌醇受体的特性[J].生理学报,2001;53(4):281-285.
16.Iino M.Dynamic regulation of intracellular calcium signals through calcium release channels[J].Mol Cell Biochem,1999,190:185-190.
17.Iino M.Calcium-dependent immediate feedback control of inositol 1, 4, 5-trisphosphate-induced Ca2+ release[J].Nature,1992,360:76-78.
18.Oriji GK. AngiotensinⅡstimulates hypertrophic growth of cultured neonatal rat ventricular myocytes: roles of PKC and PGF2 alpha [J]. Prostaglandins Leukot Essent Fatty Acids,2000,62(4): 233-237.
19.赵凌杰,商伟,蔡辉.血管紧张素Ⅱ在心肌纤维化形成中的作用[J].中国微循环, 2004,8(1): 5-6.
20.方淑贤,苑力哪,郑恒,等.芦沙坦对心脏成纤维细胞胶原Ⅰ、Ⅲ型mRNA表达水平的影响[J].同济医科大学学报,1999,28(4):326-328.
21.Grohe C,Kahlert S,Lobbert K,et al. Angiotensin coverting enzyme inhibition modulates cardiac growth [J].J Hypertens,1998,16:377-384.
22.Mazzolai L,Nussberger J,Auber JF,et al.Blood pressure-independent cardiac hypertrophy indued by locally activated rennin-angiotensin system[J]. Hypertension,1998,31:1324-1330.
23.Sano H,Okamoto H,Kitabatake A,et al.Increased mRNA expression of cartensive rats[J].Mol Cell Biochem,1998,178:51-58.
24.Siggi PKS,Kivlighn SD,Broten TP.Pharmaclogy of losartan,an angiotensin Ⅱreceptor antagonist , in animal of hypertension[J].J Pharmacol Exp,1995,13(Suppl 1):15.
25.Xu J , Carretero OA , Liu YH , et al.Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice.Hypertension,2002,40:244-250.
26.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
27.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
28.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
29.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
30.谢辉,郑智,龚丽娅.丹参酮IIA对自发性高血压大鼠左室肥厚的影响及机制.实用医学杂志,2004,20(3):252-254.
31.徐长庆,娄延平,杨宝峰,等.丹参酮Ⅱ-A抑制豚鼠单个心肌细胞L型钙电流和缩短动作电位时程效应的相关性分析.中国药理学通报1998,14(5):428-431.
32.Xu CQ,Fan JS,Hao XM,et al.Blocking effect of sodium tanshinoneⅡA sulfonate on L-type Ca2+ current of single ventricular myocyte from guineapig[J].Chin J Pharmacol Toxical,1999,10:81-84.
33.徐长庆,娄延平,杨宝峰,等.丹参酮Ⅱ-A抑制豚鼠单个心肌细胞L型钙电流和缩短动作电位时程效应的相关性分析.中国药理学通报,1998,14(5):428-431.
34.王照华,梁黔生,郑智.丹参酮对肥厚心肌L2型钙电流的影响.高血压杂志2006,14(6):450-454.
35.冯俊,李树生.丹参酮ⅡA抑制血管紧张素诱导大鼠心肌肥大的机制.高血压杂志,2005,13(8):488-491.
36.杨乐,冯俊,严丽,等.丹参酮Ⅱ-A磺酸钠影响血管紧张素Ⅱ诱导心肌肥大及p-JNK和丝裂原活化蛋白激酶磷酸酶1的表达.中国临床康复,2006,10(23):84-86.
1 .Frey N,Olson EN. Cardiac hypertrophy: the good,the bad,and the ugly. Annu Rev Physiol,2003,65:45-79.
2.van Empel VP,De Windt LJ. Myocyte hypertrophy and apoptosis: a balancing act. Cardiovasc Res,2004,63(3):487-499.
3.张云飞,吴先均,文秀华,等.心肌肥厚机制研究进展.心血管病学进展,2005,26(2):197-200.
4.Kanai AJ,Mesaros S,Finkel MS,et al.Beta-adrenergic regulation of constitutive nitri coxide synthase in cardiac myocytes. Am J Physiol,1997,273:C1371-C1377.
5.Sun Y, Carretero OA, Xu J, Rhaleb NE, et al. Lack of inducible NO synthase reduces oxidative stress and enhances cardiac response to isoproterenol in mice with deoxycorticosterone acetate-salt hypertension[J]. Hypertension, 2005, 46(6): 1355-361.
6.Koyanagi M,Egashira K,Kitamoto S,et al. Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis[J]. Circulation,2000,102(18):2243-2248.
7.刘培庆,鲁伟,潘敬运.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制[J].生理学报,2002,54(3):213-218.
8. Kacimi R,Long CS,Karliner JS. Chronic hypoxia modulates the interleukin-1 stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation,1997,96:1937-1943.
9.郭益民,朱小南,潘敬运.一氧化氮在肾性高血压大鼠心肌肥厚中的作用[J].中山医科大学学报,1999,20(2):107-110.
10.刘培庆,鲁伟,潘敬运.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制。生理学报,2002,54(3):213-218.
11.郑惠珍,安国顺,聂思槐,等.一氧化氮抑制内皮素促血管平滑肌细胞增殖作用的信号转导途径[J].生理学报,1998,50(4):379-384.
12.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
13.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
14.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
15.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
16.李永胜,王照华,梁黔生,等.丹参酮ⅡA对血管紧张素Ⅱ作用下的主动脉内皮细胞一氧化氮的产生及细胞内游离钙离子的影响.中华高血压杂志,2006,14(11):882-885.
17.吴杨,胡亚娥,张元媛.一氧化氮合酶mRNA在压力超负荷心肌肥厚中的作用.临床心血管病杂志,2005,21(9):54-57.
18.Mc Call T, Vallance P. Nitric oxide takes centerstage with newly defined roles. TIPS, 1992, 13: 1-5.
19.Werner-Felmayer G, Werner ER, Fuchs D, et al. On multiple forms of NO synthase and their occulrence in human cells. Res Immunol 1991, 142: 555-561.
20.Kaye DM,Wiviott SD,Balligand JL,et al.Frequency-dependent activation of a constitutive nitric oxide synthase and regulation of contractile function in adult rat ventricular myocytes.Circ Res,1996,78:217-224.
21.De Gasparo M.AngiotensinⅡand nitric oxide interaction.Heart Fail Rev,2002,7(4):347-358.
22.Raij L.Hypertension and cardiovascular risk factors. Hypertension,2001,37(2):767-773.
23.符史干,谢协驹,吉丽敏等.一氧化氮和血管紧张素Ⅱ在压力超负荷心肌肥大中的作用.海南医学院报,2002,8:1-6.
24.符史干,谢协驹,吉丽敏等.Losartan压抑压力超负荷高血压和心肌肥大的实验.海南大学学报自然科学版,2001,19:373-376.
25.钟南田,符史干,符皎荣,等.一氧化氮在压力超负荷心肌肥大作用中的定量分析.解剖学杂志,2005,28(5):517-519.
26.刘培庆,鲁伟,潘敬运,等.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制.生理学报,2002,54(3):213-218.
27.Massin PB,Balligand JL.Modulation of cardiac contraction relaxatio and rate by the endothelial nitric oxide synthase (eNOS):lessons from genetically modified mice.J Physiol,2003,546:63-75.
28.Ozaki M,Kawashima S,Yamashita T,et al.Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion.Circ J,2002,66:851-856.
29.Kobayashi N,Hara K,Watanabe S,et al.Effect of imidapril on myocardial remodeling in L-NAME-induced hypertensive rats is associated with gene expression of NOS and ACE mRNA.Am J Hypertens,2000,13:199-207.
30.Matsuoka H,Nakata M,Kohno K.Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats[J].Hypertension,1996,27:14.
31.郭国庆,沈伟哉.外源性一氧化氮抑制剂和促进剂对高血压大鼠心室壁厚度和心肌血管紧张素的影响.暨南大学学报(医学版), 2004,25(6):697-701.
32.郭益民,朱小南,潘敬运.一氧化氮在肾性高血压大鼠心肌肥厚中的作用.中山医科大学学报,1999,20(2):107-110.
33.王庭槐,吴滨,潘敬运.左旋精氨酸抑制血管紧张素Ⅱ诱导培养心肌细胞的肥大反应.生理学通报,1996,13:9.
34.尹时华,肖立新,陈业文,等.L-精氨酸对肾性高血压心肌肥厚大鼠左心室肌原癌基因c-fos蛋白表达及血浆NO含量的影响.高血压杂志,2001,8(1):85-88.
35.Martinez Y,Martinez S,Meaney A,et al. Angiotensin type 1 receptor blockade restores nitric oxide-dependent renal vascular responses in renovascular hypertension[J].J Cardiovasc Pharmacol,2002,40(3):381-387.
36.Cruzado M,Castro C,Risler N,et al.Changes of inducible nitric oxide synthase in aortic cells during the development of hypertension: effect of angiotensin[J].Biocell,2002,26(1):61-67.
37.何敏,徐济良,郑民,等.缬沙坦对2型糖尿病大鼠心肌病变的防治作用[J].中国药理学通报,2004,20(12):1386-1389.
38.Xu J , Carretoro OA , Liu YH , et al.Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-250.
39.Brede M,Roell W,Ritter O,et al.Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice.Hypertension,2003,42:1177-1182.
40.Isenovic E R,Meng Y,Divald A,et al.Role of phosphatidylinositol 3-kinase/Akt pathway in angiotensinⅡand insulin-like growth factor-1 modulation of nitric oxide synthase in vascular smooth muscle cells[J].Endocrine,2002,19(3):287-292.
41.符史干,谢协驹,吉丽敏,等.一氧化氮在血管紧张素激活蛋白激酶C中的作用.生理学报,2003,55(1):53-57.
42.陈连剑,李婷,李成.丹参酮ⅡA抗大鼠肝星状细胞氧应激脂质过氧化作用的研究.中药材,2003,26(7):504-507.
43.叶龙彬,奚涛,陈峰,等.丹参酮ⅡA对大鼠局灶性脑缺血再灌注损伤的保护作用.中国药科大学学报,2004,35(3):267-270.
44.陶军,王舟琪,刘桥义,等.丹参酮防治心肌再灌注损伤的实验研究[J].中华麻醉学杂志,1996,16(5):202-204.
45.谢辉,郑智.丹参酮ⅡA对血管紧张素Ⅱ诱导的心肌细胞肥大、凋亡的影响.高血压杂志2004,12(4):359-361.
46.徐长庆,娄延平,杨宝峰,等.丹参酮Ⅱ-A抑制豚鼠单个心肌细胞L型钙电流和缩短动作电位时程效应的相关性分析.中国药理学通报1998,14(5):428-431.
47.谢辉,郑智,龚丽娅.丹参酮IIA对自发性高血压大鼠左室肥厚的影响及机制.实用医学杂志,2004,20(3):252-254.
48.冯俊,李树生.丹参酮A抑制血管紧张素诱导大鼠心肌肥大的机制.2005,13(8):488-491.
49.杨乐,冯俊,严丽,等.丹参酮Ⅱ-A磺酸钠影响血管紧张素Ⅱ诱导心肌肥大及p-JNK和丝裂原活化蛋白激酶磷酸酶I的表达.中国临床康复,2006,10(23):84-86.
1.Hefti MA,Harder BA,Eppenberger HM,et al.Signaling pathways in cardiac myocyte hypertrophy.J Mol Cell Cardiol,1997,29:2873-2892.
2.Sadoshima J,Izumo S.The cellular and molecul response of cardiac myocytes to mechanical stress.Annu Rev Physiol,1997,59:551-571.
3.Cooper G.Basic determinants of myocardial hypertrophy: A review of molecular mechanisms.Annu Rev Med,1997,48:13-23.
4.Ishigai Y,Mori T,Ikeda T,et al.Role of bradykinin -NO pathway in prevention of cardiac hypertrophy by ACE inhibit or in rat cardiomyocytes.Am J Physiol,1997,273:H2659-H2663.
5.Calderone A,Thaik CM,Takahashi N,et al. Nitric oxide, atrial natriuretic peptide,and cyclic GMP inhibit the growth - promoting effects of norepinephrine in cardiac myocytes and fibroblasts.J Clin Invest,1998,101:812-818.
6.LoreⅡBH. Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and disease[J].Am J Cardiol.1999,83(12A):48H.
7.Senbonmatsu T,Ichihara S,Price EJ,et al.Evidence for angiotensinⅡtype
2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload[J].J Clin Invest,2000,106(3):R25-29.
8.Bjom Dahlof. Left ventricular hypertrophy and angiotensinⅡantagonist[J].Am J Heart,2001,14:174.
9.Tsutsumi Y,Matsubara H,Ohkubo N,et al.AngiotensinⅡtype 2 receptor is upregulated in human heart with interstitial fibrosis and cardiac fibroblasis are the major cell type for its expression[J].Circ Res,1998,83(10):1035-1046.
10.Matsubara H. Pathophysiological role of angiotensinⅡtype 2 receptor in cardiovascular and renal diseases[J].Circ Res,1998,83(12):1182.
11.Sadoshima JI, Lezumo S. Singnal transduction pathways of angiotensinⅡinduced c-fos gene expression in cardiac myocytes in vitro[J].Circ Res,1993,73:424.
12.Tsutomu Yamszaki. Role of the rennin-angiotensin systen in cardiac hypertrophy[J]. Am J Cardiol,1999,83(12A):53H.
13.Higaki J,Aoki M,Morishita R,et al. In vivo evidence of the importance of cardiac angiotensin-converting enzyme in the pathogenesis of cardiac hypertrophy[J]. Arterioscler Thromb Vase Biol,2000,20(2):428.
14.Sadoshima J,Xu Y,Slayter HS,et al. Autocrine release of angiotensinⅡmediates stretch-induced hypertrophy of cardiac myocytes in vitro[J].Cell,1993,75(5):977.
15.Lai J,Jin H,Yang R,et al. Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vitro[J].Am J Physiol,1996,271(6,pt2):H2197.
16.Lijnen P, Petrov V.Rennin-angiotensin systen, hypertrophy and gene expression in cardiac myocyte[J].JMolCell Cardiol,1999,31(5): 949.
17.Yamazaki T,Komuro J,Kudoh S,et al. AngiotensionⅡpartly mediates mechanicalstress-induced cardiac hypertrophy[J].Circ Res,1995,77(2):258.
18.Kojima M,Shiojima J,Yamazaki T,et al.AngotensinⅡreceptor antagonist TCVI16 induces regression of hypertensiv left ventricular hypertrophy in vivo and inhibits intracellular signal pathway of stretchmediated cardiomyocyte hypertrophy in vitro[J].Circulation,1994,89(5):2204.
19.Kudoh S,Komuro J,Hiroi Y,et al.Mechanical stretch induces hypertrophic resposes in cardiac myocytes of angiotensinⅡtype 1a receptor knockout mice[J].J Biol Chem,1998,273(37):34-37.
20.Munzenmarier DH,Greene AS.Opposing actions of angiotensinⅡonmicrovascular growth and arterial blood pressure[J].Hypertension 1996,27:760-765.
21.Akishita M,Yamada H,Dzau V,et al.Increased vasoconstrictor response of the mouse lacking angiotensinⅡtype 2 receptor[J].Biochem Biophys Res Commun,1999,261:345-349.
22.Tsutsumi Y,Matsubara H,Ohkubo N,et al.AngiotensinⅡtype 2 receptor overexpression activates the vascular kinin systen and causes vasodilation[J].J Clin Invest,1999,104:925-935.
23.Widdop RE, Matrougui K, Levy B, et al. AT2 receptor mediated relaxation is preserved after long-term AT2 receptor blockade[J]. Hypertension, 2002, 40:516-520.
24.Melcalfe BL,Huentelman MJ,Parilak LD,et al.Prevention of cardiac hypertrophy by angiotensinⅡtype-2 receptor gene transfer[J].Hypertension,2004,43:1233-1238.
25.Van Kesteren CA,Van Heugten HA,Lamers JM,et al.AngiotensinⅡ-mediated growth and antigrowth effects in cultured myocytes and fibroblasts[J].J Mol Cell Cardiol,1997,29:2147-2157.
26.Bartunek J,Weinberg E,Tajima M,et al.AngiotensinⅡtype2receptor blockade ampliftes the early signals of cardiac growth response to angiotensinⅡin hypertrophied hearts[J].Circulation,1999,99: 22-25.
27.Masaki H,Kurihara J,Yamaki A,et al.Cardiac-specific overexpression of angiotensinⅡ, AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects[J]. Hypertension,1998,101:527-535.
28.Booz GW,Baker KM.Role of type-1 and type-2 angiotensin receptor in angiotensinⅡinduced cardiomyocyte hypertrophy[J].Hypertension ,1996,28:635-640.
29.Kijimad K,Matsubara H,Murasawa S,et al.Mechanical stretch induces enhanced expression of angiotensinⅡreceptors in neontatal rat cardiac myocytes[J].Circ Res,1996,79:887-897.
30.Senbonmatsu T,Saito T,Landon E. A novel angiotensinⅡtype 2 receptor signaling pathway possible role in cardiac hypertrophy[J].EMBO J,2003,22(24):6471-6482.
31.Oliviro P,Chassange C,Kolar F,et al.Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life[J].J Mol Cell Cardiol,2000,32:1631-1645.
32.Kuizinga MC,Smits JE,Arends JW. AT1 receptor blockade reduces cardiac interstitial cell DNA synthesis and cardiac funktion after rat myocardial infarction[J].J Mol Cell Cardiol,1998,30:425-434.
33.Lako-Futo Z,Szokodi J,Sarman B,et al.Evidance for a funktional role of angiotensinⅡtype 2 receptor in the cardiac hypertrophic process in vivo in the rat heart[J].Circulation,2003,108:2414-2422.
34.Widdop RE,Jones ES,Hannan RE. Angiotensin AT2 receptors cardiovascular hope or hype?[J].Br J Phamacol,2003,140(5):809-824.
35.Mc Call T, Vallance P. Nitric oxide takes centerstage with newly defined roles. TIPS, 1992, 13: 1-5.
36.Werner-Felmayer G, Werner ER, Fuchs D, et al.On multiple forms of NO synthase and their occulrence in human cells. Res Immunol 1991, 142: 555-561.
37.詹昌德,王庭槐,潘敬运.内皮型一氧化氮合酶基因在大鼠心肌细胞和非心肌细胞中的表达.基础医学与临床, 1999,19: 507-511.
38. Loscalon J, Welch G. Nitric oxide and its role in the cardiovascular system.Prog in Cardiovas Dis,1995, 38:87-104.
39.Hartman JC. The role of bradykinin and nitric oxide in thecardioprotective action of ACE inhibitors. Ann Thorac Surg,1995, 60: 789-792.
40.刘培庆,鲁伟,潘敬运.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制.生理学报,2002,54(3):213-218.
41.吴杨,胡亚娥,张元媛.一氧化氮合酶mRNA在压力超负荷心肌肥厚中的作用.临床心血管病杂志,2005,21(9):54-57.
42.Dominiczak A F,Borhr D F.Nitric oxide and its putative role in hypertension[J].Hypertension ,1995,25:1202.
43.阮长武,戴闺柱,冯宗枕,等.一氧化氮对内皮素促心肌细胞肥大及肌球蛋白基因表达的影响.临床心血管病杂志,2000,16(1):35-37.
44.齐永芬,石彦荣,卜定方,等.左旋硝基精氨酸诱导的高血压大鼠心肌和血管的肾上腺髓质素与受体活性修饰蛋白2表达的变化.生理学报,2002,54(4):337-341.
45.Matsuoka H,Nakata M,Kohno K.Chronic L - arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats[J]. Hypertension, 1996,27:14.
46.郭益民,朱小南,潘敬运.一氧化氮在肾性高血压大鼠心肌肥厚中的作用.中山医科大学学报,1999,20(2):107-110.
47.王庭槐,吴滨,潘敬运.左旋精氨酸抑制血管紧张素Ⅱ诱导培养心肌细胞的肥大反应.生理学通报,1996,13:9.
48.尹时华,肖立新,陈业文,等.L-精氨酸对肾性高血压心肌肥厚大鼠左心室肌原癌基因c-fos蛋白表达及血浆NO含量的影响.高血压杂志,2001,8(1):85-88.
49.Massin PB,Balligand JL.Modulation of cardiac contraction relaxatio and rate by the endothelial nitric oxide synthase (eNOS):lessons from genetically modified mice.J Physiol,2003,546:63-75.
50.Ozaki M,Kawashima S,Yamashita T,et al.Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronicisoproterenol infusion.Circ J,2002,66:851-856.
51.钟南田,符史干,符皎荣,等.一氧化氮在压力超负荷心肌肥大作用中的定量分析.解剖学杂志,2005,28(5):517-519.
52.鲁伟,刘培庆,王庭槐,等.MAPK信号途径在一氧化氮抑制大鼠心肌肥大中的作用.生理学报,2001,53(1):32-36.
53.刘培庆,鲁伟,潘敬运,等.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制.生理学报,2002,54(3):213-218.
54.符史干,谢协驹,吉丽敏,等.一氧化氮在血管紧张素Ⅱ激活蛋白激酶C中的作用.生理学报,2003,55(1):53-57.
55.Fiedler B,Lohmann SM,Smolenski A,et al. Inhibition of calcineurin- NFAT hypertrophy signaling by cGMP dependent protein kinase type I in cardiac myocytes[J]. Proc Natl Acad Sci USA,2002,99(17):11363-11368.
56.Barouch LA,Harrison RW,Skaf MW,et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms[J]. Nature,2002,416(21):337-340.
57.Bledsoe G,Chao L,Chao J. Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats[J].Am J Physiol Heart Circ Physiol, 2003, 285(4): H1479-H1488.
58.Arnal J F,Amrani A I,Chatellier G,et al.Cardiac weight in hypertension induced by nitric oxide synathase blockade.Hypertension,1993,22:380
59.Harding P,Carretero O A,Pointe M C.Effects of interleukin-1βand nitric oxide on cardiac myocytes[J].Hypertension,1995,25:421.
60.Macarthy PA,Shah AM. Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy[J]. Circulation,2000,101(15):1854-8160.
61.Clerk A,Sugden PH.Small guanine nucleotide-binding proteins andmyocardial hypertrophy[J].Cir Res,2000,86(10):1019-1023.
62.王春玲.小G蛋白与心肌肥厚的研究进展.《国外医学》·生理、病理科学与临床分册, 2003,23(5):459-462.
63.姜志胜.心肌肥大过程中的信号转导.中国动脉硬化杂志, 2005 ,13(2):125-128.
64. Laufs V,Kilter H,Konkol C,et al.Impact of HMG CoA reductase inhibition on small GTPases in the heart[J].J Cardiovas Res,2002,53(4):911-920.
65. Lammerding J,Kamm RD,Lee RT. Mechanotransduction in cardiac myocytes. Ann N Y Acad Sci,2004,1015:53-70.
66.Hoshijima M,Sah V P,Wang Y,et al.The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular cardiomyocytes,involvement of Rho kinase[J].J Biol Chem, 1998,273:7725-7730.
67. Sussman M A,Welch S,Walker A,et al.Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active Rac1[J].J Clin Invest,2000,105(7):875-886.
68.Indolfi C,Lorenzo ED,Perrino C,et al.Hydroxymethylglutaryl coenzyme a reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21 activaction[J]. Circulation, 2002, 106(16): 2118-2124.
69. Satoh S,Ueda Y,Koyanagi M,et al.Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure[J].J Mol Cell Cardiol,2003,35(1):59-70.
70. Kobayashi N,Horinaka S,Mita S,et al.Critica role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts[J].Cardiovasc Res,2002,55(4):757-767.
2.黄熙,藏益民.丹参酮ⅡA磺酸钠的心血管药理.国外医学中医中药分册,1995;17(1):9-12.
3.梁勇,羊裔明,袁淑兰.丹参酮药理作用及临床应用研究进展.中草药,2000;31(4):304-306.
4.钟先阳,罗仁,魏连波,等.丹参酮ⅡA对大鼠出现性休克-再灌注肾损伤的防治作用.中国中西医结合肾病杂志,2002;3(1):13-15.
5.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
6.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
7.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
8.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
1.Baker KM, Chernin MI, Wisson SK, et al. Renin-angiotensin system involvement in pressure overload cardiac hypertrophy in rats. Am J Physiol,1990;259:324-329.
2.彭亚飞,孙明,周宏研,等.亚降压剂量依那普利预防大鼠压力负荷性心肌肥厚的作用.中国现代医学杂志, 1998;8(9):7-10.
3.Takemoto M, Egashila K, Usui M, et al. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats.J Clin Invest,1997,99(2):278-287.
4. Kato H, Hou J, Chobanian AV, et al. Effects of angiotensinⅡinfusion and inhibition of nitric oxide synthase on the rat aorta[J].Hypertens, 1996;28:153-157.
5.胡文养,陈达光,苏津自,等.卡托普利治疗自发性高血压大鼠对循环和局部肾素-血管紧张素系统的长期影响[J].高血压杂志,1998;6(2):83-88.
6.张萍,何国祥,迟路湘,等. Irbesartan和培哚普利对压力超负荷大鼠循环与心脏组织RAS的影响.重庆医学,2000;29(4): 306-308.
7.Yamazaki T, Komuro I, Yazaki Y. Molecular mechanism of cardiac cellular hypertrophy by mechanical stress.J Mole Cell Cardiol,1995;27:133-140.
8. Crozatier B. Stretch-induced modification of myocardial performance:from ventricular function to cellular and molecular mechanisms. Cardiovasc Res, 1996, 32:25-37.
9. Crozatier B. Stretch-induced modification of myocardial performance:from ventricular function to cellular and molecular mechanisms. Cardiovasc Res, 1996, 32:25-37.
10.姜志胜.心肌肥大过程中的信号转导.中国动脉硬化杂志,2005,13(2):125-128.
11.Takeishi Y,Ping P,Bolli R,et al. Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy. Circ Res,2000,86(12):1218-223.
12. Mochly-Rosen D,Wu G,Hahn H,et al. Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKC epsilon translocation. Circ Res,2000,86(11):1173-1179.
13.桂波,曹红,曾因明.丝裂原活化蛋白激酶与高血压所致的心肌肥厚.《国外医学》麻醉学与复苏分册,2004,25(6): 359-361.
14.汪明慧,梁文同. MAP激酶及其在心肌肥厚中作用的研究.医学综述,2003,9(3):146-148.
15.Schmieder RE,Martus P,Klingbeil A.Reversal of left ventricular hypertrophy in essential hypertension: meta-analysis of randomized double-blind studies. JAMA,1996;275:1505-1513.
16.Dahlof B.Left ventricular hypertrophy and angiotensionⅡantagonist.Am J Hypertens,2001;14:174-182.
17.Palmieri V,Devereux RB. Angiotension converting enzyme inhibition and dihydropyridine calcium channel blockade in the treatment of left ventricular hypertrophy in arterial hypertension. Minerva Cardioangiol,2002,50:169-174.
1.朱红,王汐,刘明宇.左心室肥厚及其药物治疗新进展.中国循环杂志,2003,18(2):151-153.
2. Carsten Zobel,kassiri Z,The-Tin T,et al.Prevention of hypertrophy by overexpression of Kv4.2 in cultured neonatal cardomyocytes.Circulation 2002;106:2385-2391.
3.施新猷.现代医学试验动物学[M].北京人民军医出版社,2000:464-465.
4. Zhang TT,Koichi Takinoto,Alexandre FR,et al.Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensionⅡand phenylephrine.Cire Res,2001,88:476-482.
5. Lin Qing,Li Peng.Effects of chronic stress on blood pressure and heart rate in rats.Chinese Journal of Physiological Sciences,1990,6(2):101-107.
6. Capasso JM,Strobeck JE,Malbotra A.Contractile behavior of rat myocardium after reversal of hypertensive hypertension.Am J Physiol , 1982 ;242:H882-889.
7.彭亚飞,孙明,周宏研,等.亚降压剂量依那普利预防大鼠压力负荷性心肌肥厚的作用.中国现代医学杂志, 1998,8(9):7-10.
8. Takemoto M, Egashila K, Usui M, et al. Important role of tissue angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest, 1997, 99(2):278-287.
9.张萍,何国祥,迟路湘,等. Irbesartan和培哚普利对压力超负荷大鼠循环与心脏组织RAS的影响.重庆医学, 2000,29(4): 306-308.
10. Kato H, Hou J, Chobanian AV, et al. Effects of angiotensinⅡinfusion and inhibition of nitric oxide synthase on the rat aorta[J]. Hypertens, 1996, 28:153-157.
11.胡文养,陈达光,苏津自,等.卡托普利治疗自发性高血压大鼠对循环和局部肾素-血管紧张素系统的长期影响[J].高血压杂志, 1998, 6(2): 83-88.
12. Baker KM, Chernin MI, Wisson SK, et al. Renin-angiotensin system involvement in pressure overload cardiac hypertrophy in rats. Am J Physiol, 1990, 259:324-329
13. Yamazaki T, Komuro I, Yazaki Y. Molecular mechanism of cardiac cellular hypertrophy by mechanical stress. J Mo Cell Cardiol, 1995, 27:133-140.
14.Crozatier B. Stretch-induced modification of myocardial performance:from ventricular function to cellular and molecular mechanisms. Cardiovasc Res, 1996, 32:25-37.
15.姜志胜.心肌肥大过程中的信号转导.中国动脉硬化杂志,2005,13(2):125-128.
16.Takeishi Y,Ping P,Bolli R,et al. Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy. Circ Res,2000,86(12):1218-223.
17. Mochly-Rosen D,Wu G,Hahn H,et al. Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKC epsilon translocation. Circ Res,2000,86(11):1173-179.
18.桂波,曹红,曾因明.丝裂原活化蛋白激酶与高血压所致的心肌肥厚.《国外医学》麻醉学与复苏分册,2004,25(6): 359-361.
19.汪明慧,梁文同.MAP激酶及其在心肌肥厚中作用的研究.医学综述,2003,9(3):146-148.
20.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
21.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
22.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
23.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
1. Franz HM,Reinhard K.Left ventricular hypertrophy: a pressure-independent cardiovascular risk factor.J Cardiovasc Pharmacol,1993;22(suppl 1):S7-S13.
2.LoreⅡBH.Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and disease[J].Am J Cardiol.1999,83(12A):48H.
3.DellItalia LJ,Meng QC,Balcells E,et al. Compartmentalization of angiotensin II generation in the dog heart.Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest,1997,100:253-258.
4.Paradis P,Daliyoucef N ,Paradis FW,et al. Overexpression of angiotensin Ⅱtype1 receptors in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl, 2000,97:931-936.
5.Metcalfe BL,Huentelman MJ,Parilak LD,et al.Prevention of cardiac hypertrophy by angiotensin II type 2 receptor gene transfer.Hypertension,2004,43:1-6.
6.Senbonmatsu T,Ichihara S,Price EJ,et al.Evidence for angiotensinⅡtype 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload[J].J Clin Invest,2000,106(3):R25-29.
7.曾武涛,马虹,冷秀玉,等.血管紧张素-(1-7)对血管紧张素诱导心肌细胞原癌基因c-fos表达的影响[J].中国心血管杂志,2003,8(1):9-11
8.Harrison-Bernard LM,El-Dahr SS,O.Leary DF,etal.Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension[J].Hypertension,1999,33(1):340-346.
9.何建桂,黄艺仪,马虹,等.血管紧张素-(1-7)对压力负荷增高大鼠血管紧张素及受体的影响.中国医师杂志,2005,7(8):1035-1037.
10.Cheng HF,Burns KD,Harris RC.Reduced proximal tubule angiotensin receptor expression in streptozotocin - induced diabetes mellitus. KidneyInt,1994,46(6):1603-1610.
11.Hou M,Pantev E,Moller S,etal. Angiotensin type 1 receptor atimulate protein synthesis in human cardiac fibrobiasts via a Ca2+ - sensitive: PKC -dependent tyrosine kinase pathway. Acta Physiol Scand, 2000, 168(2): 301-309.
12.Yamada H,Horiuchi M.Regulation if vascular development and differentiation by angiotensin type 2 receptor. Hypertension, 1997, 30: 470-475.
13.Takekoshhi K,Ishii K,Shibuya S,et al. Angiotensin type 2 receptor counterregulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells[J]. Hypertension, 2002, 39(1):142-148.
14.Baker KM, Booz GW, Dostal DE. Cardiac actions of AngiotensinⅡ: role of an intracardiac rennin-angiotensin system [J]. Annu Rev Physiol, 1992,54: 227-241.
15.刘键.心肌肥厚大鼠心肌细胞核三磷酸肌醇受体的特性[J].生理学报,2001;53(4):281-285.
16.Iino M.Dynamic regulation of intracellular calcium signals through calcium release channels[J].Mol Cell Biochem,1999,190:185-190.
17.Iino M.Calcium-dependent immediate feedback control of inositol 1, 4, 5-trisphosphate-induced Ca2+ release[J].Nature,1992,360:76-78.
18.Oriji GK. AngiotensinⅡstimulates hypertrophic growth of cultured neonatal rat ventricular myocytes: roles of PKC and PGF2 alpha [J]. Prostaglandins Leukot Essent Fatty Acids,2000,62(4): 233-237.
19.赵凌杰,商伟,蔡辉.血管紧张素Ⅱ在心肌纤维化形成中的作用[J].中国微循环, 2004,8(1): 5-6.
20.方淑贤,苑力哪,郑恒,等.芦沙坦对心脏成纤维细胞胶原Ⅰ、Ⅲ型mRNA表达水平的影响[J].同济医科大学学报,1999,28(4):326-328.
21.Grohe C,Kahlert S,Lobbert K,et al. Angiotensin coverting enzyme inhibition modulates cardiac growth [J].J Hypertens,1998,16:377-384.
22.Mazzolai L,Nussberger J,Auber JF,et al.Blood pressure-independent cardiac hypertrophy indued by locally activated rennin-angiotensin system[J]. Hypertension,1998,31:1324-1330.
23.Sano H,Okamoto H,Kitabatake A,et al.Increased mRNA expression of cartensive rats[J].Mol Cell Biochem,1998,178:51-58.
24.Siggi PKS,Kivlighn SD,Broten TP.Pharmaclogy of losartan,an angiotensin Ⅱreceptor antagonist , in animal of hypertension[J].J Pharmacol Exp,1995,13(Suppl 1):15.
25.Xu J , Carretero OA , Liu YH , et al.Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice.Hypertension,2002,40:244-250.
26.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
27.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
28.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
29.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
30.谢辉,郑智,龚丽娅.丹参酮IIA对自发性高血压大鼠左室肥厚的影响及机制.实用医学杂志,2004,20(3):252-254.
31.徐长庆,娄延平,杨宝峰,等.丹参酮Ⅱ-A抑制豚鼠单个心肌细胞L型钙电流和缩短动作电位时程效应的相关性分析.中国药理学通报1998,14(5):428-431.
32.Xu CQ,Fan JS,Hao XM,et al.Blocking effect of sodium tanshinoneⅡA sulfonate on L-type Ca2+ current of single ventricular myocyte from guineapig[J].Chin J Pharmacol Toxical,1999,10:81-84.
33.徐长庆,娄延平,杨宝峰,等.丹参酮Ⅱ-A抑制豚鼠单个心肌细胞L型钙电流和缩短动作电位时程效应的相关性分析.中国药理学通报,1998,14(5):428-431.
34.王照华,梁黔生,郑智.丹参酮对肥厚心肌L2型钙电流的影响.高血压杂志2006,14(6):450-454.
35.冯俊,李树生.丹参酮ⅡA抑制血管紧张素诱导大鼠心肌肥大的机制.高血压杂志,2005,13(8):488-491.
36.杨乐,冯俊,严丽,等.丹参酮Ⅱ-A磺酸钠影响血管紧张素Ⅱ诱导心肌肥大及p-JNK和丝裂原活化蛋白激酶磷酸酶1的表达.中国临床康复,2006,10(23):84-86.
1 .Frey N,Olson EN. Cardiac hypertrophy: the good,the bad,and the ugly. Annu Rev Physiol,2003,65:45-79.
2.van Empel VP,De Windt LJ. Myocyte hypertrophy and apoptosis: a balancing act. Cardiovasc Res,2004,63(3):487-499.
3.张云飞,吴先均,文秀华,等.心肌肥厚机制研究进展.心血管病学进展,2005,26(2):197-200.
4.Kanai AJ,Mesaros S,Finkel MS,et al.Beta-adrenergic regulation of constitutive nitri coxide synthase in cardiac myocytes. Am J Physiol,1997,273:C1371-C1377.
5.Sun Y, Carretero OA, Xu J, Rhaleb NE, et al. Lack of inducible NO synthase reduces oxidative stress and enhances cardiac response to isoproterenol in mice with deoxycorticosterone acetate-salt hypertension[J]. Hypertension, 2005, 46(6): 1355-361.
6.Koyanagi M,Egashira K,Kitamoto S,et al. Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis[J]. Circulation,2000,102(18):2243-2248.
7.刘培庆,鲁伟,潘敬运.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制[J].生理学报,2002,54(3):213-218.
8. Kacimi R,Long CS,Karliner JS. Chronic hypoxia modulates the interleukin-1 stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation,1997,96:1937-1943.
9.郭益民,朱小南,潘敬运.一氧化氮在肾性高血压大鼠心肌肥厚中的作用[J].中山医科大学学报,1999,20(2):107-110.
10.刘培庆,鲁伟,潘敬运.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制。生理学报,2002,54(3):213-218.
11.郑惠珍,安国顺,聂思槐,等.一氧化氮抑制内皮素促血管平滑肌细胞增殖作用的信号转导途径[J].生理学报,1998,50(4):379-384.
12.孙联平,郑智.丹参对自发性高血压大鼠左心室肥厚及心肌肿瘤坏死因子表达的影响.高血压杂志,2004;12(3):238-241.
13.谢辉,郑智,龚丽娅.丹参酮Ⅱ-A对自发性高血压大鼠左心室肥厚的影响及机制.实用医学杂志,2004;20(3):252-254.
14.龚丽娅,郑智.丹参酮Ⅱ-A对心肌肥厚的作用及其机制研究.中国急救医学,2004;24:116-118.
15.孙联平,郑智.丹参酮Ⅱ-A对肥厚心肌细胞核因子NF-кB的影响.实用老年医学,2004;18(1):25-27.
16.李永胜,王照华,梁黔生,等.丹参酮ⅡA对血管紧张素Ⅱ作用下的主动脉内皮细胞一氧化氮的产生及细胞内游离钙离子的影响.中华高血压杂志,2006,14(11):882-885.
17.吴杨,胡亚娥,张元媛.一氧化氮合酶mRNA在压力超负荷心肌肥厚中的作用.临床心血管病杂志,2005,21(9):54-57.
18.Mc Call T, Vallance P. Nitric oxide takes centerstage with newly defined roles. TIPS, 1992, 13: 1-5.
19.Werner-Felmayer G, Werner ER, Fuchs D, et al. On multiple forms of NO synthase and their occulrence in human cells. Res Immunol 1991, 142: 555-561.
20.Kaye DM,Wiviott SD,Balligand JL,et al.Frequency-dependent activation of a constitutive nitric oxide synthase and regulation of contractile function in adult rat ventricular myocytes.Circ Res,1996,78:217-224.
21.De Gasparo M.AngiotensinⅡand nitric oxide interaction.Heart Fail Rev,2002,7(4):347-358.
22.Raij L.Hypertension and cardiovascular risk factors. Hypertension,2001,37(2):767-773.
23.符史干,谢协驹,吉丽敏等.一氧化氮和血管紧张素Ⅱ在压力超负荷心肌肥大中的作用.海南医学院报,2002,8:1-6.
24.符史干,谢协驹,吉丽敏等.Losartan压抑压力超负荷高血压和心肌肥大的实验.海南大学学报自然科学版,2001,19:373-376.
25.钟南田,符史干,符皎荣,等.一氧化氮在压力超负荷心肌肥大作用中的定量分析.解剖学杂志,2005,28(5):517-519.
26.刘培庆,鲁伟,潘敬运,等.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制.生理学报,2002,54(3):213-218.
27.Massin PB,Balligand JL.Modulation of cardiac contraction relaxatio and rate by the endothelial nitric oxide synthase (eNOS):lessons from genetically modified mice.J Physiol,2003,546:63-75.
28.Ozaki M,Kawashima S,Yamashita T,et al.Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion.Circ J,2002,66:851-856.
29.Kobayashi N,Hara K,Watanabe S,et al.Effect of imidapril on myocardial remodeling in L-NAME-induced hypertensive rats is associated with gene expression of NOS and ACE mRNA.Am J Hypertens,2000,13:199-207.
30.Matsuoka H,Nakata M,Kohno K.Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats[J].Hypertension,1996,27:14.
31.郭国庆,沈伟哉.外源性一氧化氮抑制剂和促进剂对高血压大鼠心室壁厚度和心肌血管紧张素的影响.暨南大学学报(医学版), 2004,25(6):697-701.
32.郭益民,朱小南,潘敬运.一氧化氮在肾性高血压大鼠心肌肥厚中的作用.中山医科大学学报,1999,20(2):107-110.
33.王庭槐,吴滨,潘敬运.左旋精氨酸抑制血管紧张素Ⅱ诱导培养心肌细胞的肥大反应.生理学通报,1996,13:9.
34.尹时华,肖立新,陈业文,等.L-精氨酸对肾性高血压心肌肥厚大鼠左心室肌原癌基因c-fos蛋白表达及血浆NO含量的影响.高血压杂志,2001,8(1):85-88.
35.Martinez Y,Martinez S,Meaney A,et al. Angiotensin type 1 receptor blockade restores nitric oxide-dependent renal vascular responses in renovascular hypertension[J].J Cardiovasc Pharmacol,2002,40(3):381-387.
36.Cruzado M,Castro C,Risler N,et al.Changes of inducible nitric oxide synthase in aortic cells during the development of hypertension: effect of angiotensin[J].Biocell,2002,26(1):61-67.
37.何敏,徐济良,郑民,等.缬沙坦对2型糖尿病大鼠心肌病变的防治作用[J].中国药理学通报,2004,20(12):1386-1389.
38.Xu J , Carretoro OA , Liu YH , et al.Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice. Hypertension,2002,40:244-250.
39.Brede M,Roell W,Ritter O,et al.Cardiac hypertrophy is associated with decreased eNOS expression in angiotensin AT2 receptor-deficient mice.Hypertension,2003,42:1177-1182.
40.Isenovic E R,Meng Y,Divald A,et al.Role of phosphatidylinositol 3-kinase/Akt pathway in angiotensinⅡand insulin-like growth factor-1 modulation of nitric oxide synthase in vascular smooth muscle cells[J].Endocrine,2002,19(3):287-292.
41.符史干,谢协驹,吉丽敏,等.一氧化氮在血管紧张素激活蛋白激酶C中的作用.生理学报,2003,55(1):53-57.
42.陈连剑,李婷,李成.丹参酮ⅡA抗大鼠肝星状细胞氧应激脂质过氧化作用的研究.中药材,2003,26(7):504-507.
43.叶龙彬,奚涛,陈峰,等.丹参酮ⅡA对大鼠局灶性脑缺血再灌注损伤的保护作用.中国药科大学学报,2004,35(3):267-270.
44.陶军,王舟琪,刘桥义,等.丹参酮防治心肌再灌注损伤的实验研究[J].中华麻醉学杂志,1996,16(5):202-204.
45.谢辉,郑智.丹参酮ⅡA对血管紧张素Ⅱ诱导的心肌细胞肥大、凋亡的影响.高血压杂志2004,12(4):359-361.
46.徐长庆,娄延平,杨宝峰,等.丹参酮Ⅱ-A抑制豚鼠单个心肌细胞L型钙电流和缩短动作电位时程效应的相关性分析.中国药理学通报1998,14(5):428-431.
47.谢辉,郑智,龚丽娅.丹参酮IIA对自发性高血压大鼠左室肥厚的影响及机制.实用医学杂志,2004,20(3):252-254.
48.冯俊,李树生.丹参酮A抑制血管紧张素诱导大鼠心肌肥大的机制.2005,13(8):488-491.
49.杨乐,冯俊,严丽,等.丹参酮Ⅱ-A磺酸钠影响血管紧张素Ⅱ诱导心肌肥大及p-JNK和丝裂原活化蛋白激酶磷酸酶I的表达.中国临床康复,2006,10(23):84-86.
1.Hefti MA,Harder BA,Eppenberger HM,et al.Signaling pathways in cardiac myocyte hypertrophy.J Mol Cell Cardiol,1997,29:2873-2892.
2.Sadoshima J,Izumo S.The cellular and molecul response of cardiac myocytes to mechanical stress.Annu Rev Physiol,1997,59:551-571.
3.Cooper G.Basic determinants of myocardial hypertrophy: A review of molecular mechanisms.Annu Rev Med,1997,48:13-23.
4.Ishigai Y,Mori T,Ikeda T,et al.Role of bradykinin -NO pathway in prevention of cardiac hypertrophy by ACE inhibit or in rat cardiomyocytes.Am J Physiol,1997,273:H2659-H2663.
5.Calderone A,Thaik CM,Takahashi N,et al. Nitric oxide, atrial natriuretic peptide,and cyclic GMP inhibit the growth - promoting effects of norepinephrine in cardiac myocytes and fibroblasts.J Clin Invest,1998,101:812-818.
6.LoreⅡBH. Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and disease[J].Am J Cardiol.1999,83(12A):48H.
7.Senbonmatsu T,Ichihara S,Price EJ,et al.Evidence for angiotensinⅡtype
2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload[J].J Clin Invest,2000,106(3):R25-29.
8.Bjom Dahlof. Left ventricular hypertrophy and angiotensinⅡantagonist[J].Am J Heart,2001,14:174.
9.Tsutsumi Y,Matsubara H,Ohkubo N,et al.AngiotensinⅡtype 2 receptor is upregulated in human heart with interstitial fibrosis and cardiac fibroblasis are the major cell type for its expression[J].Circ Res,1998,83(10):1035-1046.
10.Matsubara H. Pathophysiological role of angiotensinⅡtype 2 receptor in cardiovascular and renal diseases[J].Circ Res,1998,83(12):1182.
11.Sadoshima JI, Lezumo S. Singnal transduction pathways of angiotensinⅡinduced c-fos gene expression in cardiac myocytes in vitro[J].Circ Res,1993,73:424.
12.Tsutomu Yamszaki. Role of the rennin-angiotensin systen in cardiac hypertrophy[J]. Am J Cardiol,1999,83(12A):53H.
13.Higaki J,Aoki M,Morishita R,et al. In vivo evidence of the importance of cardiac angiotensin-converting enzyme in the pathogenesis of cardiac hypertrophy[J]. Arterioscler Thromb Vase Biol,2000,20(2):428.
14.Sadoshima J,Xu Y,Slayter HS,et al. Autocrine release of angiotensinⅡmediates stretch-induced hypertrophy of cardiac myocytes in vitro[J].Cell,1993,75(5):977.
15.Lai J,Jin H,Yang R,et al. Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vitro[J].Am J Physiol,1996,271(6,pt2):H2197.
16.Lijnen P, Petrov V.Rennin-angiotensin systen, hypertrophy and gene expression in cardiac myocyte[J].JMolCell Cardiol,1999,31(5): 949.
17.Yamazaki T,Komuro J,Kudoh S,et al. AngiotensionⅡpartly mediates mechanicalstress-induced cardiac hypertrophy[J].Circ Res,1995,77(2):258.
18.Kojima M,Shiojima J,Yamazaki T,et al.AngotensinⅡreceptor antagonist TCVI16 induces regression of hypertensiv left ventricular hypertrophy in vivo and inhibits intracellular signal pathway of stretchmediated cardiomyocyte hypertrophy in vitro[J].Circulation,1994,89(5):2204.
19.Kudoh S,Komuro J,Hiroi Y,et al.Mechanical stretch induces hypertrophic resposes in cardiac myocytes of angiotensinⅡtype 1a receptor knockout mice[J].J Biol Chem,1998,273(37):34-37.
20.Munzenmarier DH,Greene AS.Opposing actions of angiotensinⅡonmicrovascular growth and arterial blood pressure[J].Hypertension 1996,27:760-765.
21.Akishita M,Yamada H,Dzau V,et al.Increased vasoconstrictor response of the mouse lacking angiotensinⅡtype 2 receptor[J].Biochem Biophys Res Commun,1999,261:345-349.
22.Tsutsumi Y,Matsubara H,Ohkubo N,et al.AngiotensinⅡtype 2 receptor overexpression activates the vascular kinin systen and causes vasodilation[J].J Clin Invest,1999,104:925-935.
23.Widdop RE, Matrougui K, Levy B, et al. AT2 receptor mediated relaxation is preserved after long-term AT2 receptor blockade[J]. Hypertension, 2002, 40:516-520.
24.Melcalfe BL,Huentelman MJ,Parilak LD,et al.Prevention of cardiac hypertrophy by angiotensinⅡtype-2 receptor gene transfer[J].Hypertension,2004,43:1233-1238.
25.Van Kesteren CA,Van Heugten HA,Lamers JM,et al.AngiotensinⅡ-mediated growth and antigrowth effects in cultured myocytes and fibroblasts[J].J Mol Cell Cardiol,1997,29:2147-2157.
26.Bartunek J,Weinberg E,Tajima M,et al.AngiotensinⅡtype2receptor blockade ampliftes the early signals of cardiac growth response to angiotensinⅡin hypertrophied hearts[J].Circulation,1999,99: 22-25.
27.Masaki H,Kurihara J,Yamaki A,et al.Cardiac-specific overexpression of angiotensinⅡ, AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects[J]. Hypertension,1998,101:527-535.
28.Booz GW,Baker KM.Role of type-1 and type-2 angiotensin receptor in angiotensinⅡinduced cardiomyocyte hypertrophy[J].Hypertension ,1996,28:635-640.
29.Kijimad K,Matsubara H,Murasawa S,et al.Mechanical stretch induces enhanced expression of angiotensinⅡreceptors in neontatal rat cardiac myocytes[J].Circ Res,1996,79:887-897.
30.Senbonmatsu T,Saito T,Landon E. A novel angiotensinⅡtype 2 receptor signaling pathway possible role in cardiac hypertrophy[J].EMBO J,2003,22(24):6471-6482.
31.Oliviro P,Chassange C,Kolar F,et al.Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life[J].J Mol Cell Cardiol,2000,32:1631-1645.
32.Kuizinga MC,Smits JE,Arends JW. AT1 receptor blockade reduces cardiac interstitial cell DNA synthesis and cardiac funktion after rat myocardial infarction[J].J Mol Cell Cardiol,1998,30:425-434.
33.Lako-Futo Z,Szokodi J,Sarman B,et al.Evidance for a funktional role of angiotensinⅡtype 2 receptor in the cardiac hypertrophic process in vivo in the rat heart[J].Circulation,2003,108:2414-2422.
34.Widdop RE,Jones ES,Hannan RE. Angiotensin AT2 receptors cardiovascular hope or hype?[J].Br J Phamacol,2003,140(5):809-824.
35.Mc Call T, Vallance P. Nitric oxide takes centerstage with newly defined roles. TIPS, 1992, 13: 1-5.
36.Werner-Felmayer G, Werner ER, Fuchs D, et al.On multiple forms of NO synthase and their occulrence in human cells. Res Immunol 1991, 142: 555-561.
37.詹昌德,王庭槐,潘敬运.内皮型一氧化氮合酶基因在大鼠心肌细胞和非心肌细胞中的表达.基础医学与临床, 1999,19: 507-511.
38. Loscalon J, Welch G. Nitric oxide and its role in the cardiovascular system.Prog in Cardiovas Dis,1995, 38:87-104.
39.Hartman JC. The role of bradykinin and nitric oxide in thecardioprotective action of ACE inhibitors. Ann Thorac Surg,1995, 60: 789-792.
40.刘培庆,鲁伟,潘敬运.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制.生理学报,2002,54(3):213-218.
41.吴杨,胡亚娥,张元媛.一氧化氮合酶mRNA在压力超负荷心肌肥厚中的作用.临床心血管病杂志,2005,21(9):54-57.
42.Dominiczak A F,Borhr D F.Nitric oxide and its putative role in hypertension[J].Hypertension ,1995,25:1202.
43.阮长武,戴闺柱,冯宗枕,等.一氧化氮对内皮素促心肌细胞肥大及肌球蛋白基因表达的影响.临床心血管病杂志,2000,16(1):35-37.
44.齐永芬,石彦荣,卜定方,等.左旋硝基精氨酸诱导的高血压大鼠心肌和血管的肾上腺髓质素与受体活性修饰蛋白2表达的变化.生理学报,2002,54(4):337-341.
45.Matsuoka H,Nakata M,Kohno K.Chronic L - arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats[J]. Hypertension, 1996,27:14.
46.郭益民,朱小南,潘敬运.一氧化氮在肾性高血压大鼠心肌肥厚中的作用.中山医科大学学报,1999,20(2):107-110.
47.王庭槐,吴滨,潘敬运.左旋精氨酸抑制血管紧张素Ⅱ诱导培养心肌细胞的肥大反应.生理学通报,1996,13:9.
48.尹时华,肖立新,陈业文,等.L-精氨酸对肾性高血压心肌肥厚大鼠左心室肌原癌基因c-fos蛋白表达及血浆NO含量的影响.高血压杂志,2001,8(1):85-88.
49.Massin PB,Balligand JL.Modulation of cardiac contraction relaxatio and rate by the endothelial nitric oxide synthase (eNOS):lessons from genetically modified mice.J Physiol,2003,546:63-75.
50.Ozaki M,Kawashima S,Yamashita T,et al.Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronicisoproterenol infusion.Circ J,2002,66:851-856.
51.钟南田,符史干,符皎荣,等.一氧化氮在压力超负荷心肌肥大作用中的定量分析.解剖学杂志,2005,28(5):517-519.
52.鲁伟,刘培庆,王庭槐,等.MAPK信号途径在一氧化氮抑制大鼠心肌肥大中的作用.生理学报,2001,53(1):32-36.
53.刘培庆,鲁伟,潘敬运,等.一氧化氮抑制AngⅡ介导的心肌肥大反应的信号机制.生理学报,2002,54(3):213-218.
54.符史干,谢协驹,吉丽敏,等.一氧化氮在血管紧张素Ⅱ激活蛋白激酶C中的作用.生理学报,2003,55(1):53-57.
55.Fiedler B,Lohmann SM,Smolenski A,et al. Inhibition of calcineurin- NFAT hypertrophy signaling by cGMP dependent protein kinase type I in cardiac myocytes[J]. Proc Natl Acad Sci USA,2002,99(17):11363-11368.
56.Barouch LA,Harrison RW,Skaf MW,et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms[J]. Nature,2002,416(21):337-340.
57.Bledsoe G,Chao L,Chao J. Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats[J].Am J Physiol Heart Circ Physiol, 2003, 285(4): H1479-H1488.
58.Arnal J F,Amrani A I,Chatellier G,et al.Cardiac weight in hypertension induced by nitric oxide synathase blockade.Hypertension,1993,22:380
59.Harding P,Carretero O A,Pointe M C.Effects of interleukin-1βand nitric oxide on cardiac myocytes[J].Hypertension,1995,25:421.
60.Macarthy PA,Shah AM. Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy[J]. Circulation,2000,101(15):1854-8160.
61.Clerk A,Sugden PH.Small guanine nucleotide-binding proteins andmyocardial hypertrophy[J].Cir Res,2000,86(10):1019-1023.
62.王春玲.小G蛋白与心肌肥厚的研究进展.《国外医学》·生理、病理科学与临床分册, 2003,23(5):459-462.
63.姜志胜.心肌肥大过程中的信号转导.中国动脉硬化杂志, 2005 ,13(2):125-128.
64. Laufs V,Kilter H,Konkol C,et al.Impact of HMG CoA reductase inhibition on small GTPases in the heart[J].J Cardiovas Res,2002,53(4):911-920.
65. Lammerding J,Kamm RD,Lee RT. Mechanotransduction in cardiac myocytes. Ann N Y Acad Sci,2004,1015:53-70.
66.Hoshijima M,Sah V P,Wang Y,et al.The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular cardiomyocytes,involvement of Rho kinase[J].J Biol Chem, 1998,273:7725-7730.
67. Sussman M A,Welch S,Walker A,et al.Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active Rac1[J].J Clin Invest,2000,105(7):875-886.
68.Indolfi C,Lorenzo ED,Perrino C,et al.Hydroxymethylglutaryl coenzyme a reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21 activaction[J]. Circulation, 2002, 106(16): 2118-2124.
69. Satoh S,Ueda Y,Koyanagi M,et al.Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure[J].J Mol Cell Cardiol,2003,35(1):59-70.
70. Kobayashi N,Horinaka S,Mita S,et al.Critica role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts[J].Cardiovasc Res,2002,55(4):757-767.