美托洛尔和卡维地洛对肾血管性高血压的血压及心室重构的干预作用
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摘要
目的探讨卡维地洛和美托洛尔对肾血管性高血压的降压效应及心室重塑的干预作用。方法建立肾血管性高血压大鼠模型,随机分成单纯手术组、卡维地洛组、美托洛尔组、卡(卡维地洛)+L(一氧化氮合酶NOS抑制剂,L-NAME)组和假手术组。药物干预8周后采用HE及MASSON染色,观察病理学形态,并计算左心室质量指数(LVMI)、心肌胶原容积分数(CVF)及心肌血管周围胶原面积分数(PVCA);采用硝酸还原法测定血浆一氧化氮(NO)的水平,放免法测定血浆内皮素(ET)、降钙素基因相关肽(CGRP)的含量。结果改良缩窄大鼠左肾动脉方法可以形成稳定的肾血管性高血压模型,术后4周平均收缩压(SBP)高于160 mm Hg,3组药物干预大鼠组血压明显下降,但未降至假手术组水平(P<0.05);HE染色可见3组药物干预组得到改善,卡+L组仍有较多炎性细胞参与;MASSON染色可见3组药物干预组仍有部分蓝色胶原存在;卡维地洛组、美托洛尔组、卡+L组CVF降低,但未降至假手术组水平(P<0.01),卡+L组CVF高于卡维地洛组(P<0.01);卡维地洛组、美托洛尔组大鼠PVCA下降,并未降至假手术组水平(P<0.01),卡+L组PVCA较单纯手术组并未下降,并高于卡维地洛组(P<0.01);卡维地洛组较单纯手术组NO明显升高(P<0.01),与假手术组无明显差别(P>0.05),卡+L组NO水平低于卡维地洛组(P<0.01),美托洛尔组NO水平较单纯手术组有所上升(P<0.05),但仍低于卡维地洛组(P<0.01);卡维地洛组、美托洛尔组ET水平低于单纯手术组(P<0.01),卡+L组ET含量高于卡维地洛组(P<0.01),较单纯手术组没有差异(P>0.05);肾动脉缩窄4组大鼠血浆CGRP水平较假手术组均有上升,美托洛尔组低于卡维地洛组(P<0.05)。结论肾动脉缩窄能够形成左室重构模型,卡维地洛、美托洛尔均能改善左室重构,卡维地洛的作用可能在一定程度上与NO系统相关。
Objective To investigate the intervention effects of metoprolol and carvedilol in lowering blood pressure and ventricular remodeling in rat models with renovascular hypertension. Methods The SD rat models with renovascular hypertensive model were established by narrowing left renal artery,then the successful models were randomly divided into simple operation group,carvedilol group,metoprolol group,C + L(carvedilol + NOS depressor-L-NAME) group,and sham operation group. After 8-week phamacological intervention,the changes of pathologic morphous were observed by hematoxylin-eosin(HE) and MASSON staining,and the left ventricular mass index(LVMI),collagen volume fraction(CVF) and perivscular collagen area(PVCA) score were calculated and compared among the five groups. Moreover the NO levels were measured by nitrate reduction method and the levels plasma endothelin(ET),calcitonin generelated peptide(CGRP) were detected by radioimmunoassay. Results The improved renal artery coarctation of rats could induce stable renovascular hypertension animal models. At 4 weeks after operation,the average systolic blood pressure(SBP) was more than 160 mm Hg,and blood pressure levels in the three pharmacological intervention groups were obviously dcreased,however,which were not decreased to the levels in sham-operation group(P < 0. 05). HE staining showed there were myocardial cell hypertrophy,myofiber disorders,inflammatory cell infiltration in simple operation group,and ameliorated symptoms in three drup intervention groups. but there were still considerable inflammatory cells in C + L group. MASSON staining showed there were still partly blue collagen deposition in three intervention groups. The CVF in carvedilol group,metoprolol group and C + L group was significantly decreased(P < 0. 01),however,which was not decreased to the levels in sham-operation group. Moreover CVF in C + L group was higher than that in carvedilol group(P < 0. 01). PVCA in carvedilol group and metoprolol group was decreased,however,which was not decreased to the levels in sham-operation group(P < 0. 01),and PVCA in C + L group was not lower than that in sham-operation group,and PVCA in C + L group was higher than that in carvedilol group(P <0. 0 1). In addition the plasma levels of NO in carvedilol group were significantly higher than those in simle operation group(P < 0. 01),but there were no significant differences between carvedilol group and sham-operation group(P > 0. 05). The plasma levels of NO in C + L group were significantly lower than those in carvedilol group(P < 0. 01),which in metoprolol group were significantly higher than those in simple operation group(P < 0. 05),but lower than that in carvedilol group(P < 0. 01). Besides the plasma levels of ET in carvedilol group and metoprolol group were significantly lower than those in simple operation group(P < 0. 01),and the plasma levels of ET in C +L group were significantly highter than those in carvedilol group(P < 0. 01),however,there were no significant differences between carvedilol group and simple operation group(P > 0. 05). Finally the plasma levels of CGRP in 4 groups of renal artery operation were higher than those in sham-operation group,and plasma levels of CGRP in metoprolol group were significantly lower than those in carvedilol group(P < 0. 05). Conclusion The renal artery stegnosis operation can induce left ventricular remodeling models in rats,and both carvedilol and metoprolol can improve left ventricular remodeling,and the effects of carvedilol may be associated with NO system at some extent.
Objective To investigate the intervention effects of metoprolol and carvedilol in lowering blood pressure and ventricular remodeling in rat models with renovascular hypertension. Methods The SD rat models with renovascular hypertensive model were established by narrowing left renal artery,then the successful models were randomly divided into simple operation group,carvedilol group,metoprolol group,C + L(carvedilol + NOS depressor-L-NAME) group,and sham operation group. After 8-week phamacological intervention,the changes of pathologic morphous were observed by hematoxylin-eosin(HE) and MASSON staining,and the left ventricular mass index(LVMI),collagen volume fraction(CVF) and perivscular collagen area(PVCA) score were calculated and compared among the five groups. Moreover the NO levels were measured by nitrate reduction method and the levels plasma endothelin(ET),calcitonin generelated peptide(CGRP) were detected by radioimmunoassay. Results The improved renal artery coarctation of rats could induce stable renovascular hypertension animal models. At 4 weeks after operation,the average systolic blood pressure(SBP) was more than 160 mm Hg,and blood pressure levels in the three pharmacological intervention groups were obviously dcreased,however,which were not decreased to the levels in sham-operation group(P < 0. 05). HE staining showed there were myocardial cell hypertrophy,myofiber disorders,inflammatory cell infiltration in simple operation group,and ameliorated symptoms in three drup intervention groups. but there were still considerable inflammatory cells in C + L group. MASSON staining showed there were still partly blue collagen deposition in three intervention groups. The CVF in carvedilol group,metoprolol group and C + L group was significantly decreased(P < 0. 01),however,which was not decreased to the levels in sham-operation group. Moreover CVF in C + L group was higher than that in carvedilol group(P < 0. 01). PVCA in carvedilol group and metoprolol group was decreased,however,which was not decreased to the levels in sham-operation group(P < 0. 01),and PVCA in C + L group was not lower than that in sham-operation group,and PVCA in C + L group was higher than that in carvedilol group(P <0. 0 1). In addition the plasma levels of NO in carvedilol group were significantly higher than those in simle operation group(P < 0. 01),but there were no significant differences between carvedilol group and sham-operation group(P > 0. 05). The plasma levels of NO in C + L group were significantly lower than those in carvedilol group(P < 0. 01),which in metoprolol group were significantly higher than those in simple operation group(P < 0. 05),but lower than that in carvedilol group(P < 0. 01). Besides the plasma levels of ET in carvedilol group and metoprolol group were significantly lower than those in simple operation group(P < 0. 01),and the plasma levels of ET in C +L group were significantly highter than those in carvedilol group(P < 0. 01),however,there were no significant differences between carvedilol group and simple operation group(P > 0. 05). Finally the plasma levels of CGRP in 4 groups of renal artery operation were higher than those in sham-operation group,and plasma levels of CGRP in metoprolol group were significantly lower than those in carvedilol group(P < 0. 05). Conclusion The renal artery stegnosis operation can induce left ventricular remodeling models in rats,and both carvedilol and metoprolol can improve left ventricular remodeling,and the effects of carvedilol may be associated with NO system at some extent.
引文
1何金森,张学农,李仁杰,等.新药TJ0711对肾血管性高血压大鼠的肾脏保护作用及机制.华中科技大学学报(医学版),2012,41:142-146.
2 黄立双,刘伟丽,弓景波,等.多沙唑嗪和美托洛尔对腹主动脉缩窄致高血压大鼠血管重塑的影响.中国药理学与毒理学杂志,2015,24:208-212.
3 黄帧桧,杨帆,张培,等.美托洛尔联用阿伐他汀减轻肾性高血压大鼠左室重构.基础医学与临床,2012,32:581-582.
4 郭玉璜,商黔惠,吴芹,等.降压药物对高血压大鼠血管平滑肌细胞离子泵活性及分泌血管紧张素Ⅱ的影响.中华老年心脑血管病杂志,2011,13:456-459.
5 Afonso RA,Patarrao RS,Macedo MP,et al.Carvedilol’s actions are largely mediated by endogenous nitric oxide.Rev Port Cardiol,2006,25:911-7.
6 李祯,李润梅.氯沙坦与美托洛尔对高血压心肌肥厚影响的实验研究.河北医科大学学报,2012,33:228-230.
7 王文靖,潘毅,杨涛,等.两肾一夹型高血压大鼠模型的改良及评价.中国实验方剂学杂志,2012,18:203-205.
8 王宪利,孙玉坤,史昌乾,等.美托洛尔与硝苯地平在大鼠体内药动学的相互影响.武警医学,2012,23:575-577.
9 阮志敏,朱国富,武力勇,等.1型糖尿病对主动脉缩窄大鼠结构和功能的影响.中华老年心脑血管病杂志,2014,16:1307-1311.
10 张丁丁,韩超,蒋雄京,等.肾血管性高血压与原发性高血压患者动脉硬化比较.中国循环杂志,2014,29:182-183.
11 王雪芬.肾血管性高血压患者血压变异性及靶器官损害的临床研究.中国医药导刊,2014,16:565-566,568.
12 陆尽亚,朱健华,秦小同,等.缬沙坦对肾血管性高血压大鼠心肌钙蛋白酶Ⅰ、钙调神经磷酸酶和钙/钙调素依赖蛋白激酶Ⅱδ的影响.中华心血管病杂志,2012,40:511-515.
13 付海明,岳建伟.TGF-β1和b-FGF在肾血管性高血压大鼠血管重塑中的作用.中国心血管病研究,2015,13:89-91,96.
14 赵卫红,鲁星妍.重视肾血管性高血压.中华临床医师杂志(电子版),2013,7:2304-2306.
15 沈凯,陈芬,林卓明,等.血管紧张素Ⅱ通过细胞外信号调节激酶1/2 通路调控过氧化氢酶的表达及促进成纤维细胞表型转化.中国病理生理杂志,2014,31:711-714.
2 黄立双,刘伟丽,弓景波,等.多沙唑嗪和美托洛尔对腹主动脉缩窄致高血压大鼠血管重塑的影响.中国药理学与毒理学杂志,2015,24:208-212.
3 黄帧桧,杨帆,张培,等.美托洛尔联用阿伐他汀减轻肾性高血压大鼠左室重构.基础医学与临床,2012,32:581-582.
4 郭玉璜,商黔惠,吴芹,等.降压药物对高血压大鼠血管平滑肌细胞离子泵活性及分泌血管紧张素Ⅱ的影响.中华老年心脑血管病杂志,2011,13:456-459.
5 Afonso RA,Patarrao RS,Macedo MP,et al.Carvedilol’s actions are largely mediated by endogenous nitric oxide.Rev Port Cardiol,2006,25:911-7.
6 李祯,李润梅.氯沙坦与美托洛尔对高血压心肌肥厚影响的实验研究.河北医科大学学报,2012,33:228-230.
7 王文靖,潘毅,杨涛,等.两肾一夹型高血压大鼠模型的改良及评价.中国实验方剂学杂志,2012,18:203-205.
8 王宪利,孙玉坤,史昌乾,等.美托洛尔与硝苯地平在大鼠体内药动学的相互影响.武警医学,2012,23:575-577.
9 阮志敏,朱国富,武力勇,等.1型糖尿病对主动脉缩窄大鼠结构和功能的影响.中华老年心脑血管病杂志,2014,16:1307-1311.
10 张丁丁,韩超,蒋雄京,等.肾血管性高血压与原发性高血压患者动脉硬化比较.中国循环杂志,2014,29:182-183.
11 王雪芬.肾血管性高血压患者血压变异性及靶器官损害的临床研究.中国医药导刊,2014,16:565-566,568.
12 陆尽亚,朱健华,秦小同,等.缬沙坦对肾血管性高血压大鼠心肌钙蛋白酶Ⅰ、钙调神经磷酸酶和钙/钙调素依赖蛋白激酶Ⅱδ的影响.中华心血管病杂志,2012,40:511-515.
13 付海明,岳建伟.TGF-β1和b-FGF在肾血管性高血压大鼠血管重塑中的作用.中国心血管病研究,2015,13:89-91,96.
14 赵卫红,鲁星妍.重视肾血管性高血压.中华临床医师杂志(电子版),2013,7:2304-2306.
15 沈凯,陈芬,林卓明,等.血管紧张素Ⅱ通过细胞外信号调节激酶1/2 通路调控过氧化氢酶的表达及促进成纤维细胞表型转化.中国病理生理杂志,2014,31:711-714.