温补心阳法治疗心阳虚型慢性心力衰竭大鼠的分子机制研究
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摘要
目的：利用阿霉素建立心阳虚型慢性心力衰竭SD雄性大鼠模型,并以此模型对参附汤温补心阳法治疗心阳虚型慢性心力衰竭的分子机制进行初步研究。
方法：造模阶段,先将SD雄性大鼠随机分为2组,分别为正常组,20只,模型组,80只,模型组腹腔注射阿霉素,4mg/kg,1ml/100g,每周1次,共6周,正常组腹腔注射相同体积的生理盐水。确定造模成功后,将造模成功的大鼠随机分为3组,分别为模型组、阳性组、参附汤组,每组20只,加上之前的正常组,一共4组。阳性组给予地高辛灌胃,0.1mg/kg,1ml/100g,每天1次,共7周；参附汤组给予参附汤水煎液灌胃,1.875g/kg,1ml/100g,每天1次,共7周；正常组及模型组给予相同体积的生理盐水灌胃,每天1次,共7周。每天观察大鼠的一般情况及死亡情况,实验动物每周称体重,最后一次给药后称体重,处死前用0.6%戊巴比妥钠,1ml/100g,60mg/kg腹腔注射麻醉,仰卧于操作台上并固定,检测左心室功能,然后取标本。观察大鼠心脏外观形态、体腔积液,心脏指数测定,心脏组织病理学切片,心肌SOD、MDA、GSH-Px、NO、NOs、ET-1的检测,血清AST、LDH、CK,血浆ANP含量的检测,心肌组织中的CaN,NFAT3, Ca2+的含量,以及Na+-K+-ATP酶,Ca2+-ATP酶活性的检测。
结果：治疗后,参附汤组与模型组比较,体重增加,心脏指数降低,心功能改善,心脏的组织形态结构有明显好转,参附汤能提高大鼠心肌细胞中的SOD及GSH-Px的活性,降低MDA的含量,降低血浆ANP的含量,降低血清AST,LDH, CK活性,增加心肌NO、NOs的含量,降低心肌ET-1的含量,增加心肌组织中的Na+-K+-ATP酶、Ca2+-ATP酶活性,降低心肌CaN、Ca2+、NFAT3的含量,差异有统计学意义(P<0.05或P<0.01)。
结论：
1、参附汤能清除氧自由基,降解脂质过氧化物,保护心肌细胞免受自由基的破坏。
2、参附汤能改善心肌局部NO/ET的失衡状态,恢复心肌的血管内皮功能。
3、参附汤能改善能量代谢,使细胞内Ca2+浓度降低,抑制钙超载。
4、参附汤能抑制CaN-NFAT3信号转导通路的活性,阻止心肌肥大及心衰的发生发展,维护其正常功能,最终使心功能得到明显改善,心阳虚症状得到改善,使慢性心力衰竭得到恢复。参附汤从多个环节预防和治疗心阳虚型慢性心力衰竭。
Objective:This study was to establish heart-Yang deficiency of chronic heart failure model of male rat by adriamycin(ADR),and molecular mechanism research of Shenfu Tang warming heart-Yang on heart-Yang deficiency of chronic heart failure.
Method:The SD male rats were randomly divided into two groups,normal control group20rats, model group,20rats, model group were injected in intraperitoneal with ADR,4mg/kg,1ml/100g, once a week, a total of6weeks, normal group were injected with the same volume of saline.Determine the success of the modeling,the model rats were randomly divided into three groups, model group,digoxin group,shenfu tang group,each group has20rats,add normal control group, a total of four groups.positive group was given digoxin ig gavage,0.1mg/kg,1ml/100g, once a day a total of7weeks; Shen Fu Tang group was given Shen Fu Tang decoction ig,1.875g/kg, lml/100g,once a day, a total of7weeks; Normal group and model group were given the same volume of saline ig once a day, a total of7weeks. Rats were observed daily and mortality in general, the experimental animals weighed weekly, weighed after the last dose, Before death with0.6%sodium pentobarbital anesthesia, lml/100g,60mg/kg intraperitoneal injection, supine on the operating table and fixed detection of left ventricular function, and then take the samples. observed rat heart morphology, body cavity effusion, cardiac index determination, heart histopathology sections, SOD, MDA,GSH-Px、NO、NOs、ET-1detection. Detection of serum AST, LDH, CK, Detection of plasma ANP content, Myocardial tissue in CaN, NFAT3, Ca2+, Na+-K+-ATP enzyme, Ca2+-ATP enzyme activity.
Result:After therapy,compared with model group, shenfu tang group can gain weight, decreased cardiac index, increased heart function, cardiac morphology were significantly improved, Shen Fu Tang can improve the myocardial cells in the SOD and GSH-Px activity and decreased MDA content, decreased serum AST, LDH, CK activity,reduce the content of plasma ANP, increased the content of myocardial tissue NO、NOs,reduce the content of myocardial tissue ET-1,increased activity of myocardial tissue Na+-K+-ATP enzyme, Ca2+-ATP enzyme, the content of CaN in shenfu tang group were obviously lower, The calcium content increased significantly.In the Rats myocardial tissue,the light density ratio of dephosphorylation NFAT3/β-actin lower than model group (P<0.05or P<0.01).
Conclusion:
1.Shenfu tang can scavenge oxygen free radicals,degradation of lipid peroxides,protect myocardial cells from free radical damage.
2. Shenfu tang can improve myocardial NO/ET imbalance,restore myocardial vascular endothelial function.
3Shenfu tang can improve energy metabolism,lower intracellular Ca2+concentration,inhibit calcium overload.
4Shenfu tang can effectively inhibit the activity of CaN-NFAT3signal transduction pathway, Prevent cardiac hypertrophy and heart failure development and maintenance of its normal function,Ultimately be effectively restored heart function,improve the symptoms of heart-yang, heart failure have been restored.Shen Fu Tang prevent and treat heart yang deficiency of chronic heart failure from a number of aspects.
方法：造模阶段,先将SD雄性大鼠随机分为2组,分别为正常组,20只,模型组,80只,模型组腹腔注射阿霉素,4mg/kg,1ml/100g,每周1次,共6周,正常组腹腔注射相同体积的生理盐水。确定造模成功后,将造模成功的大鼠随机分为3组,分别为模型组、阳性组、参附汤组,每组20只,加上之前的正常组,一共4组。阳性组给予地高辛灌胃,0.1mg/kg,1ml/100g,每天1次,共7周；参附汤组给予参附汤水煎液灌胃,1.875g/kg,1ml/100g,每天1次,共7周；正常组及模型组给予相同体积的生理盐水灌胃,每天1次,共7周。每天观察大鼠的一般情况及死亡情况,实验动物每周称体重,最后一次给药后称体重,处死前用0.6%戊巴比妥钠,1ml/100g,60mg/kg腹腔注射麻醉,仰卧于操作台上并固定,检测左心室功能,然后取标本。观察大鼠心脏外观形态、体腔积液,心脏指数测定,心脏组织病理学切片,心肌SOD、MDA、GSH-Px、NO、NOs、ET-1的检测,血清AST、LDH、CK,血浆ANP含量的检测,心肌组织中的CaN,NFAT3, Ca2+的含量,以及Na+-K+-ATP酶,Ca2+-ATP酶活性的检测。
结果：治疗后,参附汤组与模型组比较,体重增加,心脏指数降低,心功能改善,心脏的组织形态结构有明显好转,参附汤能提高大鼠心肌细胞中的SOD及GSH-Px的活性,降低MDA的含量,降低血浆ANP的含量,降低血清AST,LDH, CK活性,增加心肌NO、NOs的含量,降低心肌ET-1的含量,增加心肌组织中的Na+-K+-ATP酶、Ca2+-ATP酶活性,降低心肌CaN、Ca2+、NFAT3的含量,差异有统计学意义(P<0.05或P<0.01)。
结论：
1、参附汤能清除氧自由基,降解脂质过氧化物,保护心肌细胞免受自由基的破坏。
2、参附汤能改善心肌局部NO/ET的失衡状态,恢复心肌的血管内皮功能。
3、参附汤能改善能量代谢,使细胞内Ca2+浓度降低,抑制钙超载。
4、参附汤能抑制CaN-NFAT3信号转导通路的活性,阻止心肌肥大及心衰的发生发展,维护其正常功能,最终使心功能得到明显改善,心阳虚症状得到改善,使慢性心力衰竭得到恢复。参附汤从多个环节预防和治疗心阳虚型慢性心力衰竭。
Objective:This study was to establish heart-Yang deficiency of chronic heart failure model of male rat by adriamycin(ADR),and molecular mechanism research of Shenfu Tang warming heart-Yang on heart-Yang deficiency of chronic heart failure.
Method:The SD male rats were randomly divided into two groups,normal control group20rats, model group,20rats, model group were injected in intraperitoneal with ADR,4mg/kg,1ml/100g, once a week, a total of6weeks, normal group were injected with the same volume of saline.Determine the success of the modeling,the model rats were randomly divided into three groups, model group,digoxin group,shenfu tang group,each group has20rats,add normal control group, a total of four groups.positive group was given digoxin ig gavage,0.1mg/kg,1ml/100g, once a day a total of7weeks; Shen Fu Tang group was given Shen Fu Tang decoction ig,1.875g/kg, lml/100g,once a day, a total of7weeks; Normal group and model group were given the same volume of saline ig once a day, a total of7weeks. Rats were observed daily and mortality in general, the experimental animals weighed weekly, weighed after the last dose, Before death with0.6%sodium pentobarbital anesthesia, lml/100g,60mg/kg intraperitoneal injection, supine on the operating table and fixed detection of left ventricular function, and then take the samples. observed rat heart morphology, body cavity effusion, cardiac index determination, heart histopathology sections, SOD, MDA,GSH-Px、NO、NOs、ET-1detection. Detection of serum AST, LDH, CK, Detection of plasma ANP content, Myocardial tissue in CaN, NFAT3, Ca2+, Na+-K+-ATP enzyme, Ca2+-ATP enzyme activity.
Result:After therapy,compared with model group, shenfu tang group can gain weight, decreased cardiac index, increased heart function, cardiac morphology were significantly improved, Shen Fu Tang can improve the myocardial cells in the SOD and GSH-Px activity and decreased MDA content, decreased serum AST, LDH, CK activity,reduce the content of plasma ANP, increased the content of myocardial tissue NO、NOs,reduce the content of myocardial tissue ET-1,increased activity of myocardial tissue Na+-K+-ATP enzyme, Ca2+-ATP enzyme, the content of CaN in shenfu tang group were obviously lower, The calcium content increased significantly.In the Rats myocardial tissue,the light density ratio of dephosphorylation NFAT3/β-actin lower than model group (P<0.05or P<0.01).
Conclusion:
1.Shenfu tang can scavenge oxygen free radicals,degradation of lipid peroxides,protect myocardial cells from free radical damage.
2. Shenfu tang can improve myocardial NO/ET imbalance,restore myocardial vascular endothelial function.
3Shenfu tang can improve energy metabolism,lower intracellular Ca2+concentration,inhibit calcium overload.
4Shenfu tang can effectively inhibit the activity of CaN-NFAT3signal transduction pathway, Prevent cardiac hypertrophy and heart failure development and maintenance of its normal function,Ultimately be effectively restored heart function,improve the symptoms of heart-yang, heart failure have been restored.Shen Fu Tang prevent and treat heart yang deficiency of chronic heart failure from a number of aspects.
引文
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