香丹注射液对SD大鼠慢性心脏毒性作用的研究
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摘要
目的探讨长期应用香丹注射液对SD大鼠的心脏毒性作用。方法将72只SD大鼠分为4个组,分别为空白组(生理盐水1 mL·kg~(-1))和香丹注射液低、中、高剂量组(香丹注射液原液1、3、9 mL·kg~(-1)),连续尾静脉注射30 d和45 d后取材,将血清和一半心脏组织于-80℃存储,测定血清谷草转氨酶(AST)、乳酸脱氢酶(LDH)和肌酸激酶(CK)活性,Western Blot法检测心肌组织中凋亡相关蛋白Bcl-2和Bax的表达水平;另一半心肌组织存储在10%的福尔马林中,用HE染色观察心肌组织病理改变,用TUNEL细胞凋亡检测试剂盒检测细胞凋亡的情况。结果与空白组比较,香丹注射液给药30 d后,各给药组血清AST活性明显升高(P <0.05);给药45 d后,中剂量血清AST活性显著升高(P <0.05),高剂量血清AST和LDH活性显著升高(P <0.05);CK活性呈现上升的趋势(P> 0.05)。组织病理学检查显示,给药组部分大鼠心肌细胞出现损伤;TUNEL细胞凋亡检测可见心肌细胞发生凋亡;给药组心肌中的凋亡相关蛋白Bax/Bcl-2的蛋白比值升高。结论大剂量、长时间给予香丹注射液对SD大鼠心肌细胞有一定的毒性,其作用机制可能与心肌细胞凋亡有关。
Objective The objective of this study was to evaluate the chronic effects of Xiangdan Injection(XDI)on cardiomyocytes in SD rats. Methods Seventy-two SD rats were received an intravenous(iv. 1 mL·kg~(-1)) dose of normal saline,and intravenous(iv. 1,3,9 mL·kg~(-1),respectively) doses of XDI once daily for 30 days and 45 days respectively. After last administration,the serum and half of the heart tissue were acquired and stored at-80 ℃for determination of the activities of aspartate transaminase(AST),lactate dehydrogenase(LDH),creatine kinase(CK) in serum and the myocardial protein expression of Bcl-2 and Bax in cardiomyocytes. The other half of the heart tissue was fixed in 10% formalin,which was used for HE staining and terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling(TUNEL) assay. Results The results clearly showed that XDI affects various biochemical parameters,such as activities of AST,LDH,and CK,which are directly related to heart dysfunction.The pathologic examination confirmed heart damage in the animals administered an XDI compared with those in the control group. The administration of XDI also induced apoptosis in TUNEL positive cells and upregulation of Bax/Bcl-2 apoptotic genes. Conclusion In conclusion,the results suggest that long-term injection of XDI into the tail vein of SD rats induces heart damage,resulting in the possible expression of certain apoptosis genes,especially at high doses.
Objective The objective of this study was to evaluate the chronic effects of Xiangdan Injection(XDI)on cardiomyocytes in SD rats. Methods Seventy-two SD rats were received an intravenous(iv. 1 mL·kg~(-1)) dose of normal saline,and intravenous(iv. 1,3,9 mL·kg~(-1),respectively) doses of XDI once daily for 30 days and 45 days respectively. After last administration,the serum and half of the heart tissue were acquired and stored at-80 ℃for determination of the activities of aspartate transaminase(AST),lactate dehydrogenase(LDH),creatine kinase(CK) in serum and the myocardial protein expression of Bcl-2 and Bax in cardiomyocytes. The other half of the heart tissue was fixed in 10% formalin,which was used for HE staining and terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling(TUNEL) assay. Results The results clearly showed that XDI affects various biochemical parameters,such as activities of AST,LDH,and CK,which are directly related to heart dysfunction.The pathologic examination confirmed heart damage in the animals administered an XDI compared with those in the control group. The administration of XDI also induced apoptosis in TUNEL positive cells and upregulation of Bax/Bcl-2 apoptotic genes. Conclusion In conclusion,the results suggest that long-term injection of XDI into the tail vein of SD rats induces heart damage,resulting in the possible expression of certain apoptosis genes,especially at high doses.
引文
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[2]林卫. 265例香丹注射液不良反应的报告分析[J].贵阳中医学院学报,2011,33(4):65-67.
[3]吴勇,钱崇付. 717例香丹注射液不良反应报告分析[J].药物流行病学杂志,2013,22(1):12-14.
[4]赵伟,张永玲,郑林,等. 2067篇588例香丹注射液不良反应文献分析[J].河南中医,2011,31(3):298-302.
[5]丁杰,都鹏飞.表没食子儿茶素没食子酸酯干预柔红霉素致小鼠心肌损伤的疗效观察[J].中华全科医学,2018,1(16):26-29
[6]汤健,丁金凤,唐朝枢.心血管疾病基础与临床[M].北京:北京医科大学、中国协和医科大学联合出版社,1990:166
[7]赵阳,马百平,王升启,等.中药所含甾体皂苷与三萜皂苷防治心血管疾病的研究进展[J].中国药学杂志,2003,38(1):3-7.
[8]李国华. PI3K-PKB/Art-GSK-3β信号通路在FGF-2心肌保护中的作用研究[D].衡阳:南华大学,2016.
[9] PALOJOKI E,SARASTE A,ERIKSSON A,et al. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats[J]. Am J Physiol Heart Circ Physiol, 2001, 280(6):H2726-H2731.
[10]荆娇,马海玲,闫文升,等.辛伐他汀对大鼠肾缺血再灌注损伤后心肌Bcl-2和Bax蛋白表达的影响[J].中国病理生理杂志,2017,33(12):2274-2277.
[11]李雅蓉,李兴.脂联素对高糖环境下人心肌细胞凋亡及Bax、Bcl-2表达的影响[J].中西医结合心脑血管病杂志,2012,10(1):37-39.