姜附汤干预阿霉素所致心脏毒性损伤大鼠的药效学实验研究
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摘要
目的:探讨姜附汤干预阿霉素(adriamycin,ADR)心脏毒性损伤大鼠的效应强度,初步比较干姜、附子及姜附汤干预阿霉素心脏毒性损伤大鼠影响的差异性。
材料与方法:成年健康SD大鼠96只,SPF级,体重220～240g,按体重随机分为7组,分别为正常组(N=11)、模型组(N=15)、附子+正常组(N=14)、中药对照组(N=14)、附子+模型组(N=14)、干姜组(N=14)、姜附组(N=14)。采用ADR腹腔注射法建立ADR心脏毒性模型。以实验大鼠心电图、超声心动指标、心脏指数、心肌组织及心肌细胞超微结构、心肌细胞丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性、谷胱甘肽过氧化物酶(GSH-Px)活性作为观察指标。实验数据用统计分析软件SPSS15.0进行统计学处理。
结果:
1.一般状态:模型组大鼠毛色枯萎,精神萎靡,反应迟钝,喜卧,懒动,体重增长缓慢,实验末期,出现脱毛、体重减轻现象,严重者可见血渍、腹水、腹泻等症状。除附子+模型组外,各给药组均出现了模型组相类似的不良状态,但出现得较晚,不良状态较轻,而附子+模型组的一切不良状态较模型组出现的早,程度重。
2.姜附汤对ADR所致心脏毒性损伤大鼠心电图的影响:与正常组比较,模型组大鼠心率明显下降,QRS波群电压和显著降低,Q-T间期延长,具有统计学意义(P<0.05);与模型组比较,姜附组、干姜组、附子+模型组的心率,QRS波群电压和明显提高,Q-T间期显著缩短,并具有统计学意义(P<0.05);与附子+正常组比较,模型组的心率明显下降,QRS波群电压和明显降低,Q-T间期延长,均具有统计学意义(P<0.05);与附子+正常组比较,附子+模型组Q-T间期延长,均具有统计学意义(P<0.05);治疗组之间的比较,干姜组的QRS波群电压和Q-T间期明显低于其他两个治疗组,并具有统计学意义(P<0.05)。
3.姜附汤对ADR所致心脏毒性损伤大鼠的彩色超声心动Doppler的影响:模型组大鼠超声心动改变较正常组的EF%、FS%明显下降,LVIDd、LVIDs有所上升,均具有统计学意义(P<0.05)。与模型组比较,附子+模型组、附子+正常组的LVIDs下降,有统计学意义(P<0.05)。
4.姜附汤对ADR所致心脏毒性损伤大鼠心脏重量的影响:与正常组比较,模型组的心脏重量下降,有统计学意义(P<0.05)。
5.姜附汤对ADR所致心脏毒性损伤大鼠心肌组织结构的影响:光镜下观察,模型组大鼠的心肌间隙增宽,肌纤维断裂,出现明显的空泡变性、颗粒变性、淋巴细胞浸润现象,甚至有发生质变现象。电镜下观察,模型组大鼠心肌出现明显损伤,肌纤维断裂,肌丝紊乱,Z线宽窄不一,部分溶解,线粒体肿胀,嵴模糊不清,甚至断裂,个别已经出现大小不等的空泡变性。各给药组呈现不同程度的心肌组织损伤,其中以附子+模型组心肌细胞的病理损伤最为严重。
6.姜附汤对ADR所致心脏毒性损伤大鼠心肌细胞SOD、GSH-Px、MDA的影响:与正常组比较,模型组大鼠心肌细胞SOD、GSH-Px活性明显下降,心肌细胞MDA含量显著上升,均有统计学意义(P<0.05);与模型组比较,姜附组SOD活性显著升高,有统计学意义(P<0.05),GSH-Px活性、MDA含量均呈升高趋势;治疗组之间比较,姜附组SOD活性与干姜组、附子+模型组比较,SOD活性明显升高,有统计学意义(P<0.05)。
结论:
在本实验条件下,
1.姜附汤可能具有改善阿霉素所致心脏毒性大鼠心脏功能的作用。
2.姜附汤能够抑制阿霉素所致心脏毒性大鼠心肌组织结构的病理改变。
3.姜附汤可能通过提高抗氧化应激酶的活性,降低阿霉素的心脏毒性。
Objective:
To study the intervention effect of classical traditional Chinese medicine prescriptions of Jiangfu Decoction on adriamycin-induced Myocardial Damage.
Material and method:
Health adult male SD rats were 96,weighting 220～240g,were randomly divided into seven group: the first group is control one (N=11):regular feeding ,no treatment; the second group is model one (N=15):with ADR intraperitioneal injection of adriamycin cardiactoxicity model,2.5mg/kg,week 1,while fed distill water ,1ml/100g, day 1,continuous medication for 4 week; the third group is the third one(N=14): Adriamycin use the same second group,while fed Shengmaiyin (including the amount of liquid 3.5ml/kg/d);the forth group is an attached to an empty group (N=14):with equal physial saline instead of adriamycin,while gavage monkshood decoction (including the amount of crude drug 1.75g/kg/d),drug delivery approach with the model group;the fifth sixth seventh group separated monkshood one (N=14),rhizoma zingiberis one (N=14),Jiangfu one(N=14):use the same model of adriamycin group,were fed at the same time monkshood decoction (including the amount of crude drug 1.75g/kg/d), rhizoma zingiberis group (including the amount of 0.875g/kg/d),Jiangfu group decoction(including the amount of crude drug 2.625g/kg/d),drug delivery approach with the model group. After 4 weeks,rat in each group detected ECG and echocardiography ;the first killed animals and removed heart to calculate the heart index numbler;the second specimens from a part of myocardial specimen were light and electron microscopy to observe the microscopic structure of myocardial tissue and cell ultrastructure changes; the last,we will be made of the remaining myocardial cell homogenate,using chemical colorimetric assay in rat myocardial cells malondialdehyde(MDA) content and superoxide dismutase (SOD),glutethione peroxidase (GSH-Px) activity, a preliminary study intervention Jiang Fu Tang effecting Adriamycin cardiac toxicity in rat.
Results:
1. General state: model rats, coat wither, listlessness, unresponsive, the lie, lazy to move, slow growth, end the weight, appear hair removal, weight loss phenomenon, a serious stones, ascites, visible diarrhea. In addition to the radix aconiti + model group, the treatment group all appear the model group similar bad state, but came much later, bad state is lighter; And all the radix aconiti + model group bad state a model group appear early, degree of weight.
2. Ginger with soup (ADR) of heart toxic injury caused by rat electrocardiogram impact: normal group comparison, model rats, heart rate decreased obviously, QRS complex group of voltage and significantly reduced, Q-T stage was extended, between a statistically significant (P < 0.05); And the model group compared with group, ginger, dry ginger group, radix aconiti + model group of heart rate, QRS complex group of voltage and improved obviously, Q-T stage, and shortens significantly between a statistically significant (P < 0.05); And radix aconiti + group compared to normal, model group of heart rate decreased obviously, QRS complex group of voltage and reduced significantly, and Q-between T stage was extended, radix aconiti + model group more Q-between T stage was extended, which will have a statistically significant (P < 0.05). The comparison between treatment group, dry ginger group of QRS complex group of voltage and Q-T stage between obviously lower than the other two treatment groups, and a statistically significant (P < 0.05).
3. Ginger with soup (ADR) of heart toxic injury caused by the rat color Doppler echocardiography influence: model rats, echocardiography change the normal group of EF, FS % declined obviously, and LVIDd, LVIDs increased, which will have a statistically significant (P < 0.05). Group compared with model, radix aconiti + model group, radix aconiti + normal group of LVIDs drop, a statistically significant (P < 0.05).
4. Ginger with soup (ADR) of heart toxic injury caused by rat heart heavy influence: group compared with normal, the heart of the model group, a statistically significant weight down (P < 0.05).
5. Ginger with soup (ADR) of heart toxic injury caused by rat heart tissue structure influences: light-microscopy, model of rats, myocardial clearance linewidths of muscle fiber, fracture, apparent empty bubble degeneration, particle degeneration, lymphocytic infiltrates phenomenon, and even a qualitative change happened phenomenon. By electron microscopy observation, model rats, myocardial significant damage, muscle fiber fracture, muscle silk disorder, Z line size is differ, partly dissolved, mitochondria swell, cristae vague, and even rupture, individual has appeared sizes of empty bubble degeneration. The treatment group present different degree of myocardial tissue damage, among them, radix aconiti + model group of myocardial cell pathological damage is the most serious.
6. Ginger with soup (ADR) of heart toxic injury caused by rat heart muscle cells SOD, GSH-Px, MDA impact: the normal group compared with model rats, myocardial cell SOD, GSH-Px activity declined obviously, myocardial cell MDA content to rise significantly, all have statistically significant (P < 0.05). And the model group compared with group, ginger SOD activity, a significant rise was statistically significant (P < 0.05), GSH-Px activity, MDA content increased by a trend. Comparison between treatment group, ginger attached group SOD activity and dry ginger group, radix aconiti + model group, SOD activity is obviously higher, a statistically significant (P < 0.05).
Conclusion:
1.Jiangfu decotion to some extent may improve Adriamycin heart toxicity of rats caused by heart function.
2. Jiangfu decotion may inhibit doxorubicin toxic rats induced by heart pathological changes of the myocardial tissue structure.
3. Jiangfu decotion may reduce Adriamycin heart toxicity through increasing Antioxidant should kinase activity.
4.Jiangfu decotion may product Anti doxorubicin heart toxicity of the effective components/parts that dried ginger or aconite did not possess.
材料与方法:成年健康SD大鼠96只,SPF级,体重220～240g,按体重随机分为7组,分别为正常组(N=11)、模型组(N=15)、附子+正常组(N=14)、中药对照组(N=14)、附子+模型组(N=14)、干姜组(N=14)、姜附组(N=14)。采用ADR腹腔注射法建立ADR心脏毒性模型。以实验大鼠心电图、超声心动指标、心脏指数、心肌组织及心肌细胞超微结构、心肌细胞丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性、谷胱甘肽过氧化物酶(GSH-Px)活性作为观察指标。实验数据用统计分析软件SPSS15.0进行统计学处理。
结果:
1.一般状态:模型组大鼠毛色枯萎,精神萎靡,反应迟钝,喜卧,懒动,体重增长缓慢,实验末期,出现脱毛、体重减轻现象,严重者可见血渍、腹水、腹泻等症状。除附子+模型组外,各给药组均出现了模型组相类似的不良状态,但出现得较晚,不良状态较轻,而附子+模型组的一切不良状态较模型组出现的早,程度重。
2.姜附汤对ADR所致心脏毒性损伤大鼠心电图的影响:与正常组比较,模型组大鼠心率明显下降,QRS波群电压和显著降低,Q-T间期延长,具有统计学意义(P<0.05);与模型组比较,姜附组、干姜组、附子+模型组的心率,QRS波群电压和明显提高,Q-T间期显著缩短,并具有统计学意义(P<0.05);与附子+正常组比较,模型组的心率明显下降,QRS波群电压和明显降低,Q-T间期延长,均具有统计学意义(P<0.05);与附子+正常组比较,附子+模型组Q-T间期延长,均具有统计学意义(P<0.05);治疗组之间的比较,干姜组的QRS波群电压和Q-T间期明显低于其他两个治疗组,并具有统计学意义(P<0.05)。
3.姜附汤对ADR所致心脏毒性损伤大鼠的彩色超声心动Doppler的影响:模型组大鼠超声心动改变较正常组的EF%、FS%明显下降,LVIDd、LVIDs有所上升,均具有统计学意义(P<0.05)。与模型组比较,附子+模型组、附子+正常组的LVIDs下降,有统计学意义(P<0.05)。
4.姜附汤对ADR所致心脏毒性损伤大鼠心脏重量的影响:与正常组比较,模型组的心脏重量下降,有统计学意义(P<0.05)。
5.姜附汤对ADR所致心脏毒性损伤大鼠心肌组织结构的影响:光镜下观察,模型组大鼠的心肌间隙增宽,肌纤维断裂,出现明显的空泡变性、颗粒变性、淋巴细胞浸润现象,甚至有发生质变现象。电镜下观察,模型组大鼠心肌出现明显损伤,肌纤维断裂,肌丝紊乱,Z线宽窄不一,部分溶解,线粒体肿胀,嵴模糊不清,甚至断裂,个别已经出现大小不等的空泡变性。各给药组呈现不同程度的心肌组织损伤,其中以附子+模型组心肌细胞的病理损伤最为严重。
6.姜附汤对ADR所致心脏毒性损伤大鼠心肌细胞SOD、GSH-Px、MDA的影响:与正常组比较,模型组大鼠心肌细胞SOD、GSH-Px活性明显下降,心肌细胞MDA含量显著上升,均有统计学意义(P<0.05);与模型组比较,姜附组SOD活性显著升高,有统计学意义(P<0.05),GSH-Px活性、MDA含量均呈升高趋势;治疗组之间比较,姜附组SOD活性与干姜组、附子+模型组比较,SOD活性明显升高,有统计学意义(P<0.05)。
结论:
在本实验条件下,
1.姜附汤可能具有改善阿霉素所致心脏毒性大鼠心脏功能的作用。
2.姜附汤能够抑制阿霉素所致心脏毒性大鼠心肌组织结构的病理改变。
3.姜附汤可能通过提高抗氧化应激酶的活性,降低阿霉素的心脏毒性。
Objective:
To study the intervention effect of classical traditional Chinese medicine prescriptions of Jiangfu Decoction on adriamycin-induced Myocardial Damage.
Material and method:
Health adult male SD rats were 96,weighting 220～240g,were randomly divided into seven group: the first group is control one (N=11):regular feeding ,no treatment; the second group is model one (N=15):with ADR intraperitioneal injection of adriamycin cardiactoxicity model,2.5mg/kg,week 1,while fed distill water ,1ml/100g, day 1,continuous medication for 4 week; the third group is the third one(N=14): Adriamycin use the same second group,while fed Shengmaiyin (including the amount of liquid 3.5ml/kg/d);the forth group is an attached to an empty group (N=14):with equal physial saline instead of adriamycin,while gavage monkshood decoction (including the amount of crude drug 1.75g/kg/d),drug delivery approach with the model group;the fifth sixth seventh group separated monkshood one (N=14),rhizoma zingiberis one (N=14),Jiangfu one(N=14):use the same model of adriamycin group,were fed at the same time monkshood decoction (including the amount of crude drug 1.75g/kg/d), rhizoma zingiberis group (including the amount of 0.875g/kg/d),Jiangfu group decoction(including the amount of crude drug 2.625g/kg/d),drug delivery approach with the model group. After 4 weeks,rat in each group detected ECG and echocardiography ;the first killed animals and removed heart to calculate the heart index numbler;the second specimens from a part of myocardial specimen were light and electron microscopy to observe the microscopic structure of myocardial tissue and cell ultrastructure changes; the last,we will be made of the remaining myocardial cell homogenate,using chemical colorimetric assay in rat myocardial cells malondialdehyde(MDA) content and superoxide dismutase (SOD),glutethione peroxidase (GSH-Px) activity, a preliminary study intervention Jiang Fu Tang effecting Adriamycin cardiac toxicity in rat.
Results:
1. General state: model rats, coat wither, listlessness, unresponsive, the lie, lazy to move, slow growth, end the weight, appear hair removal, weight loss phenomenon, a serious stones, ascites, visible diarrhea. In addition to the radix aconiti + model group, the treatment group all appear the model group similar bad state, but came much later, bad state is lighter; And all the radix aconiti + model group bad state a model group appear early, degree of weight.
2. Ginger with soup (ADR) of heart toxic injury caused by rat electrocardiogram impact: normal group comparison, model rats, heart rate decreased obviously, QRS complex group of voltage and significantly reduced, Q-T stage was extended, between a statistically significant (P < 0.05); And the model group compared with group, ginger, dry ginger group, radix aconiti + model group of heart rate, QRS complex group of voltage and improved obviously, Q-T stage, and shortens significantly between a statistically significant (P < 0.05); And radix aconiti + group compared to normal, model group of heart rate decreased obviously, QRS complex group of voltage and reduced significantly, and Q-between T stage was extended, radix aconiti + model group more Q-between T stage was extended, which will have a statistically significant (P < 0.05). The comparison between treatment group, dry ginger group of QRS complex group of voltage and Q-T stage between obviously lower than the other two treatment groups, and a statistically significant (P < 0.05).
3. Ginger with soup (ADR) of heart toxic injury caused by the rat color Doppler echocardiography influence: model rats, echocardiography change the normal group of EF, FS % declined obviously, and LVIDd, LVIDs increased, which will have a statistically significant (P < 0.05). Group compared with model, radix aconiti + model group, radix aconiti + normal group of LVIDs drop, a statistically significant (P < 0.05).
4. Ginger with soup (ADR) of heart toxic injury caused by rat heart heavy influence: group compared with normal, the heart of the model group, a statistically significant weight down (P < 0.05).
5. Ginger with soup (ADR) of heart toxic injury caused by rat heart tissue structure influences: light-microscopy, model of rats, myocardial clearance linewidths of muscle fiber, fracture, apparent empty bubble degeneration, particle degeneration, lymphocytic infiltrates phenomenon, and even a qualitative change happened phenomenon. By electron microscopy observation, model rats, myocardial significant damage, muscle fiber fracture, muscle silk disorder, Z line size is differ, partly dissolved, mitochondria swell, cristae vague, and even rupture, individual has appeared sizes of empty bubble degeneration. The treatment group present different degree of myocardial tissue damage, among them, radix aconiti + model group of myocardial cell pathological damage is the most serious.
6. Ginger with soup (ADR) of heart toxic injury caused by rat heart muscle cells SOD, GSH-Px, MDA impact: the normal group compared with model rats, myocardial cell SOD, GSH-Px activity declined obviously, myocardial cell MDA content to rise significantly, all have statistically significant (P < 0.05). And the model group compared with group, ginger SOD activity, a significant rise was statistically significant (P < 0.05), GSH-Px activity, MDA content increased by a trend. Comparison between treatment group, ginger attached group SOD activity and dry ginger group, radix aconiti + model group, SOD activity is obviously higher, a statistically significant (P < 0.05).
Conclusion:
1.Jiangfu decotion to some extent may improve Adriamycin heart toxicity of rats caused by heart function.
2. Jiangfu decotion may inhibit doxorubicin toxic rats induced by heart pathological changes of the myocardial tissue structure.
3. Jiangfu decotion may reduce Adriamycin heart toxicity through increasing Antioxidant should kinase activity.
4.Jiangfu decotion may product Anti doxorubicin heart toxicity of the effective components/parts that dried ginger or aconite did not possess.
引文
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