安心注射液的抗心肌缺血作用及机制研究
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摘要
目的探讨安心注射液的抗心肌缺血作用及其机制,开展安心注射液的临床前药效学研究,为开发新型具有抗心肌缺血或心血管保护作用的临床用药奠定基础。
方法左冠状动脉前降支近第一分支处结扎家兔的冠脉,建立心肌缺血模型;0.1%硝基四氮唑蓝(NBT)染色确定心肌缺血的范围;石蜡包埋,常规切片,伊红染色,观察心肌梗死的显微形态学改变。以针形电极插入四肢皮下连续监测标准Ⅱ导联心电图;多普勒测定升主动脉血流;股动脉置管监测心脏血液动力学检测HR(心率)、MAP(平均动脉压)、CO(心输出量)、左室收缩压(LVSP)、左室舒张末压(LVEDP)和心率收缩压乘积(RPP);自动生化分析仪检测血中肌酸磷酸激酶(CPK)、乳酸脱氢酶(LDH):用硫代巴比妥比色法测定血中丙二醛(MDA)含量;用黄嘌呤氧化酶比色法测定超氧化物歧化酶(SOD)活性;用硝酸还原酶比巨法测定一氧化氮(NO)活性;Chandler体外法测定体外血栓形成情况;按照Born氏比浊法,检测血小板凝集率,LBY—NJ2血小板聚集仪绘制聚集曲线及计算最大聚集率,分析药物对血小板聚集的影响;全自动血流变快测仪分别测定全血粘度、全血还原粘度、红细胞聚集指数;用文氏管法测红细胞压积,Wintrobe管法测血沉,用SPSS 11.0统计软件进行方差和相关分析。组心肌梗塞梗死面积达到了29.4±3.7%,显微镜下观察发现,病变心肌处出现大量的炎性细胞侵润、充血水肿明显;肌横纹较模糊,线粒体嵴模糊不清。基质淡甚至空泡化,心肌细胞出现明显的凝聚、肿胀、坏死、溶解,亦可观察到大量核浓缩、核变小;核膜皱缩、异形,有伪足样突起;染色质凝集成块,边集等典型的凋亡细胞特征,说明心肌梗死模型建立成功。
2.安心注射液低、中、高剂量治疗后,心肌坏死面积分别下降至25±3.2%、17±3.5%、14±2.9%;与心肌缺血模型组比较差异有显著性;显微形态学观察发现;心肌炎性浸润及心肌细胞坏死明显减轻,提示,安心注射液有较好的缩小梗死心肌面积范围,保护缺血心肌的作用,其中安心注射液高剂量组,效果稍强于硝酸甘油对照组。
3.安心注射液治疗后,家兔标准导联心电图S-T段、T波缺血性改变型程度的程度较模型组均明显减低(P＜0.05)病理性Q波和室性心律失常的百分数均明显下降,(P＜0.05),提示安心注射液能显著改善急性缺血心肌心电图改变,减慢心率、降低心肌耗氧,防治心律失常。
4.安心注射液治疗后缺血心脏心率减慢,平均动脉压(MAP)下降,心输出量(CO)降低,左室收缩压(LVSP),左室舒张末压(LVEDP)升高,心率收缩压乘积(RPP)下降(P＜0.05),说明安心注射液具有改善心肌缺血后心脏的血液动力学,增加心肌供血的作用。
5.安心注射液治疗后肌酸磷酸激酶(CPK)、乳酸脱氢酶(LDH)显著下降(P＜0.05),其中对CPK的作用强于硝酸甘油组,而对LDH的作用稍弱于硝酸甘油组;丙二醛(MDA)显著下降,超氧化物歧化酶(SOD)和一氧化氮(NO)明显升高(P＜0.05);提示安心注射液具有显著的改善缺血心肌的心肌细胞代谢及抗氧化能力的作用。
6.安心注射液治疗后,心肌缺血家兔血栓形成长度明显缩短(P＜0.05),血栓湿重及干重有减轻。安心注射液可以明显地降低心肌缺血家兔二磷酸腺苷(ADP)和胶原诱导的血小板聚集率,对花生四烯酸(AA)诱导的家兔血小板聚集率有降低趋势。还可显著抑制心肌缺血家兔模型的全血粘度、血浆粘度、全血还原粘度,降低血沉和红细胞压积。提示安心注射液的抗心肌缺血作用与其显著改善全身的血液流变学状况有关。
结论安心注射液具有良好的抗心肌缺血作用,其机制可能与其改善心脏的血液动力学指标和缺血心肌的细胞的代谢及抗氧化能力,抑制血小板聚集和改善血液流变学的作用有关。
Object:To discuss the effect and mechanism of anti-myocardial ischemia of Anxin injection,carry out its preclinical Pharmacodynamics studies,and to lay the foundation for development of the new clinical drug with effects of anti-myocardial ischemia and cardiovascular protection.
Method:Rabbit's crown arteries were tied up near the first branch place in the from falling branch of the left coronary artery to establish the mode of myocardial ischemia.The scope of ischemia cardiac muscle was identified with the 0.1%NBT dyeing.Through applying the method of paraffin wax embedding,conventional slice and Iraq red dyes,the micromorphological change of myocardial infarction was observed.The standardⅡ-lead electrocardiogram was detected continuously by the needle electrode inserting under the hypodermis of limbs.The ascending aorta's blood stream was determined by Doppler method.The cardio hemodynamics was monitored through placing the pipe in the femoral artery to detect the HR,MAP,CO,LVSP,LVEDP and RPP.The CK and LDH in the blood are detected by automatic biochemistry analyzer.NO, SOD and MDA were determined by different colorimetric methods.The forming of thrombus in vitro was detected through the Chandler method. The aggregation ratio of platelet was determined under the Born nephelometry.Through using the LBY—NJ2 platelet aggregator,the platelet aggregation curve is drawn and the highest aggregation ratio is calculated,which can be used to analyze the effect of the drug on platelet aggregation.Blood Specific Viscosity,Blood Reduced Viscosity and Aggregation Index of RBC are determined respectively.The packed cellvolume is determined and the ESR is determined by Wintrobe method. The statistic software SPSS 11.0 is used to calculate the variance and analyze related data.
Results:
1.When the rabbit's crown artery was blocked for 60 min.,the infarction area of myocardial ischemia reached 29.4±3.7%in the model group.A mass of inflammation cells near the pathological cardiac muscle and hyperemia and dropsy were obviously observed under the microscope.They were also found that the cross striation and ridge cast of mitochondria come to be blurry,the matrix was light even to be bubbly and the cardiac muscle cells were taken on obvious aggregation, tumefaction,death and dissolution.Additionally,the typical characteristics of apototic cells,which were condensed nucleus,crinkled and abnormal karyotheca and coagulated chromatin,were also observed. All the observations mentioned above proved the successful modeling of myocardial ischemia.
2.After the treatments with the low,medium and high dosage of Anxin injection,the cardiac muscle necrosis area was decreased to 25±3.2%,17±3.5%,14±2.9%,respectively.It was significantly different when compared with the model group.According to Micromorphology,it was observed that the inflammation and necrosis of cardiac muscle cells were markedly reduced,Which showed that the Anxin injection could reduce the cardiac muscle necrosis area and protect the ischemic cardiac muscle.The effect was better in the Anxin injection group with high dosage than that of the parallel group with glonoin.
3.After the treatment with Anxin injection,the degree of the height and inversion of "S-T" phase and "T" phase in the rabbit's standard cardiogram dropped distinctly in contrast with the model group (P＜0.05～0.01),the percent of pathologic "Q" and ventricular arrhythmia declined remarkably(P＜0.05),which showed that the injection can remarkably improve the change of cardiogram of acute myocardial ischemia,slow HR,reduce the oxygen consumption of cardiac muscle and prevent arrhythrnia.
4.After the treatment with Anxin injection,the rhythm of the ischemic heart became slow,and several indexes,such as MAP,CO, LVSP,RPP,were dropped while LVEDP was raised(P＜0.05).It showed that Anxin injection could improve the heart hemodynamics after being myocardial ischemia,and increase the supplementation of blood of cardiac muscle.
5.After the treatment with Anxin injection,CPK and LDH decreased obviously(P＜0.05).And the effect on CPK was better than that of the glonoine group while the effect on LDH was worse than that of the glonoine group.MDA had the marked decreasing and the SOD and NO had increasing(P＜0.05),which is distinctly different from the model group.(P＜0.01).It proved that the injection could improve the metabolism and the ability of anti-oxidization of ischemia cardiac muscle cell.
6.After the treatment with Anxin injection,the length of the rabbit's thrombus was shortened obviously(P＜0.05)and the weight of thrombus was also listened.The Anxin injection can obviously reduce ADP and the ratio of platelet aggregation induced by either collagen or AA.It could also inhibit the Whole Blood Viscosity,Blood Specific Viscosity and Blood Reduced Viscosity of the rabbit in the trials,decrease the ESR and RBC,It showed that the effect of anti-myocardial ischemia of Anxin injection is related to its amelioration to the body's haemorheology.
Conclusion:Anxin injection has good effect on anti-myocardial ischemia.The mechanism of its function might be related to that it can improve the index of the heart's hemodynamics and the metabolism and the anti- oxidization ability of ischemic cardiac muscle cell as well as inhibit the platetet aggregation and improve the hemorheology.
方法左冠状动脉前降支近第一分支处结扎家兔的冠脉,建立心肌缺血模型;0.1%硝基四氮唑蓝(NBT)染色确定心肌缺血的范围;石蜡包埋,常规切片,伊红染色,观察心肌梗死的显微形态学改变。以针形电极插入四肢皮下连续监测标准Ⅱ导联心电图;多普勒测定升主动脉血流;股动脉置管监测心脏血液动力学检测HR(心率)、MAP(平均动脉压)、CO(心输出量)、左室收缩压(LVSP)、左室舒张末压(LVEDP)和心率收缩压乘积(RPP);自动生化分析仪检测血中肌酸磷酸激酶(CPK)、乳酸脱氢酶(LDH):用硫代巴比妥比色法测定血中丙二醛(MDA)含量;用黄嘌呤氧化酶比色法测定超氧化物歧化酶(SOD)活性;用硝酸还原酶比巨法测定一氧化氮(NO)活性;Chandler体外法测定体外血栓形成情况;按照Born氏比浊法,检测血小板凝集率,LBY—NJ2血小板聚集仪绘制聚集曲线及计算最大聚集率,分析药物对血小板聚集的影响;全自动血流变快测仪分别测定全血粘度、全血还原粘度、红细胞聚集指数;用文氏管法测红细胞压积,Wintrobe管法测血沉,用SPSS 11.0统计软件进行方差和相关分析。组心肌梗塞梗死面积达到了29.4±3.7%,显微镜下观察发现,病变心肌处出现大量的炎性细胞侵润、充血水肿明显;肌横纹较模糊,线粒体嵴模糊不清。基质淡甚至空泡化,心肌细胞出现明显的凝聚、肿胀、坏死、溶解,亦可观察到大量核浓缩、核变小;核膜皱缩、异形,有伪足样突起;染色质凝集成块,边集等典型的凋亡细胞特征,说明心肌梗死模型建立成功。
2.安心注射液低、中、高剂量治疗后,心肌坏死面积分别下降至25±3.2%、17±3.5%、14±2.9%;与心肌缺血模型组比较差异有显著性;显微形态学观察发现;心肌炎性浸润及心肌细胞坏死明显减轻,提示,安心注射液有较好的缩小梗死心肌面积范围,保护缺血心肌的作用,其中安心注射液高剂量组,效果稍强于硝酸甘油对照组。
3.安心注射液治疗后,家兔标准导联心电图S-T段、T波缺血性改变型程度的程度较模型组均明显减低(P＜0.05)病理性Q波和室性心律失常的百分数均明显下降,(P＜0.05),提示安心注射液能显著改善急性缺血心肌心电图改变,减慢心率、降低心肌耗氧,防治心律失常。
4.安心注射液治疗后缺血心脏心率减慢,平均动脉压(MAP)下降,心输出量(CO)降低,左室收缩压(LVSP),左室舒张末压(LVEDP)升高,心率收缩压乘积(RPP)下降(P＜0.05),说明安心注射液具有改善心肌缺血后心脏的血液动力学,增加心肌供血的作用。
5.安心注射液治疗后肌酸磷酸激酶(CPK)、乳酸脱氢酶(LDH)显著下降(P＜0.05),其中对CPK的作用强于硝酸甘油组,而对LDH的作用稍弱于硝酸甘油组;丙二醛(MDA)显著下降,超氧化物歧化酶(SOD)和一氧化氮(NO)明显升高(P＜0.05);提示安心注射液具有显著的改善缺血心肌的心肌细胞代谢及抗氧化能力的作用。
6.安心注射液治疗后,心肌缺血家兔血栓形成长度明显缩短(P＜0.05),血栓湿重及干重有减轻。安心注射液可以明显地降低心肌缺血家兔二磷酸腺苷(ADP)和胶原诱导的血小板聚集率,对花生四烯酸(AA)诱导的家兔血小板聚集率有降低趋势。还可显著抑制心肌缺血家兔模型的全血粘度、血浆粘度、全血还原粘度,降低血沉和红细胞压积。提示安心注射液的抗心肌缺血作用与其显著改善全身的血液流变学状况有关。
结论安心注射液具有良好的抗心肌缺血作用,其机制可能与其改善心脏的血液动力学指标和缺血心肌的细胞的代谢及抗氧化能力,抑制血小板聚集和改善血液流变学的作用有关。
Object:To discuss the effect and mechanism of anti-myocardial ischemia of Anxin injection,carry out its preclinical Pharmacodynamics studies,and to lay the foundation for development of the new clinical drug with effects of anti-myocardial ischemia and cardiovascular protection.
Method:Rabbit's crown arteries were tied up near the first branch place in the from falling branch of the left coronary artery to establish the mode of myocardial ischemia.The scope of ischemia cardiac muscle was identified with the 0.1%NBT dyeing.Through applying the method of paraffin wax embedding,conventional slice and Iraq red dyes,the micromorphological change of myocardial infarction was observed.The standardⅡ-lead electrocardiogram was detected continuously by the needle electrode inserting under the hypodermis of limbs.The ascending aorta's blood stream was determined by Doppler method.The cardio hemodynamics was monitored through placing the pipe in the femoral artery to detect the HR,MAP,CO,LVSP,LVEDP and RPP.The CK and LDH in the blood are detected by automatic biochemistry analyzer.NO, SOD and MDA were determined by different colorimetric methods.The forming of thrombus in vitro was detected through the Chandler method. The aggregation ratio of platelet was determined under the Born nephelometry.Through using the LBY—NJ2 platelet aggregator,the platelet aggregation curve is drawn and the highest aggregation ratio is calculated,which can be used to analyze the effect of the drug on platelet aggregation.Blood Specific Viscosity,Blood Reduced Viscosity and Aggregation Index of RBC are determined respectively.The packed cellvolume is determined and the ESR is determined by Wintrobe method. The statistic software SPSS 11.0 is used to calculate the variance and analyze related data.
Results:
1.When the rabbit's crown artery was blocked for 60 min.,the infarction area of myocardial ischemia reached 29.4±3.7%in the model group.A mass of inflammation cells near the pathological cardiac muscle and hyperemia and dropsy were obviously observed under the microscope.They were also found that the cross striation and ridge cast of mitochondria come to be blurry,the matrix was light even to be bubbly and the cardiac muscle cells were taken on obvious aggregation, tumefaction,death and dissolution.Additionally,the typical characteristics of apototic cells,which were condensed nucleus,crinkled and abnormal karyotheca and coagulated chromatin,were also observed. All the observations mentioned above proved the successful modeling of myocardial ischemia.
2.After the treatments with the low,medium and high dosage of Anxin injection,the cardiac muscle necrosis area was decreased to 25±3.2%,17±3.5%,14±2.9%,respectively.It was significantly different when compared with the model group.According to Micromorphology,it was observed that the inflammation and necrosis of cardiac muscle cells were markedly reduced,Which showed that the Anxin injection could reduce the cardiac muscle necrosis area and protect the ischemic cardiac muscle.The effect was better in the Anxin injection group with high dosage than that of the parallel group with glonoin.
3.After the treatment with Anxin injection,the degree of the height and inversion of "S-T" phase and "T" phase in the rabbit's standard cardiogram dropped distinctly in contrast with the model group (P＜0.05～0.01),the percent of pathologic "Q" and ventricular arrhythmia declined remarkably(P＜0.05),which showed that the injection can remarkably improve the change of cardiogram of acute myocardial ischemia,slow HR,reduce the oxygen consumption of cardiac muscle and prevent arrhythrnia.
4.After the treatment with Anxin injection,the rhythm of the ischemic heart became slow,and several indexes,such as MAP,CO, LVSP,RPP,were dropped while LVEDP was raised(P＜0.05).It showed that Anxin injection could improve the heart hemodynamics after being myocardial ischemia,and increase the supplementation of blood of cardiac muscle.
5.After the treatment with Anxin injection,CPK and LDH decreased obviously(P＜0.05).And the effect on CPK was better than that of the glonoine group while the effect on LDH was worse than that of the glonoine group.MDA had the marked decreasing and the SOD and NO had increasing(P＜0.05),which is distinctly different from the model group.(P＜0.01).It proved that the injection could improve the metabolism and the ability of anti-oxidization of ischemia cardiac muscle cell.
6.After the treatment with Anxin injection,the length of the rabbit's thrombus was shortened obviously(P＜0.05)and the weight of thrombus was also listened.The Anxin injection can obviously reduce ADP and the ratio of platelet aggregation induced by either collagen or AA.It could also inhibit the Whole Blood Viscosity,Blood Specific Viscosity and Blood Reduced Viscosity of the rabbit in the trials,decrease the ESR and RBC,It showed that the effect of anti-myocardial ischemia of Anxin injection is related to its amelioration to the body's haemorheology.
Conclusion:Anxin injection has good effect on anti-myocardial ischemia.The mechanism of its function might be related to that it can improve the index of the heart's hemodynamics and the metabolism and the anti- oxidization ability of ischemic cardiac muscle cell as well as inhibit the platetet aggregation and improve the hemorheology.
引文
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