人参皂苷对复苏大鼠线粒体功能的作用及实验模型的选择
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摘要
目的比较3种常用心脏停搏实验模型——电刺激法、氯化钾注射法和窒息法的模拟效果及对机体生化环境与能量代谢的影响；探讨人参皂苷对心脏停搏大鼠自主循环恢复率、复苏后存活情况、能量代谢及线粒体功能等方面的作用。
方法实验共分两个部分。第一部分为模型比较,成年Wistar大鼠共102只,随机分为3组：电刺激组(n=36)、氯化钾组(n=44)和窒息组(n=22),分别采用经食道心脏调搏、经颈静脉注射氯化钾溶液以及阻断通气3种不同方法诱发心脏停搏(CA)；以上每组根据不同时间点各分为复苏前和复苏后2个亚组(总计6个实验组),复苏前组处置的时间点为CA后5min、心肺复苏(CPR)实施前,复苏后组处置的时间点为恢复自主循环(ROSC)后即刻。每组动物从诱发CA出现到开始CPR的间期(非干预间期)统一为5min；CPR措施包括胸外按压、人工通气以及静脉注射肾上腺素(100μg／kg)等。观察各组动物模型的CA发生率、CA的心电图类型、ROSC比率及其前后的生命体征变化(体温、心率、血压等)；检测各组复苏前后血气、电解质、血糖及乳酸等指标的变化；此外,使用高效液相色谱法检测组织磷酸腺苷(AMP、ADP及ATP)的含量并计算能荷(EC)。第二部分为人参皂苷的作用研究。成年Wistar大鼠870只,随机分为5组：①肾上腺素组(n=450)、②肾上腺素加山莨菪碱组(n=110,简称山莨菪碱组)、③肾上腺素加人参皂苷组(n=160,简称人参皂苷组)、④肾上腺素加人参皂苷加山莨菪碱组(n=110,简称联合用药组)和⑤假手术组(n=40),该组不诱发CA,不进行CPR等处理。前4组使用电刺激法诱发CA,非干预间期5min后行CPR(参见第一部分)。以上5组根据ROSC后观察处置的不同时间又分为ROSC即刻、3h、6h、12h和24h共5个亚组。观察记录各组的ROSC率、存活时间、生命体征变化；检测各组不同时间点的ATP值并计算能荷；使用激光共聚焦显微镜及荧光酶标仪检测各组不同时间点的膜电位和活性氧簇(ROS)水平；电镜下观察线粒体形态学变化并进行计数统计。
结果第一部分：窒息组的CA发生率、ROSC率、复苏前乳酸水平和PCO2均显著高于其他2组(p<0.05),而复苏前、后的能荷水平均显著低于其他2组(p<0.05)；氯化钾组复苏前、后的能荷水平及钾离子浓度均显著高于其余2组(p<0.05),而CA发生率显著低于其余2组(p<0.05)；电刺激组和氯化钾组诱发CA的心电图类型表现多样,以室颤和室速为主,而窒息组CA的形式主要为无脉电活动或心电静止。第二部分：人参皂苷组对ROSC率的影响较肾上腺素组无统计学差异(p=0.086)；人参皂苷组、山莨菪碱组和联合用药组均可提高大鼠的存活率(p<0.05),但3者之间无统计学差异(p>0.05)；在对能荷、膜电位及活性氧的影响方面,人参皂苷、山莨菪碱以及二者之间的交互效应均有统计学意义(p<0.05),人参皂苷在ROSC后3h能荷显著高于山莨菪碱组(p<0.05),而在ROSC后即刻～6h之间的膜电位水平则低于山莨菪碱组,与肾上腺素组比较无显著提高(p>0.05)。联合用药组的活性氧水平低于单独用药组。电镜下形态学观察结果：人参皂苷在ROSC后3h线粒体形态即基本恢复正常,并出现功能代偿性增强表现；计数结果人参皂苷组在ROSC后3h线粒体坏死的发生率显著低于肾上腺素组(p<0.05)。
结论1.电刺激法模型对大鼠机体生化环境影响小,CA的心电类型与临床相符,诱发CA的发生率及对机体能量代谢的影响程度介于另2种模型之间,相对较稳定,因此综合效果最佳；2.人参皂苷可显著改善大鼠ROSC后的生存率及机体的能量代谢水平,其原因可能与促进正常线粒体的功能代偿性增强及受损线粒体的结构和功能恢复有关；3.人参皂苷对大鼠ROSC率影响不显著；4.人参皂苷与山莨菪碱联合应用对ROSC早期能荷的增加及线粒体ROS的减低具有一定协同效果,并且可以同时发挥2药各自的优点。
Objective Part 1:To compare the characters of three commonly used rat models of cardiac arrest (CA) which were induced by electric stimulation, KC1 and asphyxia respectively. Their influence on organismal environment and energy metabolism was also studied. Part 2:To investigate the effect of Ginsenoside on structural and functional changes of mitochondrion as well as survival rate and energy metabolism of the organism after Return of Spontaneous Circulation (ROSC) in the rat model of Electric Stimulation induced CA.
Methods Part 1:102 male Wstera rats were randomly devided into 3 groups:1) Electric Stimulation group (n=36):CA was induced by alternating current via pacing electrode placed in esophagus.2) KC1 group (n=44):CA was induced by KC1 injected intravenously.3) Asphyxia group (n=22):CA was induced by clamping the tracheal tube. Each of the upper groups was devided into 2 subgroups respectively according to the intervention time -- 1) 5min after CA but no resuscitation (CA5),2) right after ROSC (R0). After 5-min-interval of CA, chest compression (about 200/min) was begun together with epinephrine (100μg/kg) and artificial ventilation in the R0 subgroup. For each model, the CA incidence (CAI), the electrocardiographic manifestation of CA and the ROSC ratio were recorded. The vital sign, blood gas, serum electrolyte, Glucose and Lactic Acid (LA) value were measured. Meanwheal, the AMP, ADP and ATP content of myocardium were detected by high-performance liquid chromatography (HPLC), and then energy charge (EC) was calculated. Part 2:Another 870 male Wstera rats were randomly devided into 5 groups according to the drugs administered during cardiopulmonary resuscitation (CPR):1) epinephrine (E) group (n=450), epinephrine(100μg/kg) was injected; 2) anisodamine (A) group (n=110), anisodamine (10mg/kg) and epinephrine(100μg/kg) was injected; 3) ginsenoside (G) group (n=160), ginsenoside rgl (20mg/kg) and epinephrine(100μg/kg) was injected; 4) combination (C) group (n=110), ginsenoside rgl (20mg/kg) and anisodamine (10mg/kg) and epinephrine (100μg/kg) was injected; 5) Sham group (n=40). All animals in the fomer 4 groups got CA induced by electric stimulation and experienced CPR operation as described in Part 1. Those in Sham group were performed sham operation. Animals in each of the upper groups were devided into 5 subgroups respectively according to the survival time after ROSC (Oh,3h,6h,12h and 24h subgroup). For each group, the ROSC ratio and survival time were recorded, the EC of myocardium was detected. Heart mitochondria were harvested to measure the Membrane Potential (MP) and Reactive Oxygen Species (ROS) by Laser Scanning Confocal Fluorescence Microscope and Fluorescence Microplate Reader. Morphology changes of heart tissue was observed through electronmicroscope.
Results Part 1:The Asphyxia group had a higher CAI, ROSC ratio, LA level and PCO2, whereas a lower EC level compared with the other two groups (p<0.05). The KC1 group had a higher EC and potassium level, whereas a lower CAI (p<0.05). Both Electric Stimulation and KC1 group can induce multiple arrhythmia, predominantly ventricular fibrillation and ventricular tachycardia. However, Asphyxia group can just induce pulseless electrical activity or electrical asystole. Part 2:G, A and C group had a higher survival ratio compared with E group (p<0.05), but there were no significant defference among the former 3 groups (p>0.05). As for EC, MP and ROS, the main effect of ginsenoside and anisodamine and their interaction were all significant (p<0.05). ROS level in C group was lower than G and A group. the EC of G3h subgroup was higher than A3h subgroup, whereas the MP of G0h-G6h subgroups were lower than A0h-A6h subgroupos respectively (p<0.05). Electronmicroscope showed the impaired mitochondrion recovered 3 hours after ROSC with functional enhancement appearance.
Conclusion 1. Electric Stimulation method can induce a condition of CA similar to Clinical pathophysiology with slight influence on organismal environment. Its CAI and influence on EC were intermediate between KC1 and Asphyxia group. So the method was more suitable for our experiment. 2. Ginsenoside rgl can improve the survial and energy metabolism of the asystole rats after ROSC, which attributed to its promoting functional compensation of nomal mitochondria and improving the structure and function of the impired mitochondria. 3. Ginsenoside didn't increase the ROSC ritio. 4. Combinated with anisodamine help to decrease the production of ROS.
方法实验共分两个部分。第一部分为模型比较,成年Wistar大鼠共102只,随机分为3组：电刺激组(n=36)、氯化钾组(n=44)和窒息组(n=22),分别采用经食道心脏调搏、经颈静脉注射氯化钾溶液以及阻断通气3种不同方法诱发心脏停搏(CA)；以上每组根据不同时间点各分为复苏前和复苏后2个亚组(总计6个实验组),复苏前组处置的时间点为CA后5min、心肺复苏(CPR)实施前,复苏后组处置的时间点为恢复自主循环(ROSC)后即刻。每组动物从诱发CA出现到开始CPR的间期(非干预间期)统一为5min；CPR措施包括胸外按压、人工通气以及静脉注射肾上腺素(100μg／kg)等。观察各组动物模型的CA发生率、CA的心电图类型、ROSC比率及其前后的生命体征变化(体温、心率、血压等)；检测各组复苏前后血气、电解质、血糖及乳酸等指标的变化；此外,使用高效液相色谱法检测组织磷酸腺苷(AMP、ADP及ATP)的含量并计算能荷(EC)。第二部分为人参皂苷的作用研究。成年Wistar大鼠870只,随机分为5组：①肾上腺素组(n=450)、②肾上腺素加山莨菪碱组(n=110,简称山莨菪碱组)、③肾上腺素加人参皂苷组(n=160,简称人参皂苷组)、④肾上腺素加人参皂苷加山莨菪碱组(n=110,简称联合用药组)和⑤假手术组(n=40),该组不诱发CA,不进行CPR等处理。前4组使用电刺激法诱发CA,非干预间期5min后行CPR(参见第一部分)。以上5组根据ROSC后观察处置的不同时间又分为ROSC即刻、3h、6h、12h和24h共5个亚组。观察记录各组的ROSC率、存活时间、生命体征变化；检测各组不同时间点的ATP值并计算能荷；使用激光共聚焦显微镜及荧光酶标仪检测各组不同时间点的膜电位和活性氧簇(ROS)水平；电镜下观察线粒体形态学变化并进行计数统计。
结果第一部分：窒息组的CA发生率、ROSC率、复苏前乳酸水平和PCO2均显著高于其他2组(p<0.05),而复苏前、后的能荷水平均显著低于其他2组(p<0.05)；氯化钾组复苏前、后的能荷水平及钾离子浓度均显著高于其余2组(p<0.05),而CA发生率显著低于其余2组(p<0.05)；电刺激组和氯化钾组诱发CA的心电图类型表现多样,以室颤和室速为主,而窒息组CA的形式主要为无脉电活动或心电静止。第二部分：人参皂苷组对ROSC率的影响较肾上腺素组无统计学差异(p=0.086)；人参皂苷组、山莨菪碱组和联合用药组均可提高大鼠的存活率(p<0.05),但3者之间无统计学差异(p>0.05)；在对能荷、膜电位及活性氧的影响方面,人参皂苷、山莨菪碱以及二者之间的交互效应均有统计学意义(p<0.05),人参皂苷在ROSC后3h能荷显著高于山莨菪碱组(p<0.05),而在ROSC后即刻～6h之间的膜电位水平则低于山莨菪碱组,与肾上腺素组比较无显著提高(p>0.05)。联合用药组的活性氧水平低于单独用药组。电镜下形态学观察结果：人参皂苷在ROSC后3h线粒体形态即基本恢复正常,并出现功能代偿性增强表现；计数结果人参皂苷组在ROSC后3h线粒体坏死的发生率显著低于肾上腺素组(p<0.05)。
结论1.电刺激法模型对大鼠机体生化环境影响小,CA的心电类型与临床相符,诱发CA的发生率及对机体能量代谢的影响程度介于另2种模型之间,相对较稳定,因此综合效果最佳；2.人参皂苷可显著改善大鼠ROSC后的生存率及机体的能量代谢水平,其原因可能与促进正常线粒体的功能代偿性增强及受损线粒体的结构和功能恢复有关；3.人参皂苷对大鼠ROSC率影响不显著；4.人参皂苷与山莨菪碱联合应用对ROSC早期能荷的增加及线粒体ROS的减低具有一定协同效果,并且可以同时发挥2药各自的优点。
Objective Part 1:To compare the characters of three commonly used rat models of cardiac arrest (CA) which were induced by electric stimulation, KC1 and asphyxia respectively. Their influence on organismal environment and energy metabolism was also studied. Part 2:To investigate the effect of Ginsenoside on structural and functional changes of mitochondrion as well as survival rate and energy metabolism of the organism after Return of Spontaneous Circulation (ROSC) in the rat model of Electric Stimulation induced CA.
Methods Part 1:102 male Wstera rats were randomly devided into 3 groups:1) Electric Stimulation group (n=36):CA was induced by alternating current via pacing electrode placed in esophagus.2) KC1 group (n=44):CA was induced by KC1 injected intravenously.3) Asphyxia group (n=22):CA was induced by clamping the tracheal tube. Each of the upper groups was devided into 2 subgroups respectively according to the intervention time -- 1) 5min after CA but no resuscitation (CA5),2) right after ROSC (R0). After 5-min-interval of CA, chest compression (about 200/min) was begun together with epinephrine (100μg/kg) and artificial ventilation in the R0 subgroup. For each model, the CA incidence (CAI), the electrocardiographic manifestation of CA and the ROSC ratio were recorded. The vital sign, blood gas, serum electrolyte, Glucose and Lactic Acid (LA) value were measured. Meanwheal, the AMP, ADP and ATP content of myocardium were detected by high-performance liquid chromatography (HPLC), and then energy charge (EC) was calculated. Part 2:Another 870 male Wstera rats were randomly devided into 5 groups according to the drugs administered during cardiopulmonary resuscitation (CPR):1) epinephrine (E) group (n=450), epinephrine(100μg/kg) was injected; 2) anisodamine (A) group (n=110), anisodamine (10mg/kg) and epinephrine(100μg/kg) was injected; 3) ginsenoside (G) group (n=160), ginsenoside rgl (20mg/kg) and epinephrine(100μg/kg) was injected; 4) combination (C) group (n=110), ginsenoside rgl (20mg/kg) and anisodamine (10mg/kg) and epinephrine (100μg/kg) was injected; 5) Sham group (n=40). All animals in the fomer 4 groups got CA induced by electric stimulation and experienced CPR operation as described in Part 1. Those in Sham group were performed sham operation. Animals in each of the upper groups were devided into 5 subgroups respectively according to the survival time after ROSC (Oh,3h,6h,12h and 24h subgroup). For each group, the ROSC ratio and survival time were recorded, the EC of myocardium was detected. Heart mitochondria were harvested to measure the Membrane Potential (MP) and Reactive Oxygen Species (ROS) by Laser Scanning Confocal Fluorescence Microscope and Fluorescence Microplate Reader. Morphology changes of heart tissue was observed through electronmicroscope.
Results Part 1:The Asphyxia group had a higher CAI, ROSC ratio, LA level and PCO2, whereas a lower EC level compared with the other two groups (p<0.05). The KC1 group had a higher EC and potassium level, whereas a lower CAI (p<0.05). Both Electric Stimulation and KC1 group can induce multiple arrhythmia, predominantly ventricular fibrillation and ventricular tachycardia. However, Asphyxia group can just induce pulseless electrical activity or electrical asystole. Part 2:G, A and C group had a higher survival ratio compared with E group (p<0.05), but there were no significant defference among the former 3 groups (p>0.05). As for EC, MP and ROS, the main effect of ginsenoside and anisodamine and their interaction were all significant (p<0.05). ROS level in C group was lower than G and A group. the EC of G3h subgroup was higher than A3h subgroup, whereas the MP of G0h-G6h subgroups were lower than A0h-A6h subgroupos respectively (p<0.05). Electronmicroscope showed the impaired mitochondrion recovered 3 hours after ROSC with functional enhancement appearance.
Conclusion 1. Electric Stimulation method can induce a condition of CA similar to Clinical pathophysiology with slight influence on organismal environment. Its CAI and influence on EC were intermediate between KC1 and Asphyxia group. So the method was more suitable for our experiment. 2. Ginsenoside rgl can improve the survial and energy metabolism of the asystole rats after ROSC, which attributed to its promoting functional compensation of nomal mitochondria and improving the structure and function of the impired mitochondria. 3. Ginsenoside didn't increase the ROSC ritio. 4. Combinated with anisodamine help to decrease the production of ROS.
引文
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