山莨菪碱对心脏骤停大鼠复苏及内皮损伤干预的研究
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摘要
目的观察山茛菪碱(anisodamine,Ani)对心脏骤停大鼠复苏时自主循环恢复和复苏成功率的影响,及对心脏骤停大鼠内皮损伤的干预作用。观察Ani对缺氧／复氧损伤内皮细胞的影响,探讨其是否具有对内皮细胞的保护作用及其可能机制,为心肺复苏中应用Ani提供实验及可能的理论依据。
方法本研究共四部分：第一部分和第二部分观察Ani对心脏停搏后自主循环恢复和复苏成功率的影响及Ani对心脏骤停大鼠内皮损伤的干预作用。采用45只SD成年大鼠随机分为3组：对照组、肾上腺素组和肾上腺素合用Ani组。采用经食道心脏起搏诱发心室颤动或心室静止,使用电动机械胸外心脏按压机进行胸外按压,采用盲法给药对比不同组间自主循环恢复及复苏成功率。通过透射电镜观察大鼠心脏骤停后脑和心肌血管内皮细胞超微结构变化,采用放射免疫法测定血清内皮素和TNF-α水平的变化,采用免疫荧光染色法观察心室肌血管内皮Bcl-2蛋白表达的变化。第三部分和第四部分研究Ani对缺氧／复氧损伤内皮细胞凋亡及M受体的影响。实验分五组：对照组、生理盐水组、肾上腺素组、Ani组、肾上腺素合用Ani组。采用人脐静脉内皮细胞缺氧／复氧方法观察内皮细胞凋亡的变化,采用Annexin-V-FITC流式细胞术和TUNEL法检测细胞凋亡,采用放射免疫法测定细胞培养液内皮素和NO水平,采用RT-PCR法检测血管内皮细胞Bcl-2 mRNA和M受体mRNA表达水平。
结果第一部分：肾上腺素合用Ani组自主循环恢复和复苏成功率、3h存活率均高于肾上腺素组。自主循环恢复即刻肾上腺素组平均动脉压高于肾上腺素合用Ani组,自主循环恢复后5 min开始至自主循环恢复后30 min,肾上腺素组明显低于肾上腺素合用Ani组。第二部分：透射电镜观察发现肾上腺素组心肌和脑皮层血管内皮细胞损伤程度较肾上腺素合用Ani组严重。肾上腺素合用Ani组Bcl-2蛋白表达强于肾上腺素组。心肺复苏后血清内皮素和TNF-α水平均较复苏前升高,自主循环恢复5min和60min,肾上腺素合用Ani组内皮素水平较肾上腺素组升高明显,自主循环恢复60min,肾上腺素组TNF-α水平较肾上腺素合用Ani组升高。第三部分,复氧12h后肾上腺素组、肾上腺素合用Ani组及Ani组的凋亡率均较生理盐水组降低,肾上腺素组和Ani组比较未见统计学差异,肾上腺素合用Ani组凋亡率较肾上腺素组降低。复氧12h和24h后肾上腺素组、’肾上腺素合用Ani组、Ani组的Bcl-2 mRNA表达水平较生理盐水组和对照组升高,肾上腺素合用Ani组Bcl-2 mRNA表达水平升高最显著。复氧12h和24h后肾上腺素组、肾上腺素合用Ani组、Ani组的内皮素水平较生理盐水组降低,但均高于对照组,复氧12h肾上腺素合用Ani组内皮素水平较肾上腺素组降低,复氧24h两组比较无统计学差异。复氧12h和24h后肾上腺素组、肾上腺素合用Ani组、Ani组的NO水平较生理盐水组升高,但均低于对照组,复氧12h肾上腺素合用Ani组NO水平较肾上腺素组升高,复氧24h两组比较无统计学差异。第四部分：人脐静脉内皮细胞上有M2受体mRNA表达,未检测到M1和M3受体mRNA表达,复氧12h肾上腺素合用Ani组M2受体mRNA表达增加最显著。
结论心脏骤停复苏使用肾上腺素合用Ani可以提高自主循环恢复和复苏成功率。肾上腺素合用Ani可以减轻心肺复苏对心脏和脑血管内皮细胞超微结构的损害。Ani可以降低缺氧内皮细胞的凋亡。Ani干预缺氧所致血管内皮细胞损害,可能是通过影响M2受体功能实现的。Ani有可能作为临床重要的心肺复苏联合药物。
Objective To evaluate the influence of anisodamine on the return of spontaneous circulation (ROSC) rate and resuscitation rate of cardiac arrest rats and its intervention on endothelia cells'injury so as to explore its possible protective effect and mechanism, which could be an available support for the use of Ani in cardiopulmonary resuscitation (CPR).
Methods PartⅠand partⅡ:forty-five Sprague-Dawley (SD) rats were randomized to three groups:0.9% saline (control group), epinephrine group and epinephrine plus Anisodamine(Ani) group. Cardiac arrest was induced by transoesophageal cardiac pacing. A blinded drug administration and mechanical chest compression were used in the study. Return of spontaneous circulation (ROSC) rate and resuscitation rate were compared between these groups. The pathological changes of endothelia cells of brain neurons and myocardium were observed by electron microscope. Endothelin(ET) and TNF-αwere measured by radioimmunoassay. The expression of Bcl-2 was observed through immunohistochemistry methods. PartⅢand partⅣ: the study was based on human umbilical vein endothelial cell (HUVEC) line 8000.The HUVECs were divided into 5 groups:control group, anoxia/reoxygenation(A/R) 0.9% saline group, A/R epinephrine group, A/R Ani group, A/R epinephrine plus Ani group. The apoptosis of cells in each group were detected by fluorescence flow cytometry and terminal deoxynucleotide mediated nick end labeling (TUNEL). ET and NO were measured by radioimmunoassay and nitrate reduction test respectively. The gene expression of Bcl-2 and M2 receptor were detected by reverse transcription-polymerase chain reaction (RT-PCR).
Results PartⅠand partⅡ:ROSC rate, resuscitation rate and survival rate within 3 hours of epinephrine plus Ani group were higher than those of epinephrine group. Mean blood pressure (MBP) at the beginning of ROSC in epinephrine group was higher compared with epinephrine plus Ani group. Five minutes after ROSC, MBP in epinephrine group decreased qucikly than that in epinephrine plus Ani group, till thirty minutes after ROSC, MBP of epinephrine group was obviously lower than that of epinephrine plus Ani groups. The damage in neurons and myocardium of epinephrine plus Ani group were lighter than epinephrine group under electronmicroscope. In epinephrine plus Ani group, the expression of Bcl-2 was higher than that in epinephrine group. After 5min and 60min of ROSC, the level of ET of epinephrine group was higher than epinephrine group. After 60min of ROSC, the level of TNF-αof epinephrine plus Ani group were lower than epinephrine group. PartⅢand part IV:the apoptosis index(AI) of epinephrine plus Ani group were lower than epinephrine group, but higher than control group. There was no significant expression difference between epinephrine group and Ani group. In epinephrine plus Ani group, the mRNA expression of Bcl-2 was higher than epinephrine group and Ani group. In epinephrine plus Ani group, the level of ET after 12h of A/R was lower than epinephrine group, but no difference after 24h of A/R. In epinephrine plus Ani group, the level of NO after 12h of A/R was higher than epinephrine group, but no difference after 24h of A/R. The mRNA expression of M2 receptor was dectected on the HUVECs. In epinephrine plus Ani group, the mRNA expression of M2 receptor was higher than other groups.
Conclusion Administration of epinephrine plus Ani at the beginning of cardiac arrest could improve ROSC rate and resuscitation rate, and could have protective effect on the injury of endothelia cells. Ani could decrease the apoptosis after A/R. Ani could protect the function of endothelia cells after A/R by effecting M2 receptor. Ani could be an important clinical drug used in CPR combined with ephrinephrine.
方法本研究共四部分：第一部分和第二部分观察Ani对心脏停搏后自主循环恢复和复苏成功率的影响及Ani对心脏骤停大鼠内皮损伤的干预作用。采用45只SD成年大鼠随机分为3组：对照组、肾上腺素组和肾上腺素合用Ani组。采用经食道心脏起搏诱发心室颤动或心室静止,使用电动机械胸外心脏按压机进行胸外按压,采用盲法给药对比不同组间自主循环恢复及复苏成功率。通过透射电镜观察大鼠心脏骤停后脑和心肌血管内皮细胞超微结构变化,采用放射免疫法测定血清内皮素和TNF-α水平的变化,采用免疫荧光染色法观察心室肌血管内皮Bcl-2蛋白表达的变化。第三部分和第四部分研究Ani对缺氧／复氧损伤内皮细胞凋亡及M受体的影响。实验分五组：对照组、生理盐水组、肾上腺素组、Ani组、肾上腺素合用Ani组。采用人脐静脉内皮细胞缺氧／复氧方法观察内皮细胞凋亡的变化,采用Annexin-V-FITC流式细胞术和TUNEL法检测细胞凋亡,采用放射免疫法测定细胞培养液内皮素和NO水平,采用RT-PCR法检测血管内皮细胞Bcl-2 mRNA和M受体mRNA表达水平。
结果第一部分：肾上腺素合用Ani组自主循环恢复和复苏成功率、3h存活率均高于肾上腺素组。自主循环恢复即刻肾上腺素组平均动脉压高于肾上腺素合用Ani组,自主循环恢复后5 min开始至自主循环恢复后30 min,肾上腺素组明显低于肾上腺素合用Ani组。第二部分：透射电镜观察发现肾上腺素组心肌和脑皮层血管内皮细胞损伤程度较肾上腺素合用Ani组严重。肾上腺素合用Ani组Bcl-2蛋白表达强于肾上腺素组。心肺复苏后血清内皮素和TNF-α水平均较复苏前升高,自主循环恢复5min和60min,肾上腺素合用Ani组内皮素水平较肾上腺素组升高明显,自主循环恢复60min,肾上腺素组TNF-α水平较肾上腺素合用Ani组升高。第三部分,复氧12h后肾上腺素组、肾上腺素合用Ani组及Ani组的凋亡率均较生理盐水组降低,肾上腺素组和Ani组比较未见统计学差异,肾上腺素合用Ani组凋亡率较肾上腺素组降低。复氧12h和24h后肾上腺素组、’肾上腺素合用Ani组、Ani组的Bcl-2 mRNA表达水平较生理盐水组和对照组升高,肾上腺素合用Ani组Bcl-2 mRNA表达水平升高最显著。复氧12h和24h后肾上腺素组、肾上腺素合用Ani组、Ani组的内皮素水平较生理盐水组降低,但均高于对照组,复氧12h肾上腺素合用Ani组内皮素水平较肾上腺素组降低,复氧24h两组比较无统计学差异。复氧12h和24h后肾上腺素组、肾上腺素合用Ani组、Ani组的NO水平较生理盐水组升高,但均低于对照组,复氧12h肾上腺素合用Ani组NO水平较肾上腺素组升高,复氧24h两组比较无统计学差异。第四部分：人脐静脉内皮细胞上有M2受体mRNA表达,未检测到M1和M3受体mRNA表达,复氧12h肾上腺素合用Ani组M2受体mRNA表达增加最显著。
结论心脏骤停复苏使用肾上腺素合用Ani可以提高自主循环恢复和复苏成功率。肾上腺素合用Ani可以减轻心肺复苏对心脏和脑血管内皮细胞超微结构的损害。Ani可以降低缺氧内皮细胞的凋亡。Ani干预缺氧所致血管内皮细胞损害,可能是通过影响M2受体功能实现的。Ani有可能作为临床重要的心肺复苏联合药物。
Objective To evaluate the influence of anisodamine on the return of spontaneous circulation (ROSC) rate and resuscitation rate of cardiac arrest rats and its intervention on endothelia cells'injury so as to explore its possible protective effect and mechanism, which could be an available support for the use of Ani in cardiopulmonary resuscitation (CPR).
Methods PartⅠand partⅡ:forty-five Sprague-Dawley (SD) rats were randomized to three groups:0.9% saline (control group), epinephrine group and epinephrine plus Anisodamine(Ani) group. Cardiac arrest was induced by transoesophageal cardiac pacing. A blinded drug administration and mechanical chest compression were used in the study. Return of spontaneous circulation (ROSC) rate and resuscitation rate were compared between these groups. The pathological changes of endothelia cells of brain neurons and myocardium were observed by electron microscope. Endothelin(ET) and TNF-αwere measured by radioimmunoassay. The expression of Bcl-2 was observed through immunohistochemistry methods. PartⅢand partⅣ: the study was based on human umbilical vein endothelial cell (HUVEC) line 8000.The HUVECs were divided into 5 groups:control group, anoxia/reoxygenation(A/R) 0.9% saline group, A/R epinephrine group, A/R Ani group, A/R epinephrine plus Ani group. The apoptosis of cells in each group were detected by fluorescence flow cytometry and terminal deoxynucleotide mediated nick end labeling (TUNEL). ET and NO were measured by radioimmunoassay and nitrate reduction test respectively. The gene expression of Bcl-2 and M2 receptor were detected by reverse transcription-polymerase chain reaction (RT-PCR).
Results PartⅠand partⅡ:ROSC rate, resuscitation rate and survival rate within 3 hours of epinephrine plus Ani group were higher than those of epinephrine group. Mean blood pressure (MBP) at the beginning of ROSC in epinephrine group was higher compared with epinephrine plus Ani group. Five minutes after ROSC, MBP in epinephrine group decreased qucikly than that in epinephrine plus Ani group, till thirty minutes after ROSC, MBP of epinephrine group was obviously lower than that of epinephrine plus Ani groups. The damage in neurons and myocardium of epinephrine plus Ani group were lighter than epinephrine group under electronmicroscope. In epinephrine plus Ani group, the expression of Bcl-2 was higher than that in epinephrine group. After 5min and 60min of ROSC, the level of ET of epinephrine group was higher than epinephrine group. After 60min of ROSC, the level of TNF-αof epinephrine plus Ani group were lower than epinephrine group. PartⅢand part IV:the apoptosis index(AI) of epinephrine plus Ani group were lower than epinephrine group, but higher than control group. There was no significant expression difference between epinephrine group and Ani group. In epinephrine plus Ani group, the mRNA expression of Bcl-2 was higher than epinephrine group and Ani group. In epinephrine plus Ani group, the level of ET after 12h of A/R was lower than epinephrine group, but no difference after 24h of A/R. In epinephrine plus Ani group, the level of NO after 12h of A/R was higher than epinephrine group, but no difference after 24h of A/R. The mRNA expression of M2 receptor was dectected on the HUVECs. In epinephrine plus Ani group, the mRNA expression of M2 receptor was higher than other groups.
Conclusion Administration of epinephrine plus Ani at the beginning of cardiac arrest could improve ROSC rate and resuscitation rate, and could have protective effect on the injury of endothelia cells. Ani could decrease the apoptosis after A/R. Ani could protect the function of endothelia cells after A/R by effecting M2 receptor. Ani could be an important clinical drug used in CPR combined with ephrinephrine.
引文
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