山莨菪碱对心脏骤停猪心肌超微结构损伤及细胞间信号传导的保护作用
|
摘要
目的
通过氧自由基代谢、线粒体途径和内质网途径心肌细胞凋亡的研究,观察山莨菪碱对心脏骤停(CA)和复苏后心肌超微结构损伤的保护作用；并观测山莨菪碱对复苏后心肌细胞间信号传导结构和功能的影响。
方法
1.健康家猪23只随机分为对照组(n=5)、肾上腺素组(n=9)和山莨菪碱组(n=9)。电刺激法建立心脏骤停模型,室颤9min后心肺复苏,山莨菪碱组为复苏过程中联合应用山莨菪碱。计算并比较两组心脏骤停猪的心肺复苏(CPR)时间及ROSC成功率。
2.在基础时点、CA8min、自主循环恢复(ROSC)即刻、ROSC30min和ROSC24h留取血液标本,ROSC24h处死动物留取心肌组织标本。分光光度法检测超氧化物歧化酶(SOD)活力、丙二醛(MDA)含量；ELISA氵去测定细胞色素C及Caspase-3蛋白含量。
3.透射电镜下观察心肌组织超微结构；Hoechest33258染色测定心肌细胞凋亡率；RT-PCR和Western Blot方法测定心肌Caspase-12、氨基末端激酶(JNK)和calpain mRNA含量和蛋白表达量。
4.免疫荧光染色法测定心肌组织Cx43表达水平和分布；RT-PCR和Western Blot方法测定心肌组织总Cx43、Calpain mRNA含量和蛋白表达量,并测定总Cx43中p-Cx43的蛋白表达量。
结果
1.山莨菪碱组ROSC成功率77.78%较肾上腺素组55.56%提高22.22%,山莨菪碱组CPR时间较肾上腺素组缩短近100s,但差异无统计学意义(P>0.05)。
2.①山莨菪碱组心肌SOD活力明显高于肾上腺素组(P<0.01)。②山莨菪碱组ROSC30min、ROSC24h血浆MDA含量较肾上腺素组减少(P<0.05)。③山莨菪碱组ROSC30min、ROSC24h血浆CytoC蛋白含量较肾上腺素组减少(P<0.05)。④两复苏组血浆各时点及心肌Caspase-3蛋白含量均无显著差异(P>0.05)
3.肾上腺素组心肌细胞内线粒体、内质网和细胞核损伤严重。山莨菪碱组细胞超微结构损伤较肾上腺素组明显减轻,细胞器和细胞核形态基本正常。山莨菪碱负调控caspase-12,JNK和Calpain mRNA含量及蛋白表达量。
4.山莨菪碱组心肌纤维排列较规整,Cx43荧光信号高于肾上腺素组(P<0.05)；山莨菪碱组Calpain mRNA含量和蛋白表达量均低于肾上腺素组(P<0.05)；两复苏组Cx43mRNA含量和蛋白表达量无统计学差异；山莨菪碱组p-Cx43蛋白表达量高于肾上腺素组(P<0.01),接近于对照组(P>0.05)。各组组间p-Cx43/Cx43无显著差异(P>0.05)。
结论
1.经右心室电刺激法是建立心室纤颤心脏骤停模型的有效方法；室颤9min后进行复苏,山莨菪碱可以缩短复苏时间近100s,可以提高复苏成功率22.22%。
2.山莨菪碱可以改善心脏骤停复苏后氧自由基代谢紊乱,并通过抑制线粒体途径和内质网途径的心肌细胞凋亡,减轻复苏后心肌超微结构损伤程度。
3.山莨菪碱通过上调总Cx43中p-Cx43的表达量,保护心脏骤停复苏后心肌细胞间信号传导结构及功能。
Objective Through the research on the oxygen radicals, mitochondria-induced andendoplasmic reticulum-induced cell apoptosis, observe the protection ofanisodamine on myocardial ultrastructure damage induced by ischemia reperfusioninjury (IRI) in post cardiac arrest(CA) resuscitation swine. And study the effect ofanisodamine on the myocardium intercellular signal transmittion.
Methods1. After9min of electrically-induced CA, swine receivedcardiopulmonary resuscitation(CPR), and were randomly divided into groups withanisodamine administration (Ani+CA/R group, n=9)) and without anisodamineadministration (CA/R group, n=9). Restoration of spontaneous circulation(ROSC)rates and CPR time were calculated in each resuscitation group.2. The blood samplewere took at basic time, CA8min, ROSC, ROSC30min, ROSC24h, and heartswere harvested at24h after ROSC. The specimens were observed to assess theprotein changes of Cytochrome C and Caspase-3, and the enzyme activity ofsuperoxide dismutase(SOD), the content of malondialdehyde(MDA) were analyzedby chemical approach.3. The myocardial specimens were observed by transmissionelectron microscopy for ultrastructures, stained with Hoechst33258to assessapoptosis, by RT-PCR for mRNA level and western blotting for protein expressionof caspase-12, JNK, and calpain.4. The retrieved tissues were analyzed byimmunofluorescence for Cx43expression and distribution, by RT-PCR for themRNA level of Cx43and Calpain, and by western blotting to determine the levels ofp-Cx43, Cx43, and Calpain.
Results1. The ventricular fibrillation was successful approached for all animals.The ROSC rate of Ani+CA/R group are higher than CA/R group,and a shorter CPRtime than CA/R group, with no statistic difference between two CPR group.2.① The myocardium SOD activity of Ani+CA/R group was higher than CA/R group（p<0.01）.②The MDA level of Ani+CA/R group was lower than CA/R group inROSC30min, ROSC24h(p<0.05）.③The level of blood Cyto C at ROSC30minand ROSC24h of Ani+CA/R group were lower than CA/R group（p<0.05）.④Thedifference between two CPR groups both in blood and myocardium Caspase-3levelhave no statistic meaning（p>0.05）.3. The CA/R group showed a more irregulararrangement of cardiomyocytes, seriously damaged sarcoplasmic reticula andmitochondria. Anisodamine decreased cardiomyocyte apoptosis, anddown-regulated mRNA levels, protein expression of the ER related caspase-12, JNKand calpain cell apoptotic pathways.4. The Ani+CA/R group showed betterarrangement of cardiomyocytes, sarcomeres and intercalated discs with higherfluorescence intensity for Cx43than the CA/R group(p<0.05).. Compared withCA/R group, the mRNA level and protein expression of Calpain in Ani+CA/R groupwere less (p<0.05), and the p-Cx43level was higher(p<0.01), is nearly to the levelof control group. However, the three groups had similar p-Cx/43/Cx43ratios.
Conclusions1. Anisodamine can’t increase the ROSC ratio for electrically-induced9minutes CA. However, with anisodamine administration during CPR, the CPRtime was shorter100s than CA/R group, and ROSC ratio was increased by22.22%.2. Anisodamine can ameliorate the metabolic disorder of oxygen radicals after CAand CPR, and protects against cardiac IRI through modulation ofmitochrome-induced and endoplasmic reticulum-induced myocardium cell apoptoticsignaling pathways.3. Anisodamine protects myocardium conduction structure andfunction through up-regulation the ratio of p-Cx43/Cx43.
通过氧自由基代谢、线粒体途径和内质网途径心肌细胞凋亡的研究,观察山莨菪碱对心脏骤停(CA)和复苏后心肌超微结构损伤的保护作用；并观测山莨菪碱对复苏后心肌细胞间信号传导结构和功能的影响。
方法
1.健康家猪23只随机分为对照组(n=5)、肾上腺素组(n=9)和山莨菪碱组(n=9)。电刺激法建立心脏骤停模型,室颤9min后心肺复苏,山莨菪碱组为复苏过程中联合应用山莨菪碱。计算并比较两组心脏骤停猪的心肺复苏(CPR)时间及ROSC成功率。
2.在基础时点、CA8min、自主循环恢复(ROSC)即刻、ROSC30min和ROSC24h留取血液标本,ROSC24h处死动物留取心肌组织标本。分光光度法检测超氧化物歧化酶(SOD)活力、丙二醛(MDA)含量；ELISA氵去测定细胞色素C及Caspase-3蛋白含量。
3.透射电镜下观察心肌组织超微结构；Hoechest33258染色测定心肌细胞凋亡率；RT-PCR和Western Blot方法测定心肌Caspase-12、氨基末端激酶(JNK)和calpain mRNA含量和蛋白表达量。
4.免疫荧光染色法测定心肌组织Cx43表达水平和分布；RT-PCR和Western Blot方法测定心肌组织总Cx43、Calpain mRNA含量和蛋白表达量,并测定总Cx43中p-Cx43的蛋白表达量。
结果
1.山莨菪碱组ROSC成功率77.78%较肾上腺素组55.56%提高22.22%,山莨菪碱组CPR时间较肾上腺素组缩短近100s,但差异无统计学意义(P>0.05)。
2.①山莨菪碱组心肌SOD活力明显高于肾上腺素组(P<0.01)。②山莨菪碱组ROSC30min、ROSC24h血浆MDA含量较肾上腺素组减少(P<0.05)。③山莨菪碱组ROSC30min、ROSC24h血浆CytoC蛋白含量较肾上腺素组减少(P<0.05)。④两复苏组血浆各时点及心肌Caspase-3蛋白含量均无显著差异(P>0.05)
3.肾上腺素组心肌细胞内线粒体、内质网和细胞核损伤严重。山莨菪碱组细胞超微结构损伤较肾上腺素组明显减轻,细胞器和细胞核形态基本正常。山莨菪碱负调控caspase-12,JNK和Calpain mRNA含量及蛋白表达量。
4.山莨菪碱组心肌纤维排列较规整,Cx43荧光信号高于肾上腺素组(P<0.05)；山莨菪碱组Calpain mRNA含量和蛋白表达量均低于肾上腺素组(P<0.05)；两复苏组Cx43mRNA含量和蛋白表达量无统计学差异；山莨菪碱组p-Cx43蛋白表达量高于肾上腺素组(P<0.01),接近于对照组(P>0.05)。各组组间p-Cx43/Cx43无显著差异(P>0.05)。
结论
1.经右心室电刺激法是建立心室纤颤心脏骤停模型的有效方法；室颤9min后进行复苏,山莨菪碱可以缩短复苏时间近100s,可以提高复苏成功率22.22%。
2.山莨菪碱可以改善心脏骤停复苏后氧自由基代谢紊乱,并通过抑制线粒体途径和内质网途径的心肌细胞凋亡,减轻复苏后心肌超微结构损伤程度。
3.山莨菪碱通过上调总Cx43中p-Cx43的表达量,保护心脏骤停复苏后心肌细胞间信号传导结构及功能。
Objective Through the research on the oxygen radicals, mitochondria-induced andendoplasmic reticulum-induced cell apoptosis, observe the protection ofanisodamine on myocardial ultrastructure damage induced by ischemia reperfusioninjury (IRI) in post cardiac arrest(CA) resuscitation swine. And study the effect ofanisodamine on the myocardium intercellular signal transmittion.
Methods1. After9min of electrically-induced CA, swine receivedcardiopulmonary resuscitation(CPR), and were randomly divided into groups withanisodamine administration (Ani+CA/R group, n=9)) and without anisodamineadministration (CA/R group, n=9). Restoration of spontaneous circulation(ROSC)rates and CPR time were calculated in each resuscitation group.2. The blood samplewere took at basic time, CA8min, ROSC, ROSC30min, ROSC24h, and heartswere harvested at24h after ROSC. The specimens were observed to assess theprotein changes of Cytochrome C and Caspase-3, and the enzyme activity ofsuperoxide dismutase(SOD), the content of malondialdehyde(MDA) were analyzedby chemical approach.3. The myocardial specimens were observed by transmissionelectron microscopy for ultrastructures, stained with Hoechst33258to assessapoptosis, by RT-PCR for mRNA level and western blotting for protein expressionof caspase-12, JNK, and calpain.4. The retrieved tissues were analyzed byimmunofluorescence for Cx43expression and distribution, by RT-PCR for themRNA level of Cx43and Calpain, and by western blotting to determine the levels ofp-Cx43, Cx43, and Calpain.
Results1. The ventricular fibrillation was successful approached for all animals.The ROSC rate of Ani+CA/R group are higher than CA/R group,and a shorter CPRtime than CA/R group, with no statistic difference between two CPR group.2.① The myocardium SOD activity of Ani+CA/R group was higher than CA/R group（p<0.01）.②The MDA level of Ani+CA/R group was lower than CA/R group inROSC30min, ROSC24h(p<0.05）.③The level of blood Cyto C at ROSC30minand ROSC24h of Ani+CA/R group were lower than CA/R group（p<0.05）.④Thedifference between two CPR groups both in blood and myocardium Caspase-3levelhave no statistic meaning（p>0.05）.3. The CA/R group showed a more irregulararrangement of cardiomyocytes, seriously damaged sarcoplasmic reticula andmitochondria. Anisodamine decreased cardiomyocyte apoptosis, anddown-regulated mRNA levels, protein expression of the ER related caspase-12, JNKand calpain cell apoptotic pathways.4. The Ani+CA/R group showed betterarrangement of cardiomyocytes, sarcomeres and intercalated discs with higherfluorescence intensity for Cx43than the CA/R group(p<0.05).. Compared withCA/R group, the mRNA level and protein expression of Calpain in Ani+CA/R groupwere less (p<0.05), and the p-Cx43level was higher(p<0.01), is nearly to the levelof control group. However, the three groups had similar p-Cx/43/Cx43ratios.
Conclusions1. Anisodamine can’t increase the ROSC ratio for electrically-induced9minutes CA. However, with anisodamine administration during CPR, the CPRtime was shorter100s than CA/R group, and ROSC ratio was increased by22.22%.2. Anisodamine can ameliorate the metabolic disorder of oxygen radicals after CAand CPR, and protects against cardiac IRI through modulation ofmitochrome-induced and endoplasmic reticulum-induced myocardium cell apoptoticsignaling pathways.3. Anisodamine protects myocardium conduction structure andfunction through up-regulation the ratio of p-Cx43/Cx43.
引文
[1] Safar P, Escarraga LA, Elam JO. A comparison of the mouth-to-mouth and mouth-to-airwaymethods of artificial respiration with the chest-pressure arm-life methods. N Eng J Med,1958,258:671-677.
[2] Kouwenhoven W, Jude JR, Knickerbocker GG·Closed chest cardiac massage.1960,173:1064-1067.
[3] Nolan JP, Laver SR, Welch CA, et al. Outcome following admission to UK intensive careunits after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database.Anaesthesia.2007,62:1207–1216.
[4] Field JM, Hazinski MF, Sayre MR,et al.2010American Heart Association Guidelines forCardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation.2010,122：S640-S656.
[5] Garza AG, Gratton MC, Salomone JA, et al. Improved patient survival using a modifiedresuscitation protocol for out-of-hospital cardiac arrest. Circulation.2009,119(19):2597-605.
[6] European Epinephrine Study Group. A comparison of repeated high doses and repeatedstandard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med.1998,339(22):1595-1601.
[7] Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival amongpatients with out-of-hospital cardiac arrest. JAMA.2012,307(11):1161-8.
[8] Robert W, Neumar, Jerry P, et al. Post–Cardiac Arrest Syndrome Epidemiology,Pathophysiology, Treatment, and Prognostication. Circ,2008,118:2452-2483.
[9] Weisfeldt M, Becker LB. Resuscitation after cardiac arrest: a3-phase time-sensitive model.JAMA.2002,288:3035-3038.
[10] Xie JX, Zhou J, Zhang CZ, et al. Synthesis of anisodamine analogs. Acta Pharma Sin.1981,16(10):767-772.
[11] Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med J (Engl).1992,105(12):976-979.
[12]俞长兴,肖蓬,苏志红,等.山莨菪碱类药物临床应用评价.中国医院用药评价与分析.2002,2(4):208-210.
[13] JIA Lijing, SHEN Hong. The Application of Cytospaz in Cardiopulmonary-cerebralResuscitation. Chinese General Practice.2007,10(8):644-645.
[14] MENG Fanshan, SUN Jing, CHEN Wei, et al. A model of cardiac arrest andcardiopulmonary resuscitation in rats. Academic journal of PLA postgraduate medical school.2009,30(6):875-877.
[15]贾立静，陈威，沈洪,等.山莨菪碱对心脏停搏大鼠复苏中微循环的影响.中国危重病急救医学.2008,20(12):737-739.
[16]孙菁,沈洪.山莨菪碱对心脏骤停大鼠复苏及内皮损伤干预的研究.军医进修学院,博士论文,2009.
[17]孟凡山,沈洪.山莨菪碱对心脏骤停大鼠及缺氧/复氧心肌细胞影响的研究.军医进修学院,博士论文,2009.
[18]杨扬,沈洪.山莨菪碱对心脏复苏大鼠线粒体功能保护作用的研究.军医进修学院,博士论文,2010.
[19]张维,指导老师沈洪.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.军医进修学院,博士论文,2010.
[20] Xue LY, Hong Sh, Wei ZH, et al. Increasing expression of (CCAAT enhancer bindingprotein) homologous protein induced by endoplasmic reticulum stress in myocardium aftercardiac arrest and resuscitation in rat. Resuscitation.2011,8:48861-8.
[21] Xue LY, Hong Sh, Wei ZH, et al. Inhibition of Endoplasm Reticulum Stress byAnisodamine Protects against Myocardial Injury after Cardiac Arrest and Resuscitation in Rats.The American J of Chinese Medicine.2011,39:1-14.
[1]杨扬,指导老师沈洪.山莨菪碱对心脏复苏大鼠线粒体功能保护作用的研究.军医进修学院,博士论文,2010.
[2] Lurie KG, Zielinski T, McKnite S, et al.Use of an Inspiratory Impedance Valve ImprovesNeurologically Intact Survival in a Porcine Model of Ventricular Fibrillation. Circulation2002,105:124-129
[3]高维谊,盛志勇,郭振荣,等.烧伤早期山莨菪碱对胃肠保护作用的实验研究.解放军医学杂志.1995,20(2):88-91.
[4] Zhou M, Ran Q, Liu Y, et al. Effects of sustained abdominal aorta compression on coronaryperfusion pressures and restoration of spontaneous circulation during cardiopulmonaryresuscitation in swine. Resuscitation.2011,82:1087-91.
[5] Giuseppe Ristagno, Wanchun Tang, Lei Huang. Epinephrine reduces cerebral perfusionduring cardiopulmonary resuscitation. Crit Care Med.2009,(37):1408-1415.
[6] Henry R. Halperin MA, Kichang Lee. Outcomes from low versus high-flowcardiopulmonary resuscitation in a swine model of cardiac arrest. American Journal ofEmergency Medicine.2010,(28):195-202.
[7]涂建锋,蒋国平,江观玉.心脏骤停动物模型的动物和实验方法选择.中国病理生理杂志.2006,22(4):830-832.
[8] Weisfeldt M, Becker LB. Resuscitation after cardiac arrest: a3-phase time-sensitive model.JAMA.2002,288:3035-3038.
[9] Xie JX, Zhou J, Zhang CZ, et al. Synthesis of anisodamine analogs. Acta Pharma Sin.1981,16(10):767-772.
[10] Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med J(Engl).1992,105(12):976-979.
[11]俞长兴，肖蓬，苏志红，等.山莨菪碱类药物临床应用评价.中国医院用药评价与分析.2002,2(4):208-210.
[12] Jia Lijing, SHEN Hong. The Application of Cytospaz in Cardiopulmonary-cerebralResuscitation. Chinese General Practice.2007,10(8):644-645.
[1] Misra MK，Sarwat M，Bhakuni P，et al.Oxidative stress and ischemic myocardial syndromes.Med Sci Monit.2009,15(10):209-19.
[2] Griending KK, Alexander RW.Oxidative stress and cardiovascular disease. Circulation.1997,96:3264-3265.
[3]林珮仪,江慧琳,张弋,等.犬心肺复苏后心肌细胞凋亡和氧自由基的变化.岭南心血管病杂志.2005,11(3):205.
[4]杨扬,指导老师沈洪.山莨菪碱对心脏复苏大鼠线粒体功能保护作用的研究.军医进修学院,博士论文,2010.
[5] Beckman JS, Beckman TW, Chen J,et al. Apparenthydroxyl radical production byperoxynitrite. ProcNatl Acad Sci.1990,87(9):1620-1624.
[6] Han F, Da T, Riobo NA, et al. Early mitochondrial dysfunction in electron transfer activityand reactive oxygen species generation after cardiac arrest. Critical Care Medicine.2008,36(11)Suppl: S447-S453.
[7] Cain K, Bratton SB, Langlais C, et al. Apaf-1oligomerizes intobiologically active700kDand inactive1.4-kDa apoptosome complexes. J Biol Chem.2000,275(9):6067-6070.
[8] Kim JS，Jin Y，Lemasters JJ. Reactive oxygen species，but not Ca2+overloading，triggerpH-and mitochondrial permeability transition-dependent death of adult rat myocytes afterischemia-reperfusion. Am J Physiol Heart Circ Physiol.2006,290: H2024-H2034．
[9] Robert W Neumar, Jerry P Nolan, Christophe Adrie, et al. Post–Cardiac Arrest SyndromeEpidemiology, Pathophysiology, Treatment, and Prognostication. Circ.2008,118:2452-2483.
[10]林珮仪,江慧琳,张弋,等.犬心肺复苏后心肌细胞凋亡和氧自由基的变化.岭南心血管病杂志.2005,11(3):205.
[11]陈媛,周梅.自由基医学基础与病理生理学.2002,第一版:35-36.
[12]贾立静，陈威，沈洪,等.山莨菪碱对心脏停搏大鼠复苏中微循环的影响.中国危重病急救医学.2008,20(12):737-739。
[13]孙菁,指导老师沈洪.山莨菪碱对心脏骤停大鼠复苏及内皮损伤干预的研究.军医进修学院,博士论文,2009.
[14]孟凡山,指导老师沈洪.山莨菪碱对心脏骤停大鼠及缺氧/复氧心肌细胞影响的研究.军医进修学院,博士论文,2009.
[15] Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol.2000,190(3):255-266.
[16] Adrain C, Martin SJ. The mitochondrial apoptosome:a killer unleashed by the cytochromeseas.Trends Biochem Sci.2001,26(6):390-7.
[17] Suleiman MS, Halestrap AP, Griffiths EJ. Mitochondria:a target for myocardialprotection.Pharmacol Ther.2001,89(1):29-46.
[18] Regula KM, Ens K, Kirshenbaum LA. Mitochondria-assisted cell suicide:a license to kill. JMol Cell Cardiol.2003,35(6):559-67.
[19] Golstein P.Controlling cell death. Science.1997,275(5303):1081-1082.
[20] Glembotski CC. The role of the unfolded protein response in the heart. J Mol Cell Cardiol.2008,44:453-459.
[21] Xue LY, Hong Sh, Wei ZH, et al. Inhibition of Endoplasm Reticulum Stress byAnisodamine Protects against Myocardial Injury after Cardiac Arrest and Resuscitation in Rats.The American J of Chinese Medicine.2011,39:1-14.
[1] Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulumstress-induced apoptosis. EMBO Rep.2006,7:880-885.
[2] Glembotski CC. The role of the unfolded protein response in the heart. J Mol Cell Cardiol.2008,44:453-459.
[3] Xiu RJ, Hammerschmidt DE, Coppo PA, et al. Anisodamine inhibits thromboxane synthesis,granulocyte aggregation and platelet aggregation. JAMA.1982,247:1458-1460.
[4] Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med.1992,105:976-979.
[5] Fu XH, Fan WZ, Gu XS, et al. Effect of intracoronary administration of anisodamine onslow reflow phenomenon following primary percutaneous coronary intervention in patients withacute myocardial infarction. Chin Med.2007,120:1226-1231.
[6] Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene.2004,23:2838-2849.
[7] Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNK-p38MAP kinaseson apoptosis. Science.1995,270:1326-1331.
[8] Park MT, Choi JA, Kim MJ, et al. Suppression of extracellular signal-related kinase andactivation of p38MAPK are two critical events leading to caspase-8-andmitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem.2003,278:50624-50634.
[9] Sun HY, Wang NP, ALKOS HM, et al. Postconditioning attenuates cardiomyocyte apoptosisvia inhibition of JNK and p38mitogen-activated protein kinase signaling pathways.Apoptosis.2006,11:1583-1593.
[10] Nakagawa T, Zhu H, Morishima N. Caspase-12mediates endoplasmic-reticulum-specificapoptosis and cytotoxicity by amyloid-beta. Nature.2000,403:98-103.
[11] Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasm reticulumstress-specific caspase cascade in apoptosis cytochrom c-independent activation of caspase-9bycaspase-12. J Bio Chem.2002,277:34287-94.
[12] Saido TC, Sorimachi H, Suzuki K. Calpain: new perspectives in molecular diversity andphysiological-pathological involvement. Fed Am Soc Exp Biol.1994,8:814-822.
[13] Jia LJ, Shen H. Intervention of anisodamine on cardiac pathology and microcirculationduring resuscitation. Int J Emerg Crit Care Med.2007,4:1843-1844.
[14] Jia LJ, Chen W, Shen H, et al. Effects of anisodamine on microcirculation of the asystolerats during the cardiopulmonary resuscitation. Chin Critic Care Med.2008,20:737-739.
[15] Xu C, Bailly MB, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. JClin Invest.2005,115:2656-64.
[16] Oono K, Yoneda T, Manabe T, et a1. JAB1participates in unfolded protein responses byassociation and dissociation with IRE1. Neurochem Int.2004,45:765-72.
[17] Shiraishi H, Okamoto H, Yoshimura A, et al. ER stress-induced apoptosis and caspase-12activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci.2006,119:3958-66.
[18] Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology,pathophysiology, treatment, and prognostication. Resuscitation.2008,79:350-379.
[19] Ditchey RV, Lindenfeld J. Failure of epinephrine to improve the balance betweenmyocardial oxygen supply and demand during closed-chest resuscitation in dogs. Circulation.1988:78:382-389.
[20] Huang L, Sun S, Fang X, et al. Simultaneous blockade of alpha1-and beta-actions ofepinephrine during cardiopulmonary resuscitation. Crit Care Med.2006,34: S483-485.
[21] Fries M, Weil MH, Chang YT, et al. Microcirculation during cardiac arrest and resuscitation.Crit. Care Med.2006,34: S454-S457.
[22] Tang W, Weil MH, Sun S, et al. Epinephrine increases the severity of postresuscitationmyocardial dysfunction. Circulation.1995,92:3089-93.
[23] Xue LY, Hong Sh, Wei ZH, et al. Inhibition of Endoplasm Reticulum Stress byAnisodamine Protects against Myocardial Injury after Cardiac Arrest and Resuscitation in Rats.The American J of Chinese Medicine.2011,39:1-14.
[24] Xue LY, Hong Sh, Wei ZH, et al. Increasing expression of (CCAAT enhancer bindingprotein) homologous protein induced by endoplasmic reticulum stress in myocardium aftercardiac arrest and resuscitation in rat. Resuscittion.2011,8:48861-8.
[25] Malhotra JD, Kaufman RJ. The endoplasmic reticulum and the unfolded protein response.Semin Cell Dev Biol.2007,18:716-731.
[26] Tan Y, Dourdin N, Wu C, et al. Ubiquitous calpains promote caspase-12and JNK activationduring endoplasmic reticulum stress-induced apoptosis. J Biol Chem.2006,281:16016-24.
[27] Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation ofcaspase-12by calpain in apoptosis. CellBiol.2000,150:887-894.
[28] Ding C, Fu XH,Li JX,et al. Effects of Anisodamine on the area of myocardial infarction inreperfusion injured rabbits after acute myocardial infarction. Medical Journal of NationalDefending Forces in North China.2008,20;12-14.
[29] Guo HY, Lorenz RR, Vanhoutte PM. Anisodamine antagonizes acetylcholine-inducedinhibition of adrenergic neurotransmission in the canine saphenous vein. Chin Med Sci J.1992,7:32-36.
[30] Esberg L, Ren J, The oxygen radical generator pyrogallol impairs cardiomyocyte contractilefunction via a superoxide and p38MAP kinase-dependent pathway: protection by anisodamineand tetramethylpyrazine. Cardiovasc Tox.2004,4:375-384.
[31] Wang PY, Chen JW, wang FH. Anisodamine causes acyl chain interdigitation inphosphatidylglycerol. FEBS Lett.1993,332:193-196.
[32] Liu C, Shen FM, Le YY, et al. Antishock effect of anisodamine involves a novel pathwayfor activating alpha7nicotinic acetylcholine receptor. Crit Care Med.2009,37:634-641.
[33] Norby FL, Ren J. Anisodamine inhibits cardiac contraction and intracellular Ca2+transientsin isolated adult rat ventricular myocytes. Eur J Pharmacol.2002,439:21-25.
[34] Ruan, QR, Song JX, Deng ZD. Study on effect of anisodamine on expressions of tissuefactor and plasminogen activator-1inhibitor in vascular endothelial cells and its mechanisms.Chin J Integrate Traditional West Med.2004,24:422-426.
[35] Pang YH, Chen JW. Anisodamine causes the changes of structure and function in thetransmembtane domain of the Ca2+-ATPase from sarcoplasmic reticulum. Biosci BiotechnolBiochem.2004,68:126-131.
[36]杨杨,指导老师沈洪.中国人民解放军军医进修学院.博士论文,2010,年.山莨菪碱对心脏复苏大鼠心肌线粒体功能保护作用的研究.
[1] Tsuji T, Ohga Y, Yoshikawa Y, et al. Rat cardiac contractile dysfunction induced by Ca2+overload: possible link to the proteolysis of alpha-fodrin. J Physiol Heart Circ Physiol.2001,281(3): H1286-94.
[2] Yoshida K, Inui M, Harada K, et al. Reperfusion of rat heart after brief ischemia inducesproteolysis of calspectin (nonerythroid spectrin or fodrin) by Calpain. Circ Res.1995,77(3):603-10.
[3] Bartoli M, Richard I. Calpains in muscle wasting. Int J Biochem Cell Bio.2005,37（10）:2115-2133.
[4] French JP, Quindry JC, Falk DJ, et al. Ischemia-reperfusion-induced Calpain activation andSERCA2a degradation are attenuated by exercise training and Calpain inhibition. Am J PhysiolHeart Circ Physiol.2006,290(1): H128-36.
[5] Gilchrist JS, Cook T, Rashidkhani B, et al. Extensive autolytic fragmentation of membranousversus cytosolic Calpain following myocardial ischemia-reperfusion. Can J Physiol Pharmacol.2010,88(5):584-94.
[6] Inserte J, Garcia-Dorado D, Ruiz-Meana M, et al. Ischemic preconditioning attenuatesCalpain-mediated degradation of tructural proteins through aprotein kinase A-dependentmechanism. Cardiovasc Res.2004,64(1):105-14.
[7] Yoshikawa Y, Hagihara H, Ohga Y, et al. Calpain inhibitor-1protects the rat heart fromischemia-reperfusion injury: analysis by mechanical work and energetics. Am J Physiol HeartCirc Physiol.2005,288(4): H1690-8. Epub2004Nov4.
[8] Bukowska A, Lendeckel U, Bode-B ger SM, et al. Physiologic and Pathophysiologic Role ofCalpain: Implications for the Occurrence of Atrial Fibrillation. Cardiovasc Ther.2010,25. doi:10.1111/j.1755-5922.
[9] Ke L, Qi XY, Dijkhuis AJ, et al. Calpain mediates cardiac troponin degradation andcontractile dysfunction in atrial fibrillation. J Mol Cell Cardiol.2008,45(5):685-93. Epub2008Sep11.
[10] Pang YH, et al.. Anisodamine causes the changes of structure and function in thetransmembrane domain of the Ca2+-ATPase from sarcoplasmic reticulum. Biosci. Biotechnol.Biochem.2004,68:126-131.
[11] Chen JB, Huang CX, Tang QZ, et al. The effect of anisodamine on the L-type calciumchannel in ventricular myocytes of rabbit. Chin Pharmacol Bull.2000,16(2):162–164.
[12] Norby FL, Ren J. Anisodamine inhibits cardiac contraction and intracellular Ca(2+)transients in isolated adult rat ventricular myocytes. Eur J Pharmacol.2002,439(1–3):21–25.
[13] HervéJC, Dhein S. Pharmacology of cardiovascular gap junctions. Adv ardiol.2006,42:107-31.
[14] Rogers M, Berestecky JM, Hossain MZ, et al. Retinoid-enhanced gap junctionalcommunication is achieved by increased levels of connexin43mRNA and protein.. MolCarcinog.1990,3(6):335-43.
[15] Maass K, Chase SE, Lin X, et al. Cx43CT domain influences infarct size and susceptibilityto ventricular tachyarrhythmias in acutemyocardial infarction. Cardiovasc Res.2009,84(3):361-7.Epub2009Jul20.
[16] Sánchez JA, Rodríguez SA, Fernández SC, et al. Effects of a reduction in the number of gapjunction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mousehearts. Am J Physiol Heart Circ Physiol.2011,(6): H2442-53. Epub2011Sep23.
[17] Chen Z, Luo H, Zhuang M, et al. Effects of ischemic preconditioning onischemia/reperfusion-induced arrhythmias by upregulatation of connexin43expression. JCardiothorac Surg.2011,6:80.
[18] Sánchez JA, Rodríguez SA, Fernández SC, et al. Effects of a reduction in the number of gapjunction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mousehearts. Am J Physiol Heart Circ Physiol.2011,301(6): H2442-53.
[19] Beardslee MA, Lerner DL, Tadros PN, et al. Dephosphorylation and intracellularredistribution of ventricular connexin43during electrical uncoupling induced by ischemia. CircRes.2000,87(8):656-62.
[20] Jeyaraman MM, Srisakuldee W, Nickel BE, et al. Connexin43phosphorylation andcytoprotection in the heart. Biochim Biophys Acta.2011,6(3).
[21] Liu HZ, Zhong JQ, Li JS, et al. Changes in myocardial connexin43during ventricularfibrillation. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.2010,22(10):595-8.
[22] Rado inská J, Knezl V, BenováT, et al. Alterations of the intercellular coupling protein,connexin-43, during ventricular fibrillation andsinus rhythm restoration demonstrated in maleand female rat hearts: A pilot study. Exp Clin Cardiol.2011,16(4):116-20.
[23] Chen JM, Gu SL. Anti-arrhythmic effects of anisodamine. Yao Xue Xue Bao.1988,23:857-859.
[24] Yang P et al. Anti-arrhythmia and nervous system effects of anisodamine. Zhong Guo Yao LiXue Bao.1991,12:173-176.
[25] Iyer RK, King JP, Radisic M. Biphasic electrical field stimulation aids in tissue engineeringof multicell-type cardiac organoids. Tissue Eng Part A.2011,17(11-12):1465-77. Epub2008Sep10. Chiu LL
[26] Gissel H. Ca2+accumulation and cell damage in skeletal muscle during low frequencystimulation. Eur J Appl Physiol.2000,83(2-3):175-80.
[27] Meacci E, Bini F, Sassoli C, et al. Functional interaction between TRPC1channel andconnexin-43protein: a novel pathway underlying S1P action on skeletal myogenesis. Cell MolLife Sci.2010,67(24):4269-85. Epub,2010, Jul8.
[28] Laing JG, Tadros PN, Green K, et al. Proteolysis of connexin43-containing gap junctions innormal and heat-stressed cardiac myocytes. Cardiovasc Res.1998,38(3):711-8.
[29] Zhang W, Ma X, Zhong M, et al. Role of the Calpain system in pulmonary vein connexinremodeling in dogs with atrial fibrillation. Cardiology.2009,112(1):22-30. Epub,2008, Jun:25.
[1] Hunter DR, Haworth RA, Southard JH. Relationship between configuration, function, andpermeability in calcium-treated mitochondria. J Biol Chem.1976,251(16):5069–5077.
[2] Bernardi P, Broekemeier KM, Pfeiffer DR. Recent progress on regulation of themitochondrial permeability transition pore; a cyclosporine-sensitive pore in the innermitochondrial membrane. J Bioenerg Biomembr.1994,26(5):509-517.
[3] Crompton M. The mitochondrial permeability transition pore and its role in cell death.Biochem J.1999,341(Pt2):233-249.
[4] Halestrap AP, Kerr PM, Javadov S, et al. Elucidating the molecular mechanism of thepermeability transition pore and its role in reperfusion injury of the heart. Biochim BiophysActa.1998,1366(1-2):79-94.
[5] Zoratti M, Szabo I, De Marchi U. Mitochondrial permeability transitions: how many doorsto the house? Biochim Biophys Acta.2005,1706(1-2):40-52.
[6] Shoshan-Barmatz V, Israelson A, Brdiczka D, et al.The voltage-dependent anion channel(VADC): function in intracellular signalling, cell life and cell death[J].Curr Pharm Des.2006,12(18):2249-2270.
[7] SzabóI, Zoratti M. The mitochondrial permeability transition pore may comprise VDACmolecules. Binary structure and voltage dependence of the pore. FEBS Lett.1993,330(2):201-205.
[8] Baines CP, Kaiser RA, Sheiko T, et al. Voltage-dependent anion channels are dispensablefor mitochondrial-dependent cell death. Nat Cell Biol.2007,9(5):550-555.
[9] Krauskopf A, Eriksson O, Craigen WJ, et al. Properties of the permeability transition inVDAC1mitochondria. Biochm Biophys Acta.2006,1757(5-6):590-595.
[10] Woodfield K, Ruck A, Brdiczka D, et al. Direct demonstration of a specific interactionbetween cyclophilin-D and the adenine nucleotide translocase confirms their role in themitochondrial permeability transition. Biochem. J.1998,336(Pt2):287–90.
[11] Baines CP. The cardiac mitochondrion: nexus of stress. Annu Rev Physiol.2010,17(72):61-80.
[12] Fiore C, Trezeguet V, Le Saux A, et al. The mitochondrial ADP/ATP carrier: structural,physiological and pathological aspects. Biochimie.1998,80(2):137–150.
[13] Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathologicalimplications. Pflug. Arch.2003,447(5):689–709.
[14] Zamora M, Granell M, Mampel T, et al. Adenine nucleotide translocase3(ANT3)overexpression induces apoptosis in cultured cells. FEBS Lett.2004,563(1-3):155–160.
[15] Halestrap AP, Davidson AM. Inhibition of Ca2+-induced large-amplitude swelling ofliver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding tomitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with theadenine nucleotide translocase. Biochem. J.1990,268(1):153–160.
[16] Bauer MK, Schubert A, Rocks O, et al. Adenine nucleotide translocase-1, a component ofthe permeability transition pore, can dominantly induce apoptosis. J Cell Biol.1999,147(7):1493-1502.
[17] Jang JY, Choi Y, Jeon YK, et al. Over-expression of adenine nucleotide translocase1(ANT1) induces apoptosis and tumor regression in vivo. BMC Cancer.2008,4(8):160.
[18] Baines CP, Molkentin JD. Adenine nucleotide translocase-1induces cardiomyocyte deaththrough upregulation of the proapoptotic protein Bax. J Mol Cell Cardiol.2009.46(6):969–977.
[19] Kokoszka J, Waymire KG, Levy SE, et al. The ADP/ATP translocator is not essential forthe mitochondrial permeability transition pore. Nature.2004,427(6973):461–465.
[20] Da Cruz S, Parone PA, Martinon JC. Building the mitochondrial proteome. Expert ResProteomics.2005,2(4):541-551.
[21] Connern CP, Halestrap AP. Purification and N-terminal sequencing of peptidyl-prolylcis-transisomerase from rat liver mitochondrial matrix reveals the existence of a distinctmitochondrial cyclophilin. Biochem J.1992,284(Pt2):381–385.
[22] Andreeva L, Tanveer A, Crompton M. Evidence for the involvement of amembrane-associated cyclosporin-A-binding protein in the Ca2+-activated inner membranepore of heart mitochondria. Eur J Biochem.1995,230(3):1125–1132.
[23] Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of themitochondrial permeability transition and reperfusion injury of the heart by binding tocyclophilin-D at a different site from cyclosporin A. J Biol Chem.2002,277(38):34793–34799.
[24] Di Lisa F, MenabòR, Canton M, et al. Opening of the mitochondrial permeabilitytransition pore causes depletion of mitochondrial and cytosolic NAD+and is a causative eventin the death of myocytes in postischemic reperfusion of the heart. J Biol Chem.2001,276(4):2571–2575.
[25] Reutenauer J, Dorchies OM,Patthey-Vuadens O, et al. Investigation of Debio025, acyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne musculardystrophy.Br J Pharmacol.2008,155(4):574–584.
[26] Gomez L, Thibault H, Gharib A, et al. Inhibition of mitochondrial permeability transitionimproves functional recovery and reduces mortality following acute myocardial infarction inmice. Am J Physiol Heart Circ Physiol.2007,293(3): H1654–1661.
[27] Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role formitochondrial permeability transition in cell death. Nature.2005,434(7033):658–662.
[28] Basso E, Fante L, Fowlkes J, et al. Properties of the permeability transition pore inmitochondria devoid of Cyclophilin D. J Biol Chem.2005,280(19):18558–18561.
[29] Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrialpermeability transition regulates some necrotic but not apoptotic cell death. Nature.2005,434(7033):652–658.
[30] Schinzel A, Takeuchi O, Huang Z, et al. Cyclophilin D is a component of mitochondrialpermeability transition and mediates neuronal cell death after focal cerebral ischemia. ProcNatl Acad Sci USA.2005,102(34):12005–12010.
[31] Leung AW, Varanyuwatana P, Halestrap AP. The mitochondrial phosphate carrier interactswith cyclophilin D and may play a key role in the permeability transition. J Biol Chem.2008,283(39):26312–26323.
[32] Halestrap AP, Pasdois P. The role of the mitochondrial permeability transition pore inheart disease. Biochim Biophys Acta.2009,1787(11):1402-1415.
[33] Basso E, Petronilli V, Forte MA, et al. Phosphate is essential for inhibition of themitochondrial permeability transition pore by cyclosporine A and by cyclophilin D ablation. JBiol Chem.2008,283(39):26307-26311.
[34] Alcala S, Klee M, Fernandez J, et al. A high-throughput screening for mammalian celldeath effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome crelease. Oncogene.2008,27(1):44–54.
[35] Borutaite V, Brown GC. Mitochondria in apoptosis of ischemic heart. FEBS Lett.2003,541(1-3):1-5.
[36] Weiss JN, Korge P, Honda HM, et al. Role of the mitochondria permeability transition inmyocardial disease. Circ Res.2003,93(4):292-301.
[37] G Kroemer, JC Reed. Mitochondrial control of cell death[J]. Nat Med,2000,6(5):513-519.
[38] Kim JS, He L, Lemasters JI. Mitochondrial permeability transition: a common pathway tonecrosis and apoptosis. Biochem Biophys Res Commun.2003,304(3):463-470.
[39] Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol.2009,46(6):821-831.
[40] Di Lisa F, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: fixing ahole. Cardiocasc Res.2006,70(2):191-199.
[41] Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening as anendpoint to initiate cell death and as a putative target for cardioprotection. Cell PhysiolBiochem.2007,20(1-4):1-22.
[42] Griffiths EJ, Halestrap AP. Protection by Cyclosporin A of ischemia/reperfusion-induceddamage in isolated rat hearts. J Mol Cell Cardiol.1993,25(12):1461–1469.
[43] Duchen MR, McGuinness O, Brown LA, et al. On the involvement of a cyclosporin Asensitive mitochondrial pore in myocardial reperfusion injury. Cardiovasc Res.1993,27(10):1790–1794.
[44] Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transitionpore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res.2003,60(3):617–625.
[45] Kato M, Akao M, Matsumoto-Ida M, et al. The targeting of cyclophilin D by RNAi as anovel cardioprotective therapy: evidence from two-photon imaging. Cardiovasc Res.2009,83(2):335–344.
[46] Lim SY, Davidson SM, Hausenloy DJ, et al. Preconditioning and postconditioning: theessential role of the mitochondrial permeability transition pore. Cardiovasc Res.2007,75(3):530–535.
[47] Nakayama N, Chen X, Baines CP, et al. Ca2+-and mitochondrial-dependentcardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest.2007,117(9):2431–2444.
[48] Millay DP, Sargent MA, Osinska H, et al. Genetic and pharmacologic inhibition ofmitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med.2008,14(4):442–447.
[49] Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agentimatinib mesylate. Nat Med.2006,12(8):908–916.
[50] Zhou S, Starkov A, Froberg MK,et al. Cumulative and irreversible cardiac mitochondrialdysfunction induced by doxorubicin. Cancer Res.2001,61(2):771–777.
[51] Matas J, Young NT, Bourcier-Lucas C, et al. Increased expression and intramitochondrialtranslocation of cyclophilin-D associates with increased vulnerability of the permeabilitytransition pore to stress-induced opening during compensated ventricular hypertrophy. J MolCell Cardiol.2009,46(3):420–430.
[52] Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acutemyocardial infarction. N Engl J Med.2008,359(5):473–481.
[2] Kouwenhoven W, Jude JR, Knickerbocker GG·Closed chest cardiac massage.1960,173:1064-1067.
[3] Nolan JP, Laver SR, Welch CA, et al. Outcome following admission to UK intensive careunits after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database.Anaesthesia.2007,62:1207–1216.
[4] Field JM, Hazinski MF, Sayre MR,et al.2010American Heart Association Guidelines forCardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation.2010,122：S640-S656.
[5] Garza AG, Gratton MC, Salomone JA, et al. Improved patient survival using a modifiedresuscitation protocol for out-of-hospital cardiac arrest. Circulation.2009,119(19):2597-605.
[6] European Epinephrine Study Group. A comparison of repeated high doses and repeatedstandard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med.1998,339(22):1595-1601.
[7] Hagihara A, Hasegawa M, Abe T, et al. Prehospital epinephrine use and survival amongpatients with out-of-hospital cardiac arrest. JAMA.2012,307(11):1161-8.
[8] Robert W, Neumar, Jerry P, et al. Post–Cardiac Arrest Syndrome Epidemiology,Pathophysiology, Treatment, and Prognostication. Circ,2008,118:2452-2483.
[9] Weisfeldt M, Becker LB. Resuscitation after cardiac arrest: a3-phase time-sensitive model.JAMA.2002,288:3035-3038.
[10] Xie JX, Zhou J, Zhang CZ, et al. Synthesis of anisodamine analogs. Acta Pharma Sin.1981,16(10):767-772.
[11] Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med J (Engl).1992,105(12):976-979.
[12]俞长兴,肖蓬,苏志红,等.山莨菪碱类药物临床应用评价.中国医院用药评价与分析.2002,2(4):208-210.
[13] JIA Lijing, SHEN Hong. The Application of Cytospaz in Cardiopulmonary-cerebralResuscitation. Chinese General Practice.2007,10(8):644-645.
[14] MENG Fanshan, SUN Jing, CHEN Wei, et al. A model of cardiac arrest andcardiopulmonary resuscitation in rats. Academic journal of PLA postgraduate medical school.2009,30(6):875-877.
[15]贾立静，陈威，沈洪,等.山莨菪碱对心脏停搏大鼠复苏中微循环的影响.中国危重病急救医学.2008,20(12):737-739.
[16]孙菁,沈洪.山莨菪碱对心脏骤停大鼠复苏及内皮损伤干预的研究.军医进修学院,博士论文,2009.
[17]孟凡山,沈洪.山莨菪碱对心脏骤停大鼠及缺氧/复氧心肌细胞影响的研究.军医进修学院,博士论文,2009.
[18]杨扬,沈洪.山莨菪碱对心脏复苏大鼠线粒体功能保护作用的研究.军医进修学院,博士论文,2010.
[19]张维,指导老师沈洪.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.军医进修学院,博士论文,2010.
[20] Xue LY, Hong Sh, Wei ZH, et al. Increasing expression of (CCAAT enhancer bindingprotein) homologous protein induced by endoplasmic reticulum stress in myocardium aftercardiac arrest and resuscitation in rat. Resuscitation.2011,8:48861-8.
[21] Xue LY, Hong Sh, Wei ZH, et al. Inhibition of Endoplasm Reticulum Stress byAnisodamine Protects against Myocardial Injury after Cardiac Arrest and Resuscitation in Rats.The American J of Chinese Medicine.2011,39:1-14.
[1]杨扬,指导老师沈洪.山莨菪碱对心脏复苏大鼠线粒体功能保护作用的研究.军医进修学院,博士论文,2010.
[2] Lurie KG, Zielinski T, McKnite S, et al.Use of an Inspiratory Impedance Valve ImprovesNeurologically Intact Survival in a Porcine Model of Ventricular Fibrillation. Circulation2002,105:124-129
[3]高维谊,盛志勇,郭振荣,等.烧伤早期山莨菪碱对胃肠保护作用的实验研究.解放军医学杂志.1995,20(2):88-91.
[4] Zhou M, Ran Q, Liu Y, et al. Effects of sustained abdominal aorta compression on coronaryperfusion pressures and restoration of spontaneous circulation during cardiopulmonaryresuscitation in swine. Resuscitation.2011,82:1087-91.
[5] Giuseppe Ristagno, Wanchun Tang, Lei Huang. Epinephrine reduces cerebral perfusionduring cardiopulmonary resuscitation. Crit Care Med.2009,(37):1408-1415.
[6] Henry R. Halperin MA, Kichang Lee. Outcomes from low versus high-flowcardiopulmonary resuscitation in a swine model of cardiac arrest. American Journal ofEmergency Medicine.2010,(28):195-202.
[7]涂建锋,蒋国平,江观玉.心脏骤停动物模型的动物和实验方法选择.中国病理生理杂志.2006,22(4):830-832.
[8] Weisfeldt M, Becker LB. Resuscitation after cardiac arrest: a3-phase time-sensitive model.JAMA.2002,288:3035-3038.
[9] Xie JX, Zhou J, Zhang CZ, et al. Synthesis of anisodamine analogs. Acta Pharma Sin.1981,16(10):767-772.
[10] Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med J(Engl).1992,105(12):976-979.
[11]俞长兴，肖蓬，苏志红，等.山莨菪碱类药物临床应用评价.中国医院用药评价与分析.2002,2(4):208-210.
[12] Jia Lijing, SHEN Hong. The Application of Cytospaz in Cardiopulmonary-cerebralResuscitation. Chinese General Practice.2007,10(8):644-645.
[1] Misra MK，Sarwat M，Bhakuni P，et al.Oxidative stress and ischemic myocardial syndromes.Med Sci Monit.2009,15(10):209-19.
[2] Griending KK, Alexander RW.Oxidative stress and cardiovascular disease. Circulation.1997,96:3264-3265.
[3]林珮仪,江慧琳,张弋,等.犬心肺复苏后心肌细胞凋亡和氧自由基的变化.岭南心血管病杂志.2005,11(3):205.
[4]杨扬,指导老师沈洪.山莨菪碱对心脏复苏大鼠线粒体功能保护作用的研究.军医进修学院,博士论文,2010.
[5] Beckman JS, Beckman TW, Chen J,et al. Apparenthydroxyl radical production byperoxynitrite. ProcNatl Acad Sci.1990,87(9):1620-1624.
[6] Han F, Da T, Riobo NA, et al. Early mitochondrial dysfunction in electron transfer activityand reactive oxygen species generation after cardiac arrest. Critical Care Medicine.2008,36(11)Suppl: S447-S453.
[7] Cain K, Bratton SB, Langlais C, et al. Apaf-1oligomerizes intobiologically active700kDand inactive1.4-kDa apoptosome complexes. J Biol Chem.2000,275(9):6067-6070.
[8] Kim JS，Jin Y，Lemasters JJ. Reactive oxygen species，but not Ca2+overloading，triggerpH-and mitochondrial permeability transition-dependent death of adult rat myocytes afterischemia-reperfusion. Am J Physiol Heart Circ Physiol.2006,290: H2024-H2034．
[9] Robert W Neumar, Jerry P Nolan, Christophe Adrie, et al. Post–Cardiac Arrest SyndromeEpidemiology, Pathophysiology, Treatment, and Prognostication. Circ.2008,118:2452-2483.
[10]林珮仪,江慧琳,张弋,等.犬心肺复苏后心肌细胞凋亡和氧自由基的变化.岭南心血管病杂志.2005,11(3):205.
[11]陈媛,周梅.自由基医学基础与病理生理学.2002,第一版:35-36.
[12]贾立静，陈威，沈洪,等.山莨菪碱对心脏停搏大鼠复苏中微循环的影响.中国危重病急救医学.2008,20(12):737-739。
[13]孙菁,指导老师沈洪.山莨菪碱对心脏骤停大鼠复苏及内皮损伤干预的研究.军医进修学院,博士论文,2009.
[14]孟凡山,指导老师沈洪.山莨菪碱对心脏骤停大鼠及缺氧/复氧心肌细胞影响的研究.军医进修学院,博士论文,2009.
[15] Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol.2000,190(3):255-266.
[16] Adrain C, Martin SJ. The mitochondrial apoptosome:a killer unleashed by the cytochromeseas.Trends Biochem Sci.2001,26(6):390-7.
[17] Suleiman MS, Halestrap AP, Griffiths EJ. Mitochondria:a target for myocardialprotection.Pharmacol Ther.2001,89(1):29-46.
[18] Regula KM, Ens K, Kirshenbaum LA. Mitochondria-assisted cell suicide:a license to kill. JMol Cell Cardiol.2003,35(6):559-67.
[19] Golstein P.Controlling cell death. Science.1997,275(5303):1081-1082.
[20] Glembotski CC. The role of the unfolded protein response in the heart. J Mol Cell Cardiol.2008,44:453-459.
[21] Xue LY, Hong Sh, Wei ZH, et al. Inhibition of Endoplasm Reticulum Stress byAnisodamine Protects against Myocardial Injury after Cardiac Arrest and Resuscitation in Rats.The American J of Chinese Medicine.2011,39:1-14.
[1] Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulumstress-induced apoptosis. EMBO Rep.2006,7:880-885.
[2] Glembotski CC. The role of the unfolded protein response in the heart. J Mol Cell Cardiol.2008,44:453-459.
[3] Xiu RJ, Hammerschmidt DE, Coppo PA, et al. Anisodamine inhibits thromboxane synthesis,granulocyte aggregation and platelet aggregation. JAMA.1982,247:1458-1460.
[4] Su JY. Cell protection mechanism of antishock action of anisodamine. Chin Med.1992,105:976-979.
[5] Fu XH, Fan WZ, Gu XS, et al. Effect of intracoronary administration of anisodamine onslow reflow phenomenon following primary percutaneous coronary intervention in patients withacute myocardial infarction. Chin Med.2007,120:1226-1231.
[6] Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene.2004,23:2838-2849.
[7] Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNK-p38MAP kinaseson apoptosis. Science.1995,270:1326-1331.
[8] Park MT, Choi JA, Kim MJ, et al. Suppression of extracellular signal-related kinase andactivation of p38MAPK are two critical events leading to caspase-8-andmitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem.2003,278:50624-50634.
[9] Sun HY, Wang NP, ALKOS HM, et al. Postconditioning attenuates cardiomyocyte apoptosisvia inhibition of JNK and p38mitogen-activated protein kinase signaling pathways.Apoptosis.2006,11:1583-1593.
[10] Nakagawa T, Zhu H, Morishima N. Caspase-12mediates endoplasmic-reticulum-specificapoptosis and cytotoxicity by amyloid-beta. Nature.2000,403:98-103.
[11] Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasm reticulumstress-specific caspase cascade in apoptosis cytochrom c-independent activation of caspase-9bycaspase-12. J Bio Chem.2002,277:34287-94.
[12] Saido TC, Sorimachi H, Suzuki K. Calpain: new perspectives in molecular diversity andphysiological-pathological involvement. Fed Am Soc Exp Biol.1994,8:814-822.
[13] Jia LJ, Shen H. Intervention of anisodamine on cardiac pathology and microcirculationduring resuscitation. Int J Emerg Crit Care Med.2007,4:1843-1844.
[14] Jia LJ, Chen W, Shen H, et al. Effects of anisodamine on microcirculation of the asystolerats during the cardiopulmonary resuscitation. Chin Critic Care Med.2008,20:737-739.
[15] Xu C, Bailly MB, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. JClin Invest.2005,115:2656-64.
[16] Oono K, Yoneda T, Manabe T, et a1. JAB1participates in unfolded protein responses byassociation and dissociation with IRE1. Neurochem Int.2004,45:765-72.
[17] Shiraishi H, Okamoto H, Yoshimura A, et al. ER stress-induced apoptosis and caspase-12activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci.2006,119:3958-66.
[18] Nolan JP, Neumar RW, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology,pathophysiology, treatment, and prognostication. Resuscitation.2008,79:350-379.
[19] Ditchey RV, Lindenfeld J. Failure of epinephrine to improve the balance betweenmyocardial oxygen supply and demand during closed-chest resuscitation in dogs. Circulation.1988:78:382-389.
[20] Huang L, Sun S, Fang X, et al. Simultaneous blockade of alpha1-and beta-actions ofepinephrine during cardiopulmonary resuscitation. Crit Care Med.2006,34: S483-485.
[21] Fries M, Weil MH, Chang YT, et al. Microcirculation during cardiac arrest and resuscitation.Crit. Care Med.2006,34: S454-S457.
[22] Tang W, Weil MH, Sun S, et al. Epinephrine increases the severity of postresuscitationmyocardial dysfunction. Circulation.1995,92:3089-93.
[23] Xue LY, Hong Sh, Wei ZH, et al. Inhibition of Endoplasm Reticulum Stress byAnisodamine Protects against Myocardial Injury after Cardiac Arrest and Resuscitation in Rats.The American J of Chinese Medicine.2011,39:1-14.
[24] Xue LY, Hong Sh, Wei ZH, et al. Increasing expression of (CCAAT enhancer bindingprotein) homologous protein induced by endoplasmic reticulum stress in myocardium aftercardiac arrest and resuscitation in rat. Resuscittion.2011,8:48861-8.
[25] Malhotra JD, Kaufman RJ. The endoplasmic reticulum and the unfolded protein response.Semin Cell Dev Biol.2007,18:716-731.
[26] Tan Y, Dourdin N, Wu C, et al. Ubiquitous calpains promote caspase-12and JNK activationduring endoplasmic reticulum stress-induced apoptosis. J Biol Chem.2006,281:16016-24.
[27] Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation ofcaspase-12by calpain in apoptosis. CellBiol.2000,150:887-894.
[28] Ding C, Fu XH,Li JX,et al. Effects of Anisodamine on the area of myocardial infarction inreperfusion injured rabbits after acute myocardial infarction. Medical Journal of NationalDefending Forces in North China.2008,20;12-14.
[29] Guo HY, Lorenz RR, Vanhoutte PM. Anisodamine antagonizes acetylcholine-inducedinhibition of adrenergic neurotransmission in the canine saphenous vein. Chin Med Sci J.1992,7:32-36.
[30] Esberg L, Ren J, The oxygen radical generator pyrogallol impairs cardiomyocyte contractilefunction via a superoxide and p38MAP kinase-dependent pathway: protection by anisodamineand tetramethylpyrazine. Cardiovasc Tox.2004,4:375-384.
[31] Wang PY, Chen JW, wang FH. Anisodamine causes acyl chain interdigitation inphosphatidylglycerol. FEBS Lett.1993,332:193-196.
[32] Liu C, Shen FM, Le YY, et al. Antishock effect of anisodamine involves a novel pathwayfor activating alpha7nicotinic acetylcholine receptor. Crit Care Med.2009,37:634-641.
[33] Norby FL, Ren J. Anisodamine inhibits cardiac contraction and intracellular Ca2+transientsin isolated adult rat ventricular myocytes. Eur J Pharmacol.2002,439:21-25.
[34] Ruan, QR, Song JX, Deng ZD. Study on effect of anisodamine on expressions of tissuefactor and plasminogen activator-1inhibitor in vascular endothelial cells and its mechanisms.Chin J Integrate Traditional West Med.2004,24:422-426.
[35] Pang YH, Chen JW. Anisodamine causes the changes of structure and function in thetransmembtane domain of the Ca2+-ATPase from sarcoplasmic reticulum. Biosci BiotechnolBiochem.2004,68:126-131.
[36]杨杨,指导老师沈洪.中国人民解放军军医进修学院.博士论文,2010,年.山莨菪碱对心脏复苏大鼠心肌线粒体功能保护作用的研究.
[1] Tsuji T, Ohga Y, Yoshikawa Y, et al. Rat cardiac contractile dysfunction induced by Ca2+overload: possible link to the proteolysis of alpha-fodrin. J Physiol Heart Circ Physiol.2001,281(3): H1286-94.
[2] Yoshida K, Inui M, Harada K, et al. Reperfusion of rat heart after brief ischemia inducesproteolysis of calspectin (nonerythroid spectrin or fodrin) by Calpain. Circ Res.1995,77(3):603-10.
[3] Bartoli M, Richard I. Calpains in muscle wasting. Int J Biochem Cell Bio.2005,37（10）:2115-2133.
[4] French JP, Quindry JC, Falk DJ, et al. Ischemia-reperfusion-induced Calpain activation andSERCA2a degradation are attenuated by exercise training and Calpain inhibition. Am J PhysiolHeart Circ Physiol.2006,290(1): H128-36.
[5] Gilchrist JS, Cook T, Rashidkhani B, et al. Extensive autolytic fragmentation of membranousversus cytosolic Calpain following myocardial ischemia-reperfusion. Can J Physiol Pharmacol.2010,88(5):584-94.
[6] Inserte J, Garcia-Dorado D, Ruiz-Meana M, et al. Ischemic preconditioning attenuatesCalpain-mediated degradation of tructural proteins through aprotein kinase A-dependentmechanism. Cardiovasc Res.2004,64(1):105-14.
[7] Yoshikawa Y, Hagihara H, Ohga Y, et al. Calpain inhibitor-1protects the rat heart fromischemia-reperfusion injury: analysis by mechanical work and energetics. Am J Physiol HeartCirc Physiol.2005,288(4): H1690-8. Epub2004Nov4.
[8] Bukowska A, Lendeckel U, Bode-B ger SM, et al. Physiologic and Pathophysiologic Role ofCalpain: Implications for the Occurrence of Atrial Fibrillation. Cardiovasc Ther.2010,25. doi:10.1111/j.1755-5922.
[9] Ke L, Qi XY, Dijkhuis AJ, et al. Calpain mediates cardiac troponin degradation andcontractile dysfunction in atrial fibrillation. J Mol Cell Cardiol.2008,45(5):685-93. Epub2008Sep11.
[10] Pang YH, et al.. Anisodamine causes the changes of structure and function in thetransmembrane domain of the Ca2+-ATPase from sarcoplasmic reticulum. Biosci. Biotechnol.Biochem.2004,68:126-131.
[11] Chen JB, Huang CX, Tang QZ, et al. The effect of anisodamine on the L-type calciumchannel in ventricular myocytes of rabbit. Chin Pharmacol Bull.2000,16(2):162–164.
[12] Norby FL, Ren J. Anisodamine inhibits cardiac contraction and intracellular Ca(2+)transients in isolated adult rat ventricular myocytes. Eur J Pharmacol.2002,439(1–3):21–25.
[13] HervéJC, Dhein S. Pharmacology of cardiovascular gap junctions. Adv ardiol.2006,42:107-31.
[14] Rogers M, Berestecky JM, Hossain MZ, et al. Retinoid-enhanced gap junctionalcommunication is achieved by increased levels of connexin43mRNA and protein.. MolCarcinog.1990,3(6):335-43.
[15] Maass K, Chase SE, Lin X, et al. Cx43CT domain influences infarct size and susceptibilityto ventricular tachyarrhythmias in acutemyocardial infarction. Cardiovasc Res.2009,84(3):361-7.Epub2009Jul20.
[16] Sánchez JA, Rodríguez SA, Fernández SC, et al. Effects of a reduction in the number of gapjunction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mousehearts. Am J Physiol Heart Circ Physiol.2011,(6): H2442-53. Epub2011Sep23.
[17] Chen Z, Luo H, Zhuang M, et al. Effects of ischemic preconditioning onischemia/reperfusion-induced arrhythmias by upregulatation of connexin43expression. JCardiothorac Surg.2011,6:80.
[18] Sánchez JA, Rodríguez SA, Fernández SC, et al. Effects of a reduction in the number of gapjunction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mousehearts. Am J Physiol Heart Circ Physiol.2011,301(6): H2442-53.
[19] Beardslee MA, Lerner DL, Tadros PN, et al. Dephosphorylation and intracellularredistribution of ventricular connexin43during electrical uncoupling induced by ischemia. CircRes.2000,87(8):656-62.
[20] Jeyaraman MM, Srisakuldee W, Nickel BE, et al. Connexin43phosphorylation andcytoprotection in the heart. Biochim Biophys Acta.2011,6(3).
[21] Liu HZ, Zhong JQ, Li JS, et al. Changes in myocardial connexin43during ventricularfibrillation. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.2010,22(10):595-8.
[22] Rado inská J, Knezl V, BenováT, et al. Alterations of the intercellular coupling protein,connexin-43, during ventricular fibrillation andsinus rhythm restoration demonstrated in maleand female rat hearts: A pilot study. Exp Clin Cardiol.2011,16(4):116-20.
[23] Chen JM, Gu SL. Anti-arrhythmic effects of anisodamine. Yao Xue Xue Bao.1988,23:857-859.
[24] Yang P et al. Anti-arrhythmia and nervous system effects of anisodamine. Zhong Guo Yao LiXue Bao.1991,12:173-176.
[25] Iyer RK, King JP, Radisic M. Biphasic electrical field stimulation aids in tissue engineeringof multicell-type cardiac organoids. Tissue Eng Part A.2011,17(11-12):1465-77. Epub2008Sep10. Chiu LL
[26] Gissel H. Ca2+accumulation and cell damage in skeletal muscle during low frequencystimulation. Eur J Appl Physiol.2000,83(2-3):175-80.
[27] Meacci E, Bini F, Sassoli C, et al. Functional interaction between TRPC1channel andconnexin-43protein: a novel pathway underlying S1P action on skeletal myogenesis. Cell MolLife Sci.2010,67(24):4269-85. Epub,2010, Jul8.
[28] Laing JG, Tadros PN, Green K, et al. Proteolysis of connexin43-containing gap junctions innormal and heat-stressed cardiac myocytes. Cardiovasc Res.1998,38(3):711-8.
[29] Zhang W, Ma X, Zhong M, et al. Role of the Calpain system in pulmonary vein connexinremodeling in dogs with atrial fibrillation. Cardiology.2009,112(1):22-30. Epub,2008, Jun:25.
[1] Hunter DR, Haworth RA, Southard JH. Relationship between configuration, function, andpermeability in calcium-treated mitochondria. J Biol Chem.1976,251(16):5069–5077.
[2] Bernardi P, Broekemeier KM, Pfeiffer DR. Recent progress on regulation of themitochondrial permeability transition pore; a cyclosporine-sensitive pore in the innermitochondrial membrane. J Bioenerg Biomembr.1994,26(5):509-517.
[3] Crompton M. The mitochondrial permeability transition pore and its role in cell death.Biochem J.1999,341(Pt2):233-249.
[4] Halestrap AP, Kerr PM, Javadov S, et al. Elucidating the molecular mechanism of thepermeability transition pore and its role in reperfusion injury of the heart. Biochim BiophysActa.1998,1366(1-2):79-94.
[5] Zoratti M, Szabo I, De Marchi U. Mitochondrial permeability transitions: how many doorsto the house? Biochim Biophys Acta.2005,1706(1-2):40-52.
[6] Shoshan-Barmatz V, Israelson A, Brdiczka D, et al.The voltage-dependent anion channel(VADC): function in intracellular signalling, cell life and cell death[J].Curr Pharm Des.2006,12(18):2249-2270.
[7] SzabóI, Zoratti M. The mitochondrial permeability transition pore may comprise VDACmolecules. Binary structure and voltage dependence of the pore. FEBS Lett.1993,330(2):201-205.
[8] Baines CP, Kaiser RA, Sheiko T, et al. Voltage-dependent anion channels are dispensablefor mitochondrial-dependent cell death. Nat Cell Biol.2007,9(5):550-555.
[9] Krauskopf A, Eriksson O, Craigen WJ, et al. Properties of the permeability transition inVDAC1mitochondria. Biochm Biophys Acta.2006,1757(5-6):590-595.
[10] Woodfield K, Ruck A, Brdiczka D, et al. Direct demonstration of a specific interactionbetween cyclophilin-D and the adenine nucleotide translocase confirms their role in themitochondrial permeability transition. Biochem. J.1998,336(Pt2):287–90.
[11] Baines CP. The cardiac mitochondrion: nexus of stress. Annu Rev Physiol.2010,17(72):61-80.
[12] Fiore C, Trezeguet V, Le Saux A, et al. The mitochondrial ADP/ATP carrier: structural,physiological and pathological aspects. Biochimie.1998,80(2):137–150.
[13] Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathologicalimplications. Pflug. Arch.2003,447(5):689–709.
[14] Zamora M, Granell M, Mampel T, et al. Adenine nucleotide translocase3(ANT3)overexpression induces apoptosis in cultured cells. FEBS Lett.2004,563(1-3):155–160.
[15] Halestrap AP, Davidson AM. Inhibition of Ca2+-induced large-amplitude swelling ofliver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding tomitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with theadenine nucleotide translocase. Biochem. J.1990,268(1):153–160.
[16] Bauer MK, Schubert A, Rocks O, et al. Adenine nucleotide translocase-1, a component ofthe permeability transition pore, can dominantly induce apoptosis. J Cell Biol.1999,147(7):1493-1502.
[17] Jang JY, Choi Y, Jeon YK, et al. Over-expression of adenine nucleotide translocase1(ANT1) induces apoptosis and tumor regression in vivo. BMC Cancer.2008,4(8):160.
[18] Baines CP, Molkentin JD. Adenine nucleotide translocase-1induces cardiomyocyte deaththrough upregulation of the proapoptotic protein Bax. J Mol Cell Cardiol.2009.46(6):969–977.
[19] Kokoszka J, Waymire KG, Levy SE, et al. The ADP/ATP translocator is not essential forthe mitochondrial permeability transition pore. Nature.2004,427(6973):461–465.
[20] Da Cruz S, Parone PA, Martinon JC. Building the mitochondrial proteome. Expert ResProteomics.2005,2(4):541-551.
[21] Connern CP, Halestrap AP. Purification and N-terminal sequencing of peptidyl-prolylcis-transisomerase from rat liver mitochondrial matrix reveals the existence of a distinctmitochondrial cyclophilin. Biochem J.1992,284(Pt2):381–385.
[22] Andreeva L, Tanveer A, Crompton M. Evidence for the involvement of amembrane-associated cyclosporin-A-binding protein in the Ca2+-activated inner membranepore of heart mitochondria. Eur J Biochem.1995,230(3):1125–1132.
[23] Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin A acts as a potent inhibitor of themitochondrial permeability transition and reperfusion injury of the heart by binding tocyclophilin-D at a different site from cyclosporin A. J Biol Chem.2002,277(38):34793–34799.
[24] Di Lisa F, MenabòR, Canton M, et al. Opening of the mitochondrial permeabilitytransition pore causes depletion of mitochondrial and cytosolic NAD+and is a causative eventin the death of myocytes in postischemic reperfusion of the heart. J Biol Chem.2001,276(4):2571–2575.
[25] Reutenauer J, Dorchies OM,Patthey-Vuadens O, et al. Investigation of Debio025, acyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne musculardystrophy.Br J Pharmacol.2008,155(4):574–584.
[26] Gomez L, Thibault H, Gharib A, et al. Inhibition of mitochondrial permeability transitionimproves functional recovery and reduces mortality following acute myocardial infarction inmice. Am J Physiol Heart Circ Physiol.2007,293(3): H1654–1661.
[27] Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role formitochondrial permeability transition in cell death. Nature.2005,434(7033):658–662.
[28] Basso E, Fante L, Fowlkes J, et al. Properties of the permeability transition pore inmitochondria devoid of Cyclophilin D. J Biol Chem.2005,280(19):18558–18561.
[29] Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrialpermeability transition regulates some necrotic but not apoptotic cell death. Nature.2005,434(7033):652–658.
[30] Schinzel A, Takeuchi O, Huang Z, et al. Cyclophilin D is a component of mitochondrialpermeability transition and mediates neuronal cell death after focal cerebral ischemia. ProcNatl Acad Sci USA.2005,102(34):12005–12010.
[31] Leung AW, Varanyuwatana P, Halestrap AP. The mitochondrial phosphate carrier interactswith cyclophilin D and may play a key role in the permeability transition. J Biol Chem.2008,283(39):26312–26323.
[32] Halestrap AP, Pasdois P. The role of the mitochondrial permeability transition pore inheart disease. Biochim Biophys Acta.2009,1787(11):1402-1415.
[33] Basso E, Petronilli V, Forte MA, et al. Phosphate is essential for inhibition of themitochondrial permeability transition pore by cyclosporine A and by cyclophilin D ablation. JBiol Chem.2008,283(39):26307-26311.
[34] Alcala S, Klee M, Fernandez J, et al. A high-throughput screening for mammalian celldeath effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome crelease. Oncogene.2008,27(1):44–54.
[35] Borutaite V, Brown GC. Mitochondria in apoptosis of ischemic heart. FEBS Lett.2003,541(1-3):1-5.
[36] Weiss JN, Korge P, Honda HM, et al. Role of the mitochondria permeability transition inmyocardial disease. Circ Res.2003,93(4):292-301.
[37] G Kroemer, JC Reed. Mitochondrial control of cell death[J]. Nat Med,2000,6(5):513-519.
[38] Kim JS, He L, Lemasters JI. Mitochondrial permeability transition: a common pathway tonecrosis and apoptosis. Biochem Biophys Res Commun.2003,304(3):463-470.
[39] Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol.2009,46(6):821-831.
[40] Di Lisa F, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: fixing ahole. Cardiocasc Res.2006,70(2):191-199.
[41] Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening as anendpoint to initiate cell death and as a putative target for cardioprotection. Cell PhysiolBiochem.2007,20(1-4):1-22.
[42] Griffiths EJ, Halestrap AP. Protection by Cyclosporin A of ischemia/reperfusion-induceddamage in isolated rat hearts. J Mol Cell Cardiol.1993,25(12):1461–1469.
[43] Duchen MR, McGuinness O, Brown LA, et al. On the involvement of a cyclosporin Asensitive mitochondrial pore in myocardial reperfusion injury. Cardiovasc Res.1993,27(10):1790–1794.
[44] Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transitionpore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res.2003,60(3):617–625.
[45] Kato M, Akao M, Matsumoto-Ida M, et al. The targeting of cyclophilin D by RNAi as anovel cardioprotective therapy: evidence from two-photon imaging. Cardiovasc Res.2009,83(2):335–344.
[46] Lim SY, Davidson SM, Hausenloy DJ, et al. Preconditioning and postconditioning: theessential role of the mitochondrial permeability transition pore. Cardiovasc Res.2007,75(3):530–535.
[47] Nakayama N, Chen X, Baines CP, et al. Ca2+-and mitochondrial-dependentcardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest.2007,117(9):2431–2444.
[48] Millay DP, Sargent MA, Osinska H, et al. Genetic and pharmacologic inhibition ofmitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med.2008,14(4):442–447.
[49] Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agentimatinib mesylate. Nat Med.2006,12(8):908–916.
[50] Zhou S, Starkov A, Froberg MK,et al. Cumulative and irreversible cardiac mitochondrialdysfunction induced by doxorubicin. Cancer Res.2001,61(2):771–777.
[51] Matas J, Young NT, Bourcier-Lucas C, et al. Increased expression and intramitochondrialtranslocation of cyclophilin-D associates with increased vulnerability of the permeabilitytransition pore to stress-induced opening during compensated ventricular hypertrophy. J MolCell Cardiol.2009,46(3):420–430.
[52] Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acutemyocardial infarction. N Engl J Med.2008,359(5):473–481.