无创肢体缺血预处理对兔缺血性室性心律失常的影响及机制研究
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摘要
目的：研究无创肢体缺血预处理对兔缺血性室性心律失常的影响及其作用机制,为其临床应用提供实验性理论依据。方法：日本大耳白兔27只,体重(1.8±0.4)kg,雌雄不拘,随机分至单纯缺血对照组(Ctr,n=8)、无创肢体缺血预处理组(LIP,n=7)、LIP+格列本脲组(LG,n=6)和LIP+SB203580组(LSB,n=6)。动物麻醉后,经右颈外静脉插入电极至右心室记录心内膜MAP；针形电极插入四肢皮下记录标准Ⅱ导联ECG；经胸骨左缘第4或第5肋间隙开1-2mm2小孔,插入接触电极至心室外心包壁层稍加压记录心外膜MAP。Ctr组不作特殊处理,待ECG和心内、外膜MAP图形稳定后,静脉注射垂体后叶素(2U/kg)造成心肌缺血背景,再静脉注射肾上腺素(0.2ml/kg)诱发心律失常；同步记录ECG及心内、外膜MAP,观察心内、外膜MAP变化及与心律失常间的关系；LIP组：用充气止血带结扎兔双后肢使之缺血5min,松开使之再灌注5min,重复4次,余同Ctr组；LG组：先静脉注射格列本脲(0.16mg/kg),30min后行与LIP组相同的处理；LSB组：先静脉注射SB203580(0.1mg/kg),30min后行与LIP组相同的处理。用RM6280生物信号采集处理系统动态观察ECG和心内外膜MAP的变化。实验结束后,空气栓塞处死动物,摘取心脏,部分用4%多聚甲醛固定做形态学观察,部分存于-70℃冰箱待用。结果：①缺血前后,Ctr组心内膜APD90分别为(130.66±13.36)ms和(135.23±10.24)ms,心外膜APD90分别为(132.56±16.27)ms和(141.90±16.37)ms；LIP组心内膜APD90分别为(122.47±13.94)ms和(130.26±17.12)ms,心外膜APD90分别为(124.16±9.72)ms和(148.02±12.78)ms；LG组心内膜APD90分别为(127.19±36.78)ms和(134.72±46.01)ms,心外膜APD90分别为(146.20±16.21)ms和(160.78±22.73)ms；LSB组心内膜APD90分别为(100.88±13.36)ms和(104.56±28.46)ms,心外膜APD90分别为(105.77±18.59)ms和(104.10±20.69)ms。缺血后各组均出现室性心律失常,主要为室性早搏二联律和三联律。Ctr组有3例出现室性心动过速,未出现心室颤动,LIP、LG及LSB组均未出现室性心动过速及心室颤动。心律失常持续时间(s)分别为(231.54±15.78),(167.61±16.13),(159.38±29.56)和(209.83±26.39)。②心肌组织中SOD活力(U/mgprot)分别为(263.78±61.51),(322.63±50.46),(280.56±37.01)和(314.52±44.72)；MDA含量(nmol/mgprot)分别为(14.01±6.23),(5.34±2.17),(6.25±2.57)和(5.94±2.13)；NO含量(μmol/gprot)分别为(30.85±10.13),(242.17±48.84),(68.18±31.26)和(65.18±22.55)。③缺血后,各组心内膜APD90均延长,LIP及LSB组心内膜APD90短于Ctr组(P<0.05)；缺血后Ctr、LIP及LG组心外膜APD90延长而LSB组APD90缩短,LSB组心外膜APD90短于Ctr及LIP组(P<0.05)。LIP及LG组心律失常持续时间短于Ctr组(P<0.05)。LIP组SOD活力高于Ctr组(P<0.05),LG及LSB组SOD活力与Ctr及LIP组相比无差异(P>0.05);LIP、LG及LSB组MDA含量均低于Ctr组(P<0.01),LG及LSB组MDA含量与LIP组相比无差异(P>0.05)；LIP组NO含量高于Ctr组(P<0.01),LG及LSB组NO含量低于LIP组(P<0.01),LG及LSB组NO含量与Ctr组相比无差异(P>0.05)。④HSP70 mRNA的相对表达量分别为(3.04±0.20),(3.14±0.20),(2.65±0.18)和(2.61±0.31),LIP组HSP70 mRNA相对表达量与Ctr组相比无差异(P>0.05),而LG及LSB组HSP70 mRNA的相对表达量均低于Ctr及LIP组(P<0.01)；COX-2 mRNA的相对表达量分别为(1.36±0.16),(1.61±0.22),(1.47±0.19)和(1.14±0.09),LIP组COX-2 mRNA相对表达量高于Ctr组(P<0.05),LSB组COX-2 mRNA相对表达量低于Ctr及LIP组(P<0.05),LG组COX-2 mRNA相对表达量与Ctr及LIP组相比均无差异(P>0.05)；iNOS mRNA的相对表达量分别为(1.32±0.08),(1.75±0.12),(1.40±0.14)和(1.34±0.07),LIP组iNOS mRNA的相对表达量高于Ctr组(P<0.01),LG及LSB组iNOS mRNA的相对表达量低于LIP组(P<0.01)；TNFa mRNA的相对表达量分别为(0.57±0.03),(0.38±0.03),(0.55±0.06)和(0.54±0.04),LIP组TNFa mRNA的相对表达量低于Ctr组(P<0.01),LG及LSB组TNFa mRNA的相对表达量高于LIP组(P<0.01)；NF-κB mRNA的相对表达量分别为(0.62±0.05),(0.51±0.03),(0.59±0.04)和(0.60±0.04),LIP组NF-κB mRNA的相对表达量低于Ctr组(P<0.01),LG及LSB组NF-κB mRNA的相对表达量高于LIP组(P<0.01)。⑤p-p38MAPK蛋白阳性表达量在Ctr组为(0.08±0.02),LIP组为(0.15±0.03),LG组为(0.12±0.02),LIP及LG组p-p38MAPK蛋白表达均高于Ctr组(P<0.05),而p-p38MAPK蛋白在LSB组中的阳性表达量为(0.05±0.02),与Ctr、LIP及LG组相比均减少(P<0.05)。结论：1.LIP具有减轻心肌氧化损伤和改善心肌供血,进而增强兔缺血心肌电稳定性的作用；2.p38MAPK是LIP增强缺血心肌电稳定性的重要途径,KATP则在抗氧化和改善心肌供血等方面发挥了作用；3. LIP对I/R心肌起保护作用可能的机制和信号转导通路是,首先经“触发物质”启动心肌保护,然后通过“中介物质”启动信号转导,激活下游丝裂素活化蛋白激酶(MAPK)系统,进而引起信号的传递和放大,并活化核转录因子及产生“效应子”最终发挥心肌保护作用。
Abstract:Objective:To study on effects and mechanisms of the non-invasive limb ischemic preconditioning on ischemic ventricular arrhythmias in rabbits thus provides a practically theoretical basis for its clinical trial.Methods:Twenty-seven rabbits had been randomly divided into the control group(Ctr, n=8),non-invasive limb ischemic precondi-tioning group(LIP, n=7), LIP+ glibenclamide group(LG, n=6) and LIP+ SB203580 group(LSB,n=6).After anesthesia, the right external jugular vein was dissected and cannulated to the right ventricle to record the endocardium MAP. Needle electrodes were punctured in four limbs of the rabbit to record electrocardiogram (ECG).The contact electrode was inserted from the 4th or 5th ribs beside the left sternal to record the epi-cardium monophasic action potential(MAP).Ctr group does not been given any special treatment, but the vasopressin (2U/kg) was injected intravenously to produce myocardial ischemia background, then epine-phrine (0.2ml/kg) was injected to induce arrhythmia, when the records of ECG, endocardium and epicardium MAP were stabilized.The ECG, endo-cardium and epicardium MAP were simultaneously recorded, and the changes of endocardium & epicardium MAP and the relationship to arr- hythmia were observed.LIP group:pneumatic tourniquet was used to occlude the blood flow of rabbits'two hind limbs make them ischemia for 5 minutes,then loosened to reperfusion for 5 minutes,and repeated it for four times.Another methods and contents of observation were same as the Ctr group.LG group:Firstly, glibenclamide(0.16mg/kg) was intra-venous injection,30 minutes later, to carry out the same treatments as the LIP group.LSB group:After the SB203580 (0.1mg/kg) was intravenous injection for 30 minutes,to carry out the same treatment as the LIP group. ECG, the changes of endocardium & epicardium MAP, the types,inci-dence and duration of arrhythmia were simultaneously recorded.At the end of the experiment, air embolism was used to kill the animals, then remove the heart, and some parts were fixed with 4% paraformaldehyde for morphological observation, the other parts were stored in-70℃refri-gerator for another detections.Results:①Before and after ischemia, endocardium APD90 were(130.66±13.36)ms and(135.23±10.24)ms, epicardium APD90 were(132.56±16.27)ms and(141.90±16.37)ms in the Ctr group.Endocardium APD90 were(122.47±13.94)ms and(130.26±17.12)ms, epicardium APD90 were(124.16±9.72)ms and(148.02±12.78)ms in the LIP group.Endocardium APD90 were(127.19±36.78)ms and (134.72±46.01)ms, epicardium APD90 were (146.20±16.21)ms and (160.78±22.73)ms in the LG group.Endocardium APD90 were(100.88±13.36)ms and(104.56±28.46)ms,epicardium APD90 were(105.77± 18.59)ms and(104.10±20.69)ms in the LSB group.After ischemia, all rabbits presented arrhythmia, mainly represented as frequent ventricular premature contraction of bigeminy or trigeminy. There were 3 cases of ventricular tachycardia and no ventricular fibrillation in the Ctr group. There was no ventricular tachycardia and ventricular fibrillation in the LIP, LG and LSB group.The duration of arrhythmia(s)was (231.54±15.78),(167.61±16.13),(159.38±29.56) and (209.83±26.39) respec-tively.②The heart tissue detection of Ctr, LIP, LG & LSB group respectively indicated,SOD activity (U/mgprot) was (263.78±61.51), (322.63±50.46),(280.56±37.01)and(314.52±44.72).MDA content (nmol/mgprot) was(14.01±6.23),(5.34±2.17),(6.25±2.57) and (5.94±2.13).NO content(μmol/gprot) was (30.85±10.13),(242.17±48.84), (68.18±31.26)and(65.18±22.55).③After ischemia,endocardium APD90 was extended in each group,but endocardium APD90 of LIP and LSB group were shorter than Ctr group(P<0.05).Epicardium APD90 of Ctr group, LIP and LG group were extended while LSB group was shortening, and epicardium APD90 of the LSB group was shorter than Ctr and LIP group(P<0.05).The duration of arrhythmia of the LIP and LG group was shorter than the Ctr group(P<0.05).SOD activity of LIP group was higher than Ctr group(P<0.05).SOD activity of LG and LSB group compared with Ctr and LIP group no significant difference(P>0.05).The MDA levels of LIP, LG and LSB group were lower than Ctr group (P<0.01),and the MDA content of LG and LSB group compared with LIP group no significant difference(P>0.05).The NO content of LIP group was higher than Ctr group(P<0.01),and the NO content of LG and LSB group were lower than LIP group(P<0.01).④The relative expres-sion of HSP70 mRNA was(3.04±0.20),(3.14±0.20),(2.65±0.18)and (2.61±0.31)respectively. The relative expression of LIP group HSP70 mRNA compared with the Ctr group no significant difference(P>0.05), while the relative expression of LG and LSB group HSP70 mRNA were lower than Ctr and LIP group(P<0.01).The relative expression of COX-2 mRNA was(1.36±0.16),(1.61±0.22),(1.47±0.19)and(1.14±0.09) respectively. The relative expression of LIP group COX-2 mRNA was higher than Ctr group(P<0.05),and the relative expression of LSB group COX-2 mRNA was lower than Ctr and LIP group(P<0.05),while the relative expression of LG group COX-2 mRNA compared with Ctr and LIP group no significant difference(P>0.05).The relative expres-sion of iNOS mRNA was(1.32±0.08),(1.75±0.12),(1.40±0.14)and(1.34±0.07) respectively. The relative expression of LIP group iNOS mRNA was higher than Ctr group(P<0.01),and the relative expression of LG and LSB group iNOS mRNA were lower than LIP group(P<0.01).The rela-tive expression of TNFa mRNA was(0.57±0.03),(0.38±0.03),(0.55 +0.06) and (0.54±0.04)respectively. The relative expression of LIP group TNFa mRNA was lower than Ctr group(P<0.01),and the relative expression of LG and LSB group TNFαmRNA were higher than LIP group(P<0.01).The relative expression of NF-κB mRNA was (0.62±0.05),(0.51±0.03),(0.59±0.04)and (0.60±0.04)respectively. The relative expression of LIP group NF-κB mRNA was lower than Ctr group(P<0.01),and the relative expression of LG and LSB group NF-κB mRNA were higher than LIP group(P<0.01).⑤The protein expression of p-p38MAPK was (0.08±0.02)in the Ctr group,(0.15±0.03)in the LIP group, (0.12±0.02)in the LG group, The protein expression of p-p38MAPK in the LIP and LG group were higher than Ctr group (P<0.05).While it was (0.05±0.02)in the LSB group,and lower than the Ctr, LIP and LG group(P<0.05).Conclusion:1.LIP can reduce the injury of ischemic myocardial oxidative and improve myocardial blood supply, thus enhance electrical stability of ischemia myocardium.2.p38MAPK plays a very important role on LIP increasing cardiac electrophysio-logical stability, but KATP may participate only in antioxidation and to improve the blood supply of myocardium.3.The possible mechanisms and pathways of signal transduction of LIP protecting the I/R myocar-dium as follow. At first, LIP produce the "triggering substances" to switch on myocardial protection, then through the "intermediary" to start signal transduction, after that, mitogen-activated protein kinase system was activated to induce the signal transmission and amplification, and the activation of nuclear transcription factors,then the production of "effect- or" educe the myocardial protection effects.
Abstract:Objective:To study on effects and mechanisms of the non-invasive limb ischemic preconditioning on ischemic ventricular arrhythmias in rabbits thus provides a practically theoretical basis for its clinical trial.Methods:Twenty-seven rabbits had been randomly divided into the control group(Ctr, n=8),non-invasive limb ischemic precondi-tioning group(LIP, n=7), LIP+ glibenclamide group(LG, n=6) and LIP+ SB203580 group(LSB,n=6).After anesthesia, the right external jugular vein was dissected and cannulated to the right ventricle to record the endocardium MAP. Needle electrodes were punctured in four limbs of the rabbit to record electrocardiogram (ECG).The contact electrode was inserted from the 4th or 5th ribs beside the left sternal to record the epi-cardium monophasic action potential(MAP).Ctr group does not been given any special treatment, but the vasopressin (2U/kg) was injected intravenously to produce myocardial ischemia background, then epine-phrine (0.2ml/kg) was injected to induce arrhythmia, when the records of ECG, endocardium and epicardium MAP were stabilized.The ECG, endo-cardium and epicardium MAP were simultaneously recorded, and the changes of endocardium & epicardium MAP and the relationship to arr- hythmia were observed.LIP group:pneumatic tourniquet was used to occlude the blood flow of rabbits'two hind limbs make them ischemia for 5 minutes,then loosened to reperfusion for 5 minutes,and repeated it for four times.Another methods and contents of observation were same as the Ctr group.LG group:Firstly, glibenclamide(0.16mg/kg) was intra-venous injection,30 minutes later, to carry out the same treatments as the LIP group.LSB group:After the SB203580 (0.1mg/kg) was intravenous injection for 30 minutes,to carry out the same treatment as the LIP group. ECG, the changes of endocardium & epicardium MAP, the types,inci-dence and duration of arrhythmia were simultaneously recorded.At the end of the experiment, air embolism was used to kill the animals, then remove the heart, and some parts were fixed with 4% paraformaldehyde for morphological observation, the other parts were stored in-70℃refri-gerator for another detections.Results:①Before and after ischemia, endocardium APD90 were(130.66±13.36)ms and(135.23±10.24)ms, epicardium APD90 were(132.56±16.27)ms and(141.90±16.37)ms in the Ctr group.Endocardium APD90 were(122.47±13.94)ms and(130.26±17.12)ms, epicardium APD90 were(124.16±9.72)ms and(148.02±12.78)ms in the LIP group.Endocardium APD90 were(127.19±36.78)ms and (134.72±46.01)ms, epicardium APD90 were (146.20±16.21)ms and (160.78±22.73)ms in the LG group.Endocardium APD90 were(100.88±13.36)ms and(104.56±28.46)ms,epicardium APD90 were(105.77± 18.59)ms and(104.10±20.69)ms in the LSB group.After ischemia, all rabbits presented arrhythmia, mainly represented as frequent ventricular premature contraction of bigeminy or trigeminy. There were 3 cases of ventricular tachycardia and no ventricular fibrillation in the Ctr group. There was no ventricular tachycardia and ventricular fibrillation in the LIP, LG and LSB group.The duration of arrhythmia(s)was (231.54±15.78),(167.61±16.13),(159.38±29.56) and (209.83±26.39) respec-tively.②The heart tissue detection of Ctr, LIP, LG & LSB group respectively indicated,SOD activity (U/mgprot) was (263.78±61.51), (322.63±50.46),(280.56±37.01)and(314.52±44.72).MDA content (nmol/mgprot) was(14.01±6.23),(5.34±2.17),(6.25±2.57) and (5.94±2.13).NO content(μmol/gprot) was (30.85±10.13),(242.17±48.84), (68.18±31.26)and(65.18±22.55).③After ischemia,endocardium APD90 was extended in each group,but endocardium APD90 of LIP and LSB group were shorter than Ctr group(P<0.05).Epicardium APD90 of Ctr group, LIP and LG group were extended while LSB group was shortening, and epicardium APD90 of the LSB group was shorter than Ctr and LIP group(P<0.05).The duration of arrhythmia of the LIP and LG group was shorter than the Ctr group(P<0.05).SOD activity of LIP group was higher than Ctr group(P<0.05).SOD activity of LG and LSB group compared with Ctr and LIP group no significant difference(P>0.05).The MDA levels of LIP, LG and LSB group were lower than Ctr group (P<0.01),and the MDA content of LG and LSB group compared with LIP group no significant difference(P>0.05).The NO content of LIP group was higher than Ctr group(P<0.01),and the NO content of LG and LSB group were lower than LIP group(P<0.01).④The relative expres-sion of HSP70 mRNA was(3.04±0.20),(3.14±0.20),(2.65±0.18)and (2.61±0.31)respectively. The relative expression of LIP group HSP70 mRNA compared with the Ctr group no significant difference(P>0.05), while the relative expression of LG and LSB group HSP70 mRNA were lower than Ctr and LIP group(P<0.01).The relative expression of COX-2 mRNA was(1.36±0.16),(1.61±0.22),(1.47±0.19)and(1.14±0.09) respectively. The relative expression of LIP group COX-2 mRNA was higher than Ctr group(P<0.05),and the relative expression of LSB group COX-2 mRNA was lower than Ctr and LIP group(P<0.05),while the relative expression of LG group COX-2 mRNA compared with Ctr and LIP group no significant difference(P>0.05).The relative expres-sion of iNOS mRNA was(1.32±0.08),(1.75±0.12),(1.40±0.14)and(1.34±0.07) respectively. The relative expression of LIP group iNOS mRNA was higher than Ctr group(P<0.01),and the relative expression of LG and LSB group iNOS mRNA were lower than LIP group(P<0.01).The rela-tive expression of TNFa mRNA was(0.57±0.03),(0.38±0.03),(0.55 +0.06) and (0.54±0.04)respectively. The relative expression of LIP group TNFa mRNA was lower than Ctr group(P<0.01),and the relative expression of LG and LSB group TNFαmRNA were higher than LIP group(P<0.01).The relative expression of NF-κB mRNA was (0.62±0.05),(0.51±0.03),(0.59±0.04)and (0.60±0.04)respectively. The relative expression of LIP group NF-κB mRNA was lower than Ctr group(P<0.01),and the relative expression of LG and LSB group NF-κB mRNA were higher than LIP group(P<0.01).⑤The protein expression of p-p38MAPK was (0.08±0.02)in the Ctr group,(0.15±0.03)in the LIP group, (0.12±0.02)in the LG group, The protein expression of p-p38MAPK in the LIP and LG group were higher than Ctr group (P<0.05).While it was (0.05±0.02)in the LSB group,and lower than the Ctr, LIP and LG group(P<0.05).Conclusion:1.LIP can reduce the injury of ischemic myocardial oxidative and improve myocardial blood supply, thus enhance electrical stability of ischemia myocardium.2.p38MAPK plays a very important role on LIP increasing cardiac electrophysio-logical stability, but KATP may participate only in antioxidation and to improve the blood supply of myocardium.3.The possible mechanisms and pathways of signal transduction of LIP protecting the I/R myocar-dium as follow. At first, LIP produce the "triggering substances" to switch on myocardial protection, then through the "intermediary" to start signal transduction, after that, mitogen-activated protein kinase system was activated to induce the signal transmission and amplification, and the activation of nuclear transcription factors,then the production of "effect- or" educe the myocardial protection effects.
引文
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14.Hagar JM, Hale SL, Kloner RA.Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reper-fusion in the rat.Circ Res,1991 Jan;68(1):61-68
15.Oxman T, Arad M, Klein R, et al.Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol,1997;273 (4Pt2):H1707-H1712
16.夏正远,史听云,Willern Flameng,等.远端器官预缺血改善冠状动脉缺血再灌注时心肌血供及减少心律失常发生率.中国心脏起搏与心电生理杂志,2000；14(4)：254-256
17.徐威,欧阳静萍,汪长华.远距预处理对心肌缺血再灌注损伤的影响.中国心脏起搏与心电生理杂志,2002；16(6)：463-465
18.冯志强,冉兵,张春来,等.肾缺血预处理增强心脏的电稳定性.中国病理生理杂志,1999；15(5),444-446
19.Siegmund B,Schlack W, Ladilov YV, et al.Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture[J]. Circulation,1997;96(12):4372-4379
20.苏德淳,常志文,芦玲巧,等.缝隙连接蛋白43在缺血性心律失常中的作用[J].首都医科大学学报,2006；27(3)：325-328
21.Lukas A, Antzelevitch C.Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ische-mia.Role of the transient outward current[J].Circulation,1993; 88(6): 2903-2915
22.陈明,杨新春,李翠兰,等.缺血预适应对兔离体灌注心脏生化及电生理的影响[J].中国医药导刊,2008；10(3)：422-424
23.Karaguezian HS,Fenoglio JJ Jr, Weiss MB,et al.Coronary occlu-sion and reperfusion:Effects on subendocardial cardiac fibers[J].Am J Physiol,1980;238(4):H581-H593
24.Elaiopoulos DA, Tsalikakis DG,Agelakh MG, et al.Growth hormone decreases phase Ⅱ ventricular tachyarrhythmias during acute myo-cardial infarction in rats[J].Clin Sci(lond),2007;112(7):385-391
25.柳景华,任自文,汪丽蕙,等.缺血预适应对兔心脏电生理参数的影响[J].中国介入心脏病学杂志,2000；8(1)：48-51
26.朱莉,曹克特,单其俊,等.心肌梗死前后心室肌细胞单相动作电位的变化及其意义[J].南京医科大学学报(自然科学版),2002；22(3)：197-199
27.姚青海,崔长琮,吴尚勤,等.兔肥厚左心室跨壁复极离散度和室性心律失常发生机制[J].中华心律失常学杂志,2006；10(2)：153-156
28.Thomas G,Gurung IS,Killeen MJ,et al.Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3[J].physiol,2007; 578(Ptl):85-97
29.Sun XC,Xian XH, Cai JS,et al.Superoxide dismutase participates in p38MAPK mediated neuroprotection of limb ischemic precondi-tioning in global brain ischemic rats[J].Chin J Pharmacol Toxicol, 2007;21(6):455-461
30.陈晓光,马虹,王俊科,等.核因子-kappaB在肢体缺血预处理早期心肌保护中的作用.中国应用生理学杂志,2008；24(2)：166-169
31.Riksen NP,Smits P, Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅰ [J].The Neth- erlads Journal of Medcine,2004;62(10):353-363
32.Riksen NP, Smits P, Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅱ [J].The Neth-erlands Journal of Medcine,2004;62(11):409-423
33.陈晓光,马虹,王俊科,等.肢体缺血预处理对缺血／再灌注心肌保护作用及机制[J].中国药理学通报,2007；23(11)：1490-1493
34.Kim E, Raval AP, DeFazio RA,et al.Ischemic preconditioning via epsilon PKC activation requires cyclooxygenase-2 activation in vitro [J].Neuroscience,2007;145(3):931-941
35.Syeda F, Grosjean J,Rebecca A, et al.Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-κB pathways[J].Biological chemistry,2006;281(17):11792-11804
1.郑波,张奇惠,李跃荣,心肌缺血再灌注损伤机制研究进展[J].滨州医学院学报,2008；2(31)：121-123
2.Burley D S,Ferdinandy P, Baxter G F. Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion:opportunities and obs-tacles for survival signaling[J].Br J Pharmacol.2007;152(6):855-869
3.Clements-Jewery H.Mitochondria the calcium uniporter and reperfu-sion-induced ventricular fibrillation[J].Br J Pharmacol,2006; 149(7): 811-813
4.Murry CE,Jenning RB,Reimer KA, et al.Preconditioning with ischmia:a delay of cell injury in ischemic myocardium[J].Circulation, 1986;74:1124-1136
5.Riksen NP,Smits P,Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅰ [J].The Neth-erlads Journal of Medcine,2004;62(10):353-362
6.Riksen NP,Smits P,Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅱ [J].The Neth-erlands Journal of Medcine,2004;62(11):409-423
7.刘胜中,杨双强.阿片受体介导心肌缺血预适应保护作用的研究进展[J].心脏杂志,2007；19(6)：726-728
8.武宏敏,张建新.一氧化氮与心肌缺血再灌注损伤[J].河北医药, 2008；30(6)：836-838
9.Shen YT, Depre C,Yan L, et al.Repetitive ischemia by coronary stenosis induces a novel window of ischemic preconditioning[J]. Circulation,2008;118:1961-1969
10.陈隽鹏,洪丰,郑顺利.蛋白激酶C信号传导在心肌缺血预处理中的作用研究进展[J].广东医学,2006；12(27)：1914-1916
11.黄燕,刘兴奎,喻田,等.缺血预处理和吡那地尔预处理对NF-κB的影响及其心肌保护作用[J].重庆医科大学学报,2006；31(3)：326-329
12.唐白云,刘喜利,吴钟凯,等.核转录因子-κB在体外循环术缺血预处理心肌保护机制中的作用[J].中华实用外科杂志,2007；24(2)：207-208
13.Xuan YT, Guo Y, Zhu Y, et al.Endothelial nitric oxide synthase plays an obligatory role in the late phase of ischemic preconditioning by activating the protein kinase Cε-p44/42 mitogen-activated protein kinase-pSer-signal transducers and activators of transcription 1/3 pathway[J].Circulation,2007; 116:535-544
14.钟标,钟焕清,陈海生.线粒体三磷酸腺苷敏感性钾通道与心肌预适应[J].医学综述,2006；12(2)：100-101
15.曹泽玲,杨庭树,龙超良,等.心肌缺血／再灌注损伤的内源性保护机制研究进展[J].中国药理学通报,2006；22(8)：912-916
16.Loukogeorgakis SP, Williams R, Panagiotidou AT,et al. Transient limb ischemia induces remote preconditioning and remote postcon-ditioning in humans by a KATP channel-dependent mechanism[J]. Circulation,2007;116:1386-1395
17.刘颖,陈晨,吴伟康,等.细胞凋亡的线粒体信号通路在大鼠缺血延迟预适应抗心肌细胞凋亡机制中的作用[J].中国康复医学杂志,2006；21(5)：401-404
18.綦俊,杨双强.心肌缺血预适应中的细胞信号转导机制研究进展[J].重庆医学,2007；36(1)：80-83
19.Dawn B,Xuan YT, Guo Y, et al.IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2[J].Cardiovasc Res,2004;64(1):6-8
20.Bolli R, Dawn B,Xuan YT. Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury[J].Trends Cardivase Med,2003;13(2):72-79
21.Papp R, Gonczi M, Kovacs M, et al.Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic precondi-tioning[J]. Cardiovascular,2007;74(3):396-405
22.Miura T, Ohnuma Y, Kuno A, et al.Protective role of gap junctions in preconditioning against myocardial infarction[J].Am J Physiol Heart Circ Physiol,2004;286(1):H214-H221
2.陈晓光,白涛,王俊科,等.非创伤性肢体缺血预适应对心肌缺血／再灌注损伤的影响[J].中国医科大学学报,2006；35(3)：256-258
3.唐英,王泉云,黎静宜.KATP抑制剂对七氟醚诱导乳鼠心肌细胞HSP70表达的影响[J].四川大学学报(医学版),2003；34(4)：653-655
4.Zhang Ye, Gu Er wei,Zhang Jian, et al.Role of p38 mitogen-activated protein kinases in cardioprotection of morphine preconditioning[J]. Chinese Medical Journal,2007;120(9):777-781
5.祝少博,陈振光,喻爱喜,等.低剂量FK506预处理诱导移植物对缺血再灌注损伤耐受的影响[J].中华显微外科杂志,2005；28(3)：231-234
6.黄健兵,胡丰庆,罗俊辉,等.环氧化酶2在兔自体移植静脉模型中的表达[J].中国组织工程研究与临床康复,2008；12(53)：10461-10464
7.何国厚,王建,刘勇.小檗碱对颈动脉粥样硬化家兔NF-κB、MCP-1表达的影响[J].卒中与神经疾病,2009；16(2)：83-86
8.Murry CE, Jenning RB,Reimer KA, et al.Preconditioning with is-chmia:a delay of cell injury in ischemic myocardium[J].Circulation, 1986;74:1124-1136
9.Chen XG, Wu BY, Wang JK, et al.Mechanism of the protective effects of noninvasive limbs preconditioning on myocardial ischemia-reperfu-sion injury.Chinese Medical Journal,2005;118(20):1723-1727
10.Weinbrenner C,Schulze F,Sarvary L, et al.Remote preconditioning by infrarenal aortic occlusion is operative via deltal-opioid receptors and free radicals in vivo in the rat heart.Cardiovasc Res,2004 Feb 15;61(3):591-599
11.Steen BK, Ole H, Rajesh KK, et al.Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism.Am J Physiol Heart Circ Physiol,2005;288:H1252-H1256
12.Liem DA,Verdouw PD, Ploeg H, et al.Sites ofaction of adenosine in interorgan preconditioning of the heart[J].Am J Physiol Heart Circ Physiol,2002;283:H29-H37
13.Ding YF, Zhang MM, He RR.Role of renal nerve in cardioprotection provided by renal ischemic preconditioning in anesthetized rabbits[J]. Sheng Li Xue Bao.2001;53(1):7-12
14.Hagar JM, Hale SL, Kloner RA.Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reper-fusion in the rat.Circ Res,1991 Jan;68(1):61-68
15.Oxman T, Arad M, Klein R, et al.Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol,1997;273 (4Pt2):H1707-H1712
16.夏正远,史听云,Willern Flameng,等.远端器官预缺血改善冠状动脉缺血再灌注时心肌血供及减少心律失常发生率.中国心脏起搏与心电生理杂志,2000；14(4)：254-256
17.徐威,欧阳静萍,汪长华.远距预处理对心肌缺血再灌注损伤的影响.中国心脏起搏与心电生理杂志,2002；16(6)：463-465
18.冯志强,冉兵,张春来,等.肾缺血预处理增强心脏的电稳定性.中国病理生理杂志,1999；15(5),444-446
19.Siegmund B,Schlack W, Ladilov YV, et al.Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture[J]. Circulation,1997;96(12):4372-4379
20.苏德淳,常志文,芦玲巧,等.缝隙连接蛋白43在缺血性心律失常中的作用[J].首都医科大学学报,2006；27(3)：325-328
21.Lukas A, Antzelevitch C.Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ische-mia.Role of the transient outward current[J].Circulation,1993; 88(6): 2903-2915
22.陈明,杨新春,李翠兰,等.缺血预适应对兔离体灌注心脏生化及电生理的影响[J].中国医药导刊,2008；10(3)：422-424
23.Karaguezian HS,Fenoglio JJ Jr, Weiss MB,et al.Coronary occlu-sion and reperfusion:Effects on subendocardial cardiac fibers[J].Am J Physiol,1980;238(4):H581-H593
24.Elaiopoulos DA, Tsalikakis DG,Agelakh MG, et al.Growth hormone decreases phase Ⅱ ventricular tachyarrhythmias during acute myo-cardial infarction in rats[J].Clin Sci(lond),2007;112(7):385-391
25.柳景华,任自文,汪丽蕙,等.缺血预适应对兔心脏电生理参数的影响[J].中国介入心脏病学杂志,2000；8(1)：48-51
26.朱莉,曹克特,单其俊,等.心肌梗死前后心室肌细胞单相动作电位的变化及其意义[J].南京医科大学学报(自然科学版),2002；22(3)：197-199
27.姚青海,崔长琮,吴尚勤,等.兔肥厚左心室跨壁复极离散度和室性心律失常发生机制[J].中华心律失常学杂志,2006；10(2)：153-156
28.Thomas G,Gurung IS,Killeen MJ,et al.Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3[J].physiol,2007; 578(Ptl):85-97
29.Sun XC,Xian XH, Cai JS,et al.Superoxide dismutase participates in p38MAPK mediated neuroprotection of limb ischemic precondi-tioning in global brain ischemic rats[J].Chin J Pharmacol Toxicol, 2007;21(6):455-461
30.陈晓光,马虹,王俊科,等.核因子-kappaB在肢体缺血预处理早期心肌保护中的作用.中国应用生理学杂志,2008；24(2)：166-169
31.Riksen NP,Smits P, Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅰ [J].The Neth- erlads Journal of Medcine,2004;62(10):353-363
32.Riksen NP, Smits P, Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅱ [J].The Neth-erlands Journal of Medcine,2004;62(11):409-423
33.陈晓光,马虹,王俊科,等.肢体缺血预处理对缺血／再灌注心肌保护作用及机制[J].中国药理学通报,2007；23(11)：1490-1493
34.Kim E, Raval AP, DeFazio RA,et al.Ischemic preconditioning via epsilon PKC activation requires cyclooxygenase-2 activation in vitro [J].Neuroscience,2007;145(3):931-941
35.Syeda F, Grosjean J,Rebecca A, et al.Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-κB pathways[J].Biological chemistry,2006;281(17):11792-11804
1.郑波,张奇惠,李跃荣,心肌缺血再灌注损伤机制研究进展[J].滨州医学院学报,2008；2(31)：121-123
2.Burley D S,Ferdinandy P, Baxter G F. Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion:opportunities and obs-tacles for survival signaling[J].Br J Pharmacol.2007;152(6):855-869
3.Clements-Jewery H.Mitochondria the calcium uniporter and reperfu-sion-induced ventricular fibrillation[J].Br J Pharmacol,2006; 149(7): 811-813
4.Murry CE,Jenning RB,Reimer KA, et al.Preconditioning with ischmia:a delay of cell injury in ischemic myocardium[J].Circulation, 1986;74:1124-1136
5.Riksen NP,Smits P,Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅰ [J].The Neth-erlads Journal of Medcine,2004;62(10):353-362
6.Riksen NP,Smits P,Rongen GA.Ischemic preconditioning:from molecular characterization to clinical application-part Ⅱ [J].The Neth-erlands Journal of Medcine,2004;62(11):409-423
7.刘胜中,杨双强.阿片受体介导心肌缺血预适应保护作用的研究进展[J].心脏杂志,2007；19(6)：726-728
8.武宏敏,张建新.一氧化氮与心肌缺血再灌注损伤[J].河北医药, 2008；30(6)：836-838
9.Shen YT, Depre C,Yan L, et al.Repetitive ischemia by coronary stenosis induces a novel window of ischemic preconditioning[J]. Circulation,2008;118:1961-1969
10.陈隽鹏,洪丰,郑顺利.蛋白激酶C信号传导在心肌缺血预处理中的作用研究进展[J].广东医学,2006；12(27)：1914-1916
11.黄燕,刘兴奎,喻田,等.缺血预处理和吡那地尔预处理对NF-κB的影响及其心肌保护作用[J].重庆医科大学学报,2006；31(3)：326-329
12.唐白云,刘喜利,吴钟凯,等.核转录因子-κB在体外循环术缺血预处理心肌保护机制中的作用[J].中华实用外科杂志,2007；24(2)：207-208
13.Xuan YT, Guo Y, Zhu Y, et al.Endothelial nitric oxide synthase plays an obligatory role in the late phase of ischemic preconditioning by activating the protein kinase Cε-p44/42 mitogen-activated protein kinase-pSer-signal transducers and activators of transcription 1/3 pathway[J].Circulation,2007; 116:535-544
14.钟标,钟焕清,陈海生.线粒体三磷酸腺苷敏感性钾通道与心肌预适应[J].医学综述,2006；12(2)：100-101
15.曹泽玲,杨庭树,龙超良,等.心肌缺血／再灌注损伤的内源性保护机制研究进展[J].中国药理学通报,2006；22(8)：912-916
16.Loukogeorgakis SP, Williams R, Panagiotidou AT,et al. Transient limb ischemia induces remote preconditioning and remote postcon-ditioning in humans by a KATP channel-dependent mechanism[J]. Circulation,2007;116:1386-1395
17.刘颖,陈晨,吴伟康,等.细胞凋亡的线粒体信号通路在大鼠缺血延迟预适应抗心肌细胞凋亡机制中的作用[J].中国康复医学杂志,2006；21(5)：401-404
18.綦俊,杨双强.心肌缺血预适应中的细胞信号转导机制研究进展[J].重庆医学,2007；36(1)：80-83
19.Dawn B,Xuan YT, Guo Y, et al.IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2[J].Cardiovasc Res,2004;64(1):6-8
20.Bolli R, Dawn B,Xuan YT. Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury[J].Trends Cardivase Med,2003;13(2):72-79
21.Papp R, Gonczi M, Kovacs M, et al.Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic precondi-tioning[J]. Cardiovascular,2007;74(3):396-405
22.Miura T, Ohnuma Y, Kuno A, et al.Protective role of gap junctions in preconditioning against myocardial infarction[J].Am J Physiol Heart Circ Physiol,2004;286(1):H214-H221