心肌缺血期短暂肢体缺血处理对大鼠心肌保护作用的研究
|
摘要
目的：研究心肌缺血期短暂肢体缺血处理(remote perconditioning, RP)对大鼠心肌缺血再灌注(I／R)损伤的保护作用。
方法：健康雄性Wistar大鼠经胸骨下段切口暴露心脏,打活结的方式结扎或旷置冠状动脉左前降支(LAD)后,经心尖置测压管于左心室,建立在体心肌I/R损伤模型,随机分为7组。(1)假手术组(Sham组,n=8)：经冠状动脉左前降支(LAD)下穿线后,旷置；(2)缺血／再灌注组(IR组,n=12)：心脏LAD实施30min缺血／180min再灌注处理；(3)心肌缺血期短暂肢体缺血处理组(RP组,n=10)：心脏LAD实施30min缺血／180min再灌注处理；在实施心肌缺血期间对双下肢实施3次5min缺血／5min再灌注;(4)短暂肢体缺血预处理组(RIPC组,n=11)：心肌缺血前先对双下肢实施3次5min缺血／5min再灌注,而后对心脏LAD实施30min缺血／180min再灌注处理；(5)短暂肢体缺血后处理组(RI-PostC组,n=11)：对心脏LAD实施30min缺血／180min再灌注处理；再灌注开始的同时对双下肢实施3次5min缺血／5min再灌注；(6)格列苯脲组(GL组,n=11)：心脏LAD实施30min缺血／180min再灌注处理；在实施心肌缺血期间对双下肢实施3次5min缺血／5min再灌注；同时腹腔注射线粒体ATP敏感性钾通道(mKATP)抑制剂格列苯脲5mg/kg;(7)环孢霉素A组(CS组,n=10)：心脏LAD实施30min缺血／180min再灌注处理；心肌缺血期间经心脏测压管注射线粒体通透性转换孔(mPTP)抑制剂环孢霉素A (CsA) 10mg/kg。
从再灌注性心律失常(reperfusion arrhythmia, RA)、心肌舒缩能力、心肌损伤标志物、心梗范围、心肌细胞凋亡相关蛋白的表达等方面评价RP对心肌IRI的保护作用。计算缺血期心律失常(ischemia arrhythmia, IA)及RA评分、左心室发展压(LVDP)、左心室压上升／下降最大速率(±dp/dtmax)及其恢复率；ABC夹心ELISA法检测血清肌酸激酶(CK)活性和心肌肌钙蛋白T(c-TNT)、HE染色观察心肌形态学改变,TTC染色法测定心肌梗死面积,免疫组化法检测心肌细胞凋亡相关蛋白Bcl-2、Bax的表达,免疫印迹法(western blot)检测心肌凋亡蛋白caspase-3的表达。
结果：
1.动物模型的评价IR组与Sham组比较,心肌缺血期ST段显著抬高(P<0.01),缺血期及再灌注期心律失常评分显著增加(P<0.05),左心室收缩峰压(LVSPmax),±dp/dtmax在再灌注起点时下降,差异均具有统计学意义(P<0.05),c-TNT显著升高(P<0.05)。
2.RP对大鼠心肌I／R损伤所致RA、心脏舒缩功能及心梗范围的影响再灌注早期RP组RA评分为(1.50±0.97),与R组(2.33±0.71)差异有统计学意义(P=0.049<0.05)；RP组的LVSPmax、±dp/dtmax均介于Sham组与IR组之间,但与R组的差异无统计学意义。三组间CK差异无统计学意义,关于c-TNT, IR组与Sham组的差异具统计学意义(P=0.021),但RP组与IR组、sham组间差异均无统计学意义。三组关于左室心肌危险区域(缺血范围)无显著差异,RP组心梗范围显著小于IR组(P<0.01)。
3.RP对大鼠心肌I／R损伤所致细胞凋亡的影响比较R组与RP组的Bcl-2、Bax的表达结果发现,与R组相比,RP组Bax蛋白表达阳性心肌细胞百分比明显降低(P<0.05),而Bcl-2蛋白表达阳性百分比无显著性差异(P>0.05),Bcl-2/Bax比值明显升高(P<0.05)。RP组caspase-3的表达与IR组间无显著性差异(P>0.05)。
4.RP、RIPC、RI-PostC模式对大鼠心肌I／R损伤影响的比较再灌注早期RP组RA评分与IR组之间差异显著(P<0.05),但RIPC组、RI-PostC组与IR组、RP间差异均无统计学意义。RP组与R组间血流动力学数据无显著性差异。RIPC组在再灌注30 min时LVDPmin高于R组,RI-PostC组-dp/dtmax再灌注0 min时显著低于RP组(P<0.05),其余数值差异无统计学意义。四组间CK与c-TNT均无显著差异。RP、RIPC、RI-PostC组心梗范围显著低于R组(P<0.01),RP、RIPC、RI-PostC三组间无显著差异。RP组、RIPC组、RI-PostC组Bcl-2表达均高于IR组,RI-PostC组表达高于RP组与R组,RIPC组表达高于IR组(P<0.05)。RP组、RIPC组、RI-PostC组关于Bax表达相当,RP组、RIPC组显著低于R组(P<0.05)。R组Bcl-2/Bax阳性单位的比值低于RP、RI-PostC、RIPC三组,与RP组差异有统计学意义(P<0.05)。RP组、RIPC组、RI-PostC组三组间关于Bcl-2、Bax、Bcl-2/Bax差异无统计学意义。四组间caspase-3蛋白的表达差异无统计学意义。
5.应用格列苯脲干预RP处理对大鼠心肌I／R损伤的影响GL组再灌注早期RA评分低于IR组,差异具有统计学意义(P<0.05),但与RP组无显著差异。在再灌注0 min时,GL组LVSPmax及±dp/dtmaX高于R组(P<0.05)。GL组与RP组间无显著差异。GL组c-TNT表达低于R组及RP组(P<0.05)。GL组心梗范围介于RP、R组之间,与RP组差异具有统计学意义(P<0.05),与R组差异无统计学意义。
RP组、GL组关于Bcl-2表达相当,均高于IR组,GL组与R组间具有显著性差异(P<0.05)。GL组关于Bax表达介于RP、IR组之间,但差异无统计学意义。三组间Bcl-2/Bax阳性单位比值的差异缺乏统计学意义。GL组caspase-3的表达显著高于IR组和RP组,具有统计学意义(P<0.05)。
6.心肌缺血期应用CsA对大鼠心肌I／R损伤的影响CS组再灌注早期RA评分低于R组,差异具有统计学意义(P<0.05),但与RP组差异无统计学意义。CS组再灌注0、60 min, LVDPmin均高于IR组；再灌注120 min时,LVSPmax低于IR组；再灌注30-180 min的±dp/dtmax恢复率均低于IR组。再灌注60 min时-dp/dtmax,再灌注120min时LVSPmax,再灌注180 min时dp/dtmax低于RP组；再灌注30-180 min,-dp/dtmax恢复率及30-60 min dp/dtmax恢复率均低于RP组；再灌注120min, LVDP低于RP组(P<0.05)。CS组c-TNT表达低于R组及RP组,但无统计学意义。CS组心梗范围介于RP、IR组之间,显著小于R组(P<0.05)。RP、CS组关于Bcl-2表达相当,均高于IR组,但差异无统计学意义。CS组Bax表达介于IR, RP组之间,但与两组差异无统计学意义。关于Bcl-2/Bax阳性单位的比值的排序为：R组 结论：
1.经胸骨下段切口建立大鼠心肌缺血／再灌注模型简便易行,监测结果稳定可靠。
2.RP能减少大鼠心肌I／R损伤,表现为减轻再灌注性心律失常,缩小心肌梗死面积,改善心肌形态学损伤,保护左心室收缩、舒张功能。RP可能通过减少促凋亡蛋白Bax的表达来发挥对IRI诱发的心肌细胞凋亡的抑制作用。
3.肢体短暂缺血模式进行的RIPC、RP、RI-Postc三种模式均具有心肌保护作用,表现为减小心肌梗死范围,抑制心肌细胞凋亡,且保护能力相当。
4.腹腔注射格列苯脲可以减轻心肌缺血性心律失常,也部分抵消了RP的心肌保护作用。心腔注射CsA可以模拟部分RP的心肌保护作用,但其对心肌的隐匿副损伤抵消了其它的有益作用。线粒体ATP敏感性钾通道(mKATP)和线粒体通透性转换孔(mPTP)仍是RP诱导内源性心肌保护的最重要效应器。
Objective:To study the protection induced by transient limb ischemic conditioning during myocardial ischemic period against myocardial ischemia reperfusion (I/R) injury of rats.
Method:Healthy male Wistar rats were administered. The heart was exposed through lower sternal incision and the left anterior descending coronary artery was ligated by snipknot to establish the ischemia/reperfusion model. A catheter was put into the left ventricle from the apex of heart to trace the pressure of left ventricle and the pressure change index while electrocardiogram was monitored. Rats were assigned randomly into seven groups. (1)Sham group (n=8):rats were threaded a silk suture under the left coronary artery anterior descending (LAD) and laid up through out the experiment. (2)IR group (n=12):rats were subjected to 30 min LAD occlusion followed by 180 min reperfusion. (3) RP group (transient limb ischemic conditioning during myocardial ischemia period, remote preconditioning group) (n=10):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion during 30 min myocardial ischemia period which follower by 180 min reperfusion. (4) RIPC group (remote ischemia preconditioning group) (n=11):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion before 30 min myocardial ischemia period which follower by 180 min reperfusion. (5) RI-PostC group (remote ischemia post-conditioning group) (n=11):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion at the very beginning of reperfusion during 30 min myocardial ischemia and 180 min reperfusion period. (6)GL group (Glibenclamide group) (n=11):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion during 30 min myocardial ischemia period while glibenclamide was injected intraperitoneally dosed with 5 mg/kg which also follower by 180 min reperfusion. (7)CS group (Cyclosporin A group) (n=10):rats were subjected to 30 min LAD occlusion followed by 180 min reperfusion while CsA was injected into the left ventricle from the catheter dosed with 10 mg/kg.
The myocardial protection induced by RP against IRI was evaluated by reperfusion arrhythmia (RA), cardiac contractility, marker of myocardial injury, infarct size, cardiocyte death, expression of apopto sis-relevant proteins. The scores of ischemia arrhythmia and reperfusion arrhythmia, the left ventricular developing pressure, the maximal change index of LV (±dp/dtmax) and recovery percentage of maximal change index were calculated. Serum CK (creatine kinase) and c-TNT (cardiac troponin T) were tested by ABC ELISA. Myocardial definite change of tissue morphology was inspected by HE staining. Myocardial infarct size was measured by TTC staining technique. The expression of apoptosis-relevant proteins, Bcl-2 and Bax, were tested by histochemistry immunity method, and caspase-3 was tested by western blot.
Results:
1. Evaluation of animal model.
Compare IR group to Sham group, the ST segment of ischemia period was significant elevated(P<0.01), the scores of ischemia and reperfusion arrhythmia were significant increased(P<0.05), the maximum systolic pressure of left ventricular and the idp/dtmax at the reperfusion starting point were significantly decreased, and the serum c-TNT was significantly higher (P<0.05).
2. Influence on RA, cardiac contractility and infarct size of remote perconditioning against rats'ischemia reperfusion injury.
The RA score of early reperfusion phase, change index and maximal pressure of left ventricle at end point of RP group all fell in between IR group and sham group. The arrhythmic score of RP group was (1.50±0.97) and the score of IR group was (2.33±0.71). The difference between them was statistically significant (P=0.049). There was no statistically significant difference on change index and maximal pressure of left ventricle between IR group and RP group. Difference of CK among three groups was not statistically significant. While the c-TNT of IR group was significant higher than that of sham group (P=0.021), there was no statistically significant difference between RP and IR group or between RP and sham group. There was no difference of ischemia size among three groups, while infarct sizeof RP group was significant smaller than that of IR group (P<0.01).
3. Influence on cardiocyte apoptosis against rats'myocardial IRI.
Compared to IR group, the percentage of cardiocyte of RP group which expressed Bax was statistically significantly lower (P<0.05), while the percentage of Bcl-2 was not (P>0.05). The rate of Bcl-2/Bax was statistically significantly higher (P<0.05). There was no significant difference on expression of caspase-3 between RP and IR group (P>0.05).
4. Comparison among RP, RIPC and R1-PostC induced protection against rats' myocardial IRI.
RA score of RP group was smaller than IR group (P<0.05) but it of RIPC and Rl-PostC group had no statistically significant difference compared to both RP and IR groups. There were no statistically significant difference of hemodynamics data between RP group and IR group. Compared to IR group, LVDPmin of RIPC group were higher at reperfusion 30 min (P<0.05) and-dp/dtmax of RI-PostC group was lower at reperfusion 0 min (P<0.05). Other data difference was not statistically significant. Difference of serum CK and c-TNT among four groups was not statistically significant. There was no difference of ischemia size among four groups, while the infarct size of RP, RIPC and RI-PostC group was statistically significantly smaller than IR group (P<0.01). The infarct size percentage of RP group was (15.27±5.19), it of RIPC group was (14.53±3.45), and it of RI-PostC group was (19.84±5.85), while the size percentage of IR group was (34.47±7.13). There was no difference of infarct size among three conditioned groups.
Expression of Bcl-2 in three groups was higher than it of IR group. Bcl-2 of RI-PostC group was statistically significant higher than it of RP and IR groups while that of RIPC group was higher than that of IR group (P<0.05). Expression of Bax in three groups was similar and those of RP and RIPC group were statistically significant lower than it of IR group (P<0.05). The Bcl-2/Bax positive unit rate of IR group was lower than RP, RIPC and R1-PostC group. The difference between IR and RP group was statistically significant (P<0.05). There was no significant difference on Bcl-2, Bax and Bcl-2/Bax among three conditioned groups. There was also no significant difference on caspase-3 among these four groups.
5. Impact of glibenclamide on remote perconditioning induced myocardial protection.
RA scores (P<0.05) of GL group was lower than IR group. The LVSPmax and±dp/dtmax were higher than IR group (P<0.05) at reperfusion 0 min. But there were no significant difference of arrhythmia scores and cardiac contractility compared to RP group. Serum c-TNT of GL group was lower than RP and IR group (P<0.05). The infarct size of GL group fell in between RP group and IR group, the difference compared to RP group was statistically significant (P<0.05) while it compared to IR group was not.
Expression of Bcl-2 in RP group and GL group were higher than IR group and there was statistically significant difference between GL and IR group. Expression of Bax in GL group fell in between RP group and IR group, while no statistically significant difference was found compared to RP and IR group. The difference of Bcl-2/Bax positive unit rate wasn't significant. Expression of caspase-3 in GL group was higher than both IR and RP group (P<0.05).
6. Influence of CsA applied during myocardial ischemia period against rats' myocardial IRI.
RA scores (P<0.05) of CS group was lower than IR group, while no significant difference was found compared to RP group. Compared to IR group, LVDPmin was higher at reperfusion 0 and 60 min; LVSPmax was lower at reperfusion 120 min; recovery percentage of±dp/dtmax was lower from reperfusion 30 min to 180 min(P<0.05).
Compared to RP group, LVSPmax,-dp/dtmax at reperfusion 60 min, LVSPmax at 120 min and±dp/dtmax at 180 min of CS group were lower; recovery percentage of-dp/dtmax from 30 to 180 min and dp/dtmax from 30 to 60 min were lower; LVDP at 60 min was also lower than RP group (P<0.05).
Serum c-TNT of CS group was lower than RP and IR group but not statistically significant. The infarct size of CS group fell in between RP group and IR group, the difference between CS and IR group was statistically significant (P<0.05).
Expression of Bcl-2 in RP group and CS group were higher than IR group but there was no statistically significant difference. Expression of Bax in CS group fell in between RP group and IR group, while no statistically significant difference was found. The sequence of Bcl-2/Bax positive unit was IR group, CS group and RP group. The difference compared to RP group was significant (P<0.05). Expression of caspase-3 in CS group was higher than IR group (P<0.05), but had no significant difference with RP group.
Conclusions:
1.The method of establish rat myocardial ischemia/reperfusion model througu lower sternal incision is simple and convenient, and the experiment results are reliable.
2.RP method can reduce rats'myocardial IRI. It was found to alleviate RA, decrease infarct size, improve myocardial morphological lesion, and protect left ventricle contractility. It maybe the mechanism that RP inhibits IRI induced cardiocyte apoptosis by decreasi ng expression of Bax, the pro-apoptotc protein.
3.The three methods of RP, RIPC and RI-PostC executed by transient limb ischemia conditioning all have equal myocardial protection ability against IRI, displayed as decreased infarct size, inhibited cardiocyte apoptosis. RP method is even better on alleviating RA.
4.Glibenclamide injected intraperitoneally can alleviate ischemia arrhythmia score and partly counteract myocardial protection induced by RP. CsA injected into heart chamber can partly simulate RP method and induce some protection. But its hiding injury can abolish its benign effect. The most important effecters of RP induced endogenous myocardial protection is mKATP and mPTP.
方法：健康雄性Wistar大鼠经胸骨下段切口暴露心脏,打活结的方式结扎或旷置冠状动脉左前降支(LAD)后,经心尖置测压管于左心室,建立在体心肌I/R损伤模型,随机分为7组。(1)假手术组(Sham组,n=8)：经冠状动脉左前降支(LAD)下穿线后,旷置；(2)缺血／再灌注组(IR组,n=12)：心脏LAD实施30min缺血／180min再灌注处理；(3)心肌缺血期短暂肢体缺血处理组(RP组,n=10)：心脏LAD实施30min缺血／180min再灌注处理；在实施心肌缺血期间对双下肢实施3次5min缺血／5min再灌注;(4)短暂肢体缺血预处理组(RIPC组,n=11)：心肌缺血前先对双下肢实施3次5min缺血／5min再灌注,而后对心脏LAD实施30min缺血／180min再灌注处理；(5)短暂肢体缺血后处理组(RI-PostC组,n=11)：对心脏LAD实施30min缺血／180min再灌注处理；再灌注开始的同时对双下肢实施3次5min缺血／5min再灌注；(6)格列苯脲组(GL组,n=11)：心脏LAD实施30min缺血／180min再灌注处理；在实施心肌缺血期间对双下肢实施3次5min缺血／5min再灌注；同时腹腔注射线粒体ATP敏感性钾通道(mKATP)抑制剂格列苯脲5mg/kg;(7)环孢霉素A组(CS组,n=10)：心脏LAD实施30min缺血／180min再灌注处理；心肌缺血期间经心脏测压管注射线粒体通透性转换孔(mPTP)抑制剂环孢霉素A (CsA) 10mg/kg。
从再灌注性心律失常(reperfusion arrhythmia, RA)、心肌舒缩能力、心肌损伤标志物、心梗范围、心肌细胞凋亡相关蛋白的表达等方面评价RP对心肌IRI的保护作用。计算缺血期心律失常(ischemia arrhythmia, IA)及RA评分、左心室发展压(LVDP)、左心室压上升／下降最大速率(±dp/dtmax)及其恢复率；ABC夹心ELISA法检测血清肌酸激酶(CK)活性和心肌肌钙蛋白T(c-TNT)、HE染色观察心肌形态学改变,TTC染色法测定心肌梗死面积,免疫组化法检测心肌细胞凋亡相关蛋白Bcl-2、Bax的表达,免疫印迹法(western blot)检测心肌凋亡蛋白caspase-3的表达。
结果：
1.动物模型的评价IR组与Sham组比较,心肌缺血期ST段显著抬高(P<0.01),缺血期及再灌注期心律失常评分显著增加(P<0.05),左心室收缩峰压(LVSPmax),±dp/dtmax在再灌注起点时下降,差异均具有统计学意义(P<0.05),c-TNT显著升高(P<0.05)。
2.RP对大鼠心肌I／R损伤所致RA、心脏舒缩功能及心梗范围的影响再灌注早期RP组RA评分为(1.50±0.97),与R组(2.33±0.71)差异有统计学意义(P=0.049<0.05)；RP组的LVSPmax、±dp/dtmax均介于Sham组与IR组之间,但与R组的差异无统计学意义。三组间CK差异无统计学意义,关于c-TNT, IR组与Sham组的差异具统计学意义(P=0.021),但RP组与IR组、sham组间差异均无统计学意义。三组关于左室心肌危险区域(缺血范围)无显著差异,RP组心梗范围显著小于IR组(P<0.01)。
3.RP对大鼠心肌I／R损伤所致细胞凋亡的影响比较R组与RP组的Bcl-2、Bax的表达结果发现,与R组相比,RP组Bax蛋白表达阳性心肌细胞百分比明显降低(P<0.05),而Bcl-2蛋白表达阳性百分比无显著性差异(P>0.05),Bcl-2/Bax比值明显升高(P<0.05)。RP组caspase-3的表达与IR组间无显著性差异(P>0.05)。
4.RP、RIPC、RI-PostC模式对大鼠心肌I／R损伤影响的比较再灌注早期RP组RA评分与IR组之间差异显著(P<0.05),但RIPC组、RI-PostC组与IR组、RP间差异均无统计学意义。RP组与R组间血流动力学数据无显著性差异。RIPC组在再灌注30 min时LVDPmin高于R组,RI-PostC组-dp/dtmax再灌注0 min时显著低于RP组(P<0.05),其余数值差异无统计学意义。四组间CK与c-TNT均无显著差异。RP、RIPC、RI-PostC组心梗范围显著低于R组(P<0.01),RP、RIPC、RI-PostC三组间无显著差异。RP组、RIPC组、RI-PostC组Bcl-2表达均高于IR组,RI-PostC组表达高于RP组与R组,RIPC组表达高于IR组(P<0.05)。RP组、RIPC组、RI-PostC组关于Bax表达相当,RP组、RIPC组显著低于R组(P<0.05)。R组Bcl-2/Bax阳性单位的比值低于RP、RI-PostC、RIPC三组,与RP组差异有统计学意义(P<0.05)。RP组、RIPC组、RI-PostC组三组间关于Bcl-2、Bax、Bcl-2/Bax差异无统计学意义。四组间caspase-3蛋白的表达差异无统计学意义。
5.应用格列苯脲干预RP处理对大鼠心肌I／R损伤的影响GL组再灌注早期RA评分低于IR组,差异具有统计学意义(P<0.05),但与RP组无显著差异。在再灌注0 min时,GL组LVSPmax及±dp/dtmaX高于R组(P<0.05)。GL组与RP组间无显著差异。GL组c-TNT表达低于R组及RP组(P<0.05)。GL组心梗范围介于RP、R组之间,与RP组差异具有统计学意义(P<0.05),与R组差异无统计学意义。
RP组、GL组关于Bcl-2表达相当,均高于IR组,GL组与R组间具有显著性差异(P<0.05)。GL组关于Bax表达介于RP、IR组之间,但差异无统计学意义。三组间Bcl-2/Bax阳性单位比值的差异缺乏统计学意义。GL组caspase-3的表达显著高于IR组和RP组,具有统计学意义(P<0.05)。
6.心肌缺血期应用CsA对大鼠心肌I／R损伤的影响CS组再灌注早期RA评分低于R组,差异具有统计学意义(P<0.05),但与RP组差异无统计学意义。CS组再灌注0、60 min, LVDPmin均高于IR组；再灌注120 min时,LVSPmax低于IR组；再灌注30-180 min的±dp/dtmax恢复率均低于IR组。再灌注60 min时-dp/dtmax,再灌注120min时LVSPmax,再灌注180 min时dp/dtmax低于RP组；再灌注30-180 min,-dp/dtmax恢复率及30-60 min dp/dtmax恢复率均低于RP组；再灌注120min, LVDP低于RP组(P<0.05)。CS组c-TNT表达低于R组及RP组,但无统计学意义。CS组心梗范围介于RP、IR组之间,显著小于R组(P<0.05)。RP、CS组关于Bcl-2表达相当,均高于IR组,但差异无统计学意义。CS组Bax表达介于IR, RP组之间,但与两组差异无统计学意义。关于Bcl-2/Bax阳性单位的比值的排序为：R组
1.经胸骨下段切口建立大鼠心肌缺血／再灌注模型简便易行,监测结果稳定可靠。
2.RP能减少大鼠心肌I／R损伤,表现为减轻再灌注性心律失常,缩小心肌梗死面积,改善心肌形态学损伤,保护左心室收缩、舒张功能。RP可能通过减少促凋亡蛋白Bax的表达来发挥对IRI诱发的心肌细胞凋亡的抑制作用。
3.肢体短暂缺血模式进行的RIPC、RP、RI-Postc三种模式均具有心肌保护作用,表现为减小心肌梗死范围,抑制心肌细胞凋亡,且保护能力相当。
4.腹腔注射格列苯脲可以减轻心肌缺血性心律失常,也部分抵消了RP的心肌保护作用。心腔注射CsA可以模拟部分RP的心肌保护作用,但其对心肌的隐匿副损伤抵消了其它的有益作用。线粒体ATP敏感性钾通道(mKATP)和线粒体通透性转换孔(mPTP)仍是RP诱导内源性心肌保护的最重要效应器。
Objective:To study the protection induced by transient limb ischemic conditioning during myocardial ischemic period against myocardial ischemia reperfusion (I/R) injury of rats.
Method:Healthy male Wistar rats were administered. The heart was exposed through lower sternal incision and the left anterior descending coronary artery was ligated by snipknot to establish the ischemia/reperfusion model. A catheter was put into the left ventricle from the apex of heart to trace the pressure of left ventricle and the pressure change index while electrocardiogram was monitored. Rats were assigned randomly into seven groups. (1)Sham group (n=8):rats were threaded a silk suture under the left coronary artery anterior descending (LAD) and laid up through out the experiment. (2)IR group (n=12):rats were subjected to 30 min LAD occlusion followed by 180 min reperfusion. (3) RP group (transient limb ischemic conditioning during myocardial ischemia period, remote preconditioning group) (n=10):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion during 30 min myocardial ischemia period which follower by 180 min reperfusion. (4) RIPC group (remote ischemia preconditioning group) (n=11):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion before 30 min myocardial ischemia period which follower by 180 min reperfusion. (5) RI-PostC group (remote ischemia post-conditioning group) (n=11):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion at the very beginning of reperfusion during 30 min myocardial ischemia and 180 min reperfusion period. (6)GL group (Glibenclamide group) (n=11):rats were subjected to three episodes of 5 min double hind limbs occlusion followed by 5 min reperfusion during 30 min myocardial ischemia period while glibenclamide was injected intraperitoneally dosed with 5 mg/kg which also follower by 180 min reperfusion. (7)CS group (Cyclosporin A group) (n=10):rats were subjected to 30 min LAD occlusion followed by 180 min reperfusion while CsA was injected into the left ventricle from the catheter dosed with 10 mg/kg.
The myocardial protection induced by RP against IRI was evaluated by reperfusion arrhythmia (RA), cardiac contractility, marker of myocardial injury, infarct size, cardiocyte death, expression of apopto sis-relevant proteins. The scores of ischemia arrhythmia and reperfusion arrhythmia, the left ventricular developing pressure, the maximal change index of LV (±dp/dtmax) and recovery percentage of maximal change index were calculated. Serum CK (creatine kinase) and c-TNT (cardiac troponin T) were tested by ABC ELISA. Myocardial definite change of tissue morphology was inspected by HE staining. Myocardial infarct size was measured by TTC staining technique. The expression of apoptosis-relevant proteins, Bcl-2 and Bax, were tested by histochemistry immunity method, and caspase-3 was tested by western blot.
Results:
1. Evaluation of animal model.
Compare IR group to Sham group, the ST segment of ischemia period was significant elevated(P<0.01), the scores of ischemia and reperfusion arrhythmia were significant increased(P<0.05), the maximum systolic pressure of left ventricular and the idp/dtmax at the reperfusion starting point were significantly decreased, and the serum c-TNT was significantly higher (P<0.05).
2. Influence on RA, cardiac contractility and infarct size of remote perconditioning against rats'ischemia reperfusion injury.
The RA score of early reperfusion phase, change index and maximal pressure of left ventricle at end point of RP group all fell in between IR group and sham group. The arrhythmic score of RP group was (1.50±0.97) and the score of IR group was (2.33±0.71). The difference between them was statistically significant (P=0.049). There was no statistically significant difference on change index and maximal pressure of left ventricle between IR group and RP group. Difference of CK among three groups was not statistically significant. While the c-TNT of IR group was significant higher than that of sham group (P=0.021), there was no statistically significant difference between RP and IR group or between RP and sham group. There was no difference of ischemia size among three groups, while infarct sizeof RP group was significant smaller than that of IR group (P<0.01).
3. Influence on cardiocyte apoptosis against rats'myocardial IRI.
Compared to IR group, the percentage of cardiocyte of RP group which expressed Bax was statistically significantly lower (P<0.05), while the percentage of Bcl-2 was not (P>0.05). The rate of Bcl-2/Bax was statistically significantly higher (P<0.05). There was no significant difference on expression of caspase-3 between RP and IR group (P>0.05).
4. Comparison among RP, RIPC and R1-PostC induced protection against rats' myocardial IRI.
RA score of RP group was smaller than IR group (P<0.05) but it of RIPC and Rl-PostC group had no statistically significant difference compared to both RP and IR groups. There were no statistically significant difference of hemodynamics data between RP group and IR group. Compared to IR group, LVDPmin of RIPC group were higher at reperfusion 30 min (P<0.05) and-dp/dtmax of RI-PostC group was lower at reperfusion 0 min (P<0.05). Other data difference was not statistically significant. Difference of serum CK and c-TNT among four groups was not statistically significant. There was no difference of ischemia size among four groups, while the infarct size of RP, RIPC and RI-PostC group was statistically significantly smaller than IR group (P<0.01). The infarct size percentage of RP group was (15.27±5.19), it of RIPC group was (14.53±3.45), and it of RI-PostC group was (19.84±5.85), while the size percentage of IR group was (34.47±7.13). There was no difference of infarct size among three conditioned groups.
Expression of Bcl-2 in three groups was higher than it of IR group. Bcl-2 of RI-PostC group was statistically significant higher than it of RP and IR groups while that of RIPC group was higher than that of IR group (P<0.05). Expression of Bax in three groups was similar and those of RP and RIPC group were statistically significant lower than it of IR group (P<0.05). The Bcl-2/Bax positive unit rate of IR group was lower than RP, RIPC and R1-PostC group. The difference between IR and RP group was statistically significant (P<0.05). There was no significant difference on Bcl-2, Bax and Bcl-2/Bax among three conditioned groups. There was also no significant difference on caspase-3 among these four groups.
5. Impact of glibenclamide on remote perconditioning induced myocardial protection.
RA scores (P<0.05) of GL group was lower than IR group. The LVSPmax and±dp/dtmax were higher than IR group (P<0.05) at reperfusion 0 min. But there were no significant difference of arrhythmia scores and cardiac contractility compared to RP group. Serum c-TNT of GL group was lower than RP and IR group (P<0.05). The infarct size of GL group fell in between RP group and IR group, the difference compared to RP group was statistically significant (P<0.05) while it compared to IR group was not.
Expression of Bcl-2 in RP group and GL group were higher than IR group and there was statistically significant difference between GL and IR group. Expression of Bax in GL group fell in between RP group and IR group, while no statistically significant difference was found compared to RP and IR group. The difference of Bcl-2/Bax positive unit rate wasn't significant. Expression of caspase-3 in GL group was higher than both IR and RP group (P<0.05).
6. Influence of CsA applied during myocardial ischemia period against rats' myocardial IRI.
RA scores (P<0.05) of CS group was lower than IR group, while no significant difference was found compared to RP group. Compared to IR group, LVDPmin was higher at reperfusion 0 and 60 min; LVSPmax was lower at reperfusion 120 min; recovery percentage of±dp/dtmax was lower from reperfusion 30 min to 180 min(P<0.05).
Compared to RP group, LVSPmax,-dp/dtmax at reperfusion 60 min, LVSPmax at 120 min and±dp/dtmax at 180 min of CS group were lower; recovery percentage of-dp/dtmax from 30 to 180 min and dp/dtmax from 30 to 60 min were lower; LVDP at 60 min was also lower than RP group (P<0.05).
Serum c-TNT of CS group was lower than RP and IR group but not statistically significant. The infarct size of CS group fell in between RP group and IR group, the difference between CS and IR group was statistically significant (P<0.05).
Expression of Bcl-2 in RP group and CS group were higher than IR group but there was no statistically significant difference. Expression of Bax in CS group fell in between RP group and IR group, while no statistically significant difference was found. The sequence of Bcl-2/Bax positive unit was IR group, CS group and RP group. The difference compared to RP group was significant (P<0.05). Expression of caspase-3 in CS group was higher than IR group (P<0.05), but had no significant difference with RP group.
Conclusions:
1.The method of establish rat myocardial ischemia/reperfusion model througu lower sternal incision is simple and convenient, and the experiment results are reliable.
2.RP method can reduce rats'myocardial IRI. It was found to alleviate RA, decrease infarct size, improve myocardial morphological lesion, and protect left ventricle contractility. It maybe the mechanism that RP inhibits IRI induced cardiocyte apoptosis by decreasi ng expression of Bax, the pro-apoptotc protein.
3.The three methods of RP, RIPC and RI-PostC executed by transient limb ischemia conditioning all have equal myocardial protection ability against IRI, displayed as decreased infarct size, inhibited cardiocyte apoptosis. RP method is even better on alleviating RA.
4.Glibenclamide injected intraperitoneally can alleviate ischemia arrhythmia score and partly counteract myocardial protection induced by RP. CsA injected into heart chamber can partly simulate RP method and induce some protection. But its hiding injury can abolish its benign effect. The most important effecters of RP induced endogenous myocardial protection is mKATP and mPTP.
引文
1. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020:Global Burden of Disease Study. Lancet 1997; 349(9064):498-1504.
2. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation, 1993,87(3):893-899.
3. Gho BC, Schoemaker RG, Vadendel MA, et al. Myocardial protection by brief ischemia in non cardiac tissue. Circulation,1996,94 (9):2193-2200
4. Rahman I, Bonser RS. Remote ischaemic preconditioning:the current best hope for improved myocardial protection in cardiac surgery? Heart,2009; 95(19):1553-1555.
5. Venugopal V, Ludman A, Yellon M D, et al.'Conditioning'the heart during surgery. Eur J Cardiothorac Surg,2009,35(6):977-87.
6. 刘秀华.缺血后处理内源性心脏保护的研究进展,生理学报,2007,59(5)：628-634.
7. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. Am J Physiol Heart Circ physiol.2003; 285(2):H579-H588.
8. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation,2005, 112 (14):2143-2148.
9. Ma XJ, Zhang XH, Li CM, et al. Effect of postconditioning on coronary blood flow velocity and endothelial function in patients with acute myocardial infarction. Scand Cardiovasc J 2006; 40(6):327-333.
10. Luo W, Li B, Lin G, Huang R. Postconditioning in cardiac surgery for tetralogy of Fallot. J Thorac Cardiovasc Surg.2007; 133(5):1373-1374.
11. Luo W, Li B, Lin G, Chen R, Huang R. Does cardioplegia leave room for postconditioning in paediatric cardiac surgery? Cardiol Young.2008; 18(3):282-287.
12. Luo W, Li B, Chen R, Huang R, Lin G. Effect of ischemic postconditioning in adult valve replacement. Eur J Cardiothorac Surg.2008,33(2):203-208.
13. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res Cardiol 2005,100(5):404-412.
14.张兴华,李春梅,马晓静,等.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究.中华医学杂志；2006,86(12)：841-845.
15. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al, Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation.2007,116(18):1386-1395.
16. Hausenloy JD, Yellon MD. Preconditioning and postconditioning:United at reperfusion. Pharmacology& Therapeutics,2007,116(2):173-191.
17. Hausenloy JD, Yellon MD. Remote ischaemic preconditioning:underlying mechanisms and clinical application. Cardiovascular Research.2008,79 (3):377-386.
18. Weiss NJ, Korge P, Honda M H, et al. Role of the mitochondrial permeability transition in myocardial disease. Circ Res.2003,93(4):292-301.
19. Schmidt MR, Smerup M, Konstantinov IE, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATp-dependent mechanism:first demonstration of remote ischemic preconditioning. Am J Physiol Heart Circ Physiol,2007,292(4):H1883-H1890.
1.齐志敏.大鼠心肌缺血再灌注损伤模型几种开胸方法评述[J].锦州医学院学报,2004,25(6)：73-74.
2. Bhindi R, Witting PK, McMahon AC, et al. Rat models of myocardial infarction Pathogenetic insights and clinical relevance [J]. Thromb Haemost,2006,96(5): 602-610.
3. Wayman NS, McDonald MC, Chatterjee PK, et al. Models of coronary artery occlusion and reperfusion for the discovery of novel antiischemic and antiinflammatory drugs for the heart [J]. Methods Mol Biol,2003,225(1):199-208.
4. Chimenti S, Carlo E, Masson S, et al. Myocardial infarction:animal models [J]. Methods Mol Med,2004,98(1):217-226.
5. Klocke R, Tian W, Kuhlmann MT, et al. Surgical animal models of heart failure related to coronary heart disease [J]. Cardiovasc Res,2007,74(1):29-38.
6. Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems:an examination of seven scores in an in vivo model of regional myocardial ischemia [J]. Cardiovasc Res,1988,22(9):656-665.
7. 刘付平,姚宏伟,李俊.大鼠心肌缺血再灌注损伤模型的改进[J].安徽医科大学学报,2003,38(3)：234-236.
8. Hale SL, Mehra A, Leeka J, et al. Postconditioning fails to improve no reflow or alter infarct sizein an open-chest rabbit model of myocardial ischemia-reperfusion [J]. Am J Physiol Heart Circ Physiol,2008,294(1):H421-H425.
9. 李崇剑,高润霖,宋来凤,等.用结扎法建立小型猪心肌缺血再灌注损伤模型[J].中国分子心脏病学杂志,2006,6(1)：30-32.
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium. [J]Circulation,1986,74(5):1124-1136.
2. Przyklenk K, Bauer B, Ovize M et al, Regional ischemic "preconditioning" protects remote virgin myocardium from subsequent sustained coronary occlusion. [J] Circulation.1993,87(3):893-899.
3. Gho BCG, Schoemaker RG, Van den Doel MA, et al. Myocardial protection by brief ischemia in noncardiac tissue. [J]Circulation.1996,94(9):2193-2200.
4. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. [J] Am J Physiol Heart Circ Physiol.2003; 285(2):H579-H588.
5. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. [J]. Basic Res Cardiol 2005; 100(5):404-412.
6.张兴华,李春梅,马晓静,等.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究[J].中华医学杂志.2006,86(12)：841-845.
7. Schmidt MR, Smerup M, Konstantinov IE, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism:first demonstration of remote ischemic preconditioning [J]Am J Physiol Heart Circ Physiol,2007.292(4):H1883-H1890.
8. Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems:an examination of seven scores in an in vivo model of regional myocardial ischemia. [J]Cardiovasc Res,1988,22 (9):656-665.
9. Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. [J]Heart 2007; 93(6): 749-752.
10. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning:united at reperfusion. [J] Pharmacol Ther 2007; 116(2):173-191.
11. Liem DA, Verdouw PD, Ploeg H, Sites of action of adenosine in interorgan preconditioning of the heart et al. Sites of action of adenosine in interorgan preconditioning of the heart. Am J Physiol Heart Circ Physiol,2002,283(1):H29-37.
12. Xiao L, Lu R, Hu CP, et al. Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide. Eur J Pharmacol,2001,427(2):131-135.
13. Oxman T, Arad M, Klein R, et al. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia [J]. Am J Physiol.1997; 273(4):H1707-1712.
14. Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo [J]. Circulation,2002;106(23):2881-2883.
15.刘兴德,袁志柳,黄达枚.双下肢缺血后处理对大鼠心肌缺血再灌注损伤的保护作用[J].贵阳医学院学报.2004；29(1)：7-9.
16. Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs [J]. Heart 2007; 93(6):749-752.
17. Gritsopoulos G, Iliodromitis EK, Zoga A, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits [J]. Cardiovasc Drugs Ther.2009,23(3):193-8.
18. David GD. Myocardial reperfusion injury:a new review [J]. Cardiaovasc Res,2004, 61(3):363-4.
19. GalinnanesM, FowlerA G. Role of clinical pathologies inmyocardial injury following ischemia and reperfusion [J]. Cardiaovasc Res,2004,61(3):512-521.
20.王海华,戚仁斌,俞蕾,等.非创伤性预处理在离体心脏抗再灌注损伤中作用机制的探讨.中国病理生理杂志.2002,18(5)：535-539
21. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al, Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism [J]. Circulation.2007,116(12):1386-95.
22. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:underlying mechanisms and clinical application. [J]Cardiovasc Res,2008,79(3):377-386.
1. Ling H, Lou Y. Total flavones from Elsholtzia blanda reduce infarct size during acute myocardial ischemia by inhibiting myocardial apoptosis in rats. J Ethnopharmacol, 2005,101(1):169-175.
2. Das A, Xi L, Kukreja RC, et al. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem,2005,280(13):12944-12955.
3. Hotchkiss RS, Strasser A, McDunn JE, et al. Cell Death. N Engl J Med 2009; 361(16):1570-83.
4. Fliss, H., Gattinger, D. Apoptosis in ischemic and reperfused rat myocardium. Circ Res, 1996,79(5):949-956.
5. Gottlieb, RA, Burleson, KO, Kloner, RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest,1994,94(4):1621-1628.
6. Green DR, Reed JC. Mitochondria and apoptosis [J]. Science,1998,281(5381):
1309-1312.
7. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature,1999,397(6718):441-446.
8. Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature,2001,412(6842):95-99.
9. Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med,2005,11(7): 725-730.
10. Bras M, Queenan B, Susin SA. Programmed cell death via mitochondria:different modles of dying [J]. Biochemistry (Moscow),2005,70 (2):231-239.
11. Black S C, Huang J Q, Rezaiefar P, et al. Co-localization of thecysteine p rotease Caspase-3 with apop totic myocytes after in vivo myocardial ischemia and reperfusion in the rat [J]. JMol Cell Cardiol,1998,30 (4):733-742.
12. Okamura T, Miura T, Takemura G, et al. Effect of Caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation inthe ischemia-reperfused rat heart [J]. Cardiovasc Res,2000,45(3):642-650.
13. Ruixing Y, A12Ghazali R, Wenwu L, et al. Pretreatmentwith probucol attenuates cardiomyocyte apop tosis in a rabbitmodel of ischemia/reperfusion [J]. Scand J Clin Lab Invest,2006,66 (7):549-558.
14. Zhao ZQ, Morris CD, Budde JM, et al. Inhibition f myocardial apoptosis reduces infarct size and improves egional contractile dysfunction during reperfusion. Cardiovasc Res,2003,59(1):132-142.
15. Borutaite V, Jekabsone A, Morkuniene R, et al. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction cytochrome c andapoptosis induced by heart ischemia. J Mol Cell Cardiol,2003,35(4):357-366.
16. Vohra H A, GalinanesM. Effect of the degree of ischaemic injury and reoxygenation time on the type of myocardial cell death in man:role of caspases [J]. BMC Physiol, 2005,5 (3):14.
17.谢俊然,郁丽娜,骆荣华,等.环孢素A对缺血-再灌注大鼠心肌细胞凋亡的影响[J].临床麻醉学杂志,2005,21(12)：838-840.
1. Gho BC, Schoemaker RG, Vadendel MA, et al. Myocardial protection by brief ischemia in non cardiac tissue [J]. Circulation,1996,94 (9):2193-2200.
2. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. [J]Basic Res Cardiol 2005; 100(5):404-412.
3.刘兴德,袁志柳,黄达枚.双下肢缺血后处理对大鼠心肌缺血再灌注损伤的保护作用[J].贵阳医学院学报,2004；29(1)：7-9.
4. Oxman T, Arad M, Klein R, et al. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia [J]. Am J Physiol.1997; 273(4):H1707-1712.
5. Galagudza M, Kurapeev D, Minasian S, et al. Ischemic postconditioning:brief ischemia during reperfusion converts persistent ventricular fibrillation into reglar rhythm [J]. Eur Cardiothorac surg,2004; 25(6):1006-1010.
6. 陶凌,李源,高峰,等.缺血后处理对急性心肌缺血再灌注兔心脏的保护作用[J].第四军医大学学报,2000,21(6)：116-118.
7. Shliakhto EV, GalagudzaMM, Syrenskii AV, et al. Ischemic postconditioning of the myocardium:A new method of heart protection against reperfusion damage [J]. Ter Arkh.2005; 77(5):77-80.
8. Petrishchev NN, Vlasov TD, Galagudza MM, et al. Myocardial ischemic postconditioning:A brief ischemia causes conversion of resistent reperfusion induced ventricular fibrillation into the normal rhythm [J]. Ross Fiziol Zh Im I M Sechenova. 2004,90 (9):1138-44.
1.仇万山,陈亦江.线粒体结构、功能和常用研究办法.麻醉学与复苏杂志,2007,28(3),282-285.
2. Das B, Sarkar C. Is the sarcolemmal or mitochondrial K (ATP) channel activation important in the antiarrhythmic and cardioprotective effects during acute ischemiaP reperfusion in the intact anesthetized rabbit model? [J].Life Sci,2005,77 (11):1226-1248.
3. Davidson SM, Hausenloy D, DuchenMR, et al. Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection[J]. Int J Biochem Cell Biol 2006,38 (3):414-419.
4. Hausenloy DJ, Maddock HL, Baxter GF, el al. Inhibiting mitochondrial permeability transition pore opening:a new paradigm for myocardial preconditioning [J]. Cardiovasc Res,2002,55(3):534-543.
5. Bozdogan O, Gonca E, Suveren E, et al. Mechanisms of glybenclamide-mediated anti-arrhythmia and ischemic conditionining in a rat model of myocardialinfarction: role of yohimbine treatment. Turk J Med Sci 2004,34(1):21-27.
6. Krolikowski JG, Bienengraeber M, Weihrauch D, et al.Inhibition of Mitochondrial Permeability Transition Enhances Isoflurane-Induced Cardioprotection During Early Reperfusion:The Role of Mitochondrial KATP Channels. Anesth Analg 2005; 101(6):1590-1596.
7. Murata M, Akao M, O'Rourke B, et al. Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection [J]. Circ Res,2001,89 (11):891-898.
8. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion:a target for cardioprotection [J]. Cardiovasc Res,2004,61(3):372-385.
9. Yang J, Cortopassi G. Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome c [J]. Free Radic Biol Med,1998, 24(4):624-631.
10. Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism [J]. Am J Physiol Heart Circ Physiol.2005; 288(3):H1252-1256.
11. Zuurbier CJ, Eerbeek O, Meijer AJ. Ischemic preconditioning, insulin, and morphine all cause hexokinase redistribution [J]. Am J Physiol Heart Circ Physiol,2005, 289(1):H496-H499.
12. Wang G, Liem DA,Vondriska TM, et al. Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition[J]. Am J Physiol Heart Circ Physiol,2005,288(3):H1290-H1295.
13. Zhang SZ, Wang NF, Xu J, et al. kappa-Opioid receptors mediate cardioprotection by remote preconditioning [J]. Anesthesiology 2006; 105(3):550-556.
14.李杨,于金凤,张朝颖,等.环孢霉素A诱导的心肌损伤与NO和NOS的关系.哈尔滨医科大学学报,2009,43(3)：241-244,254.
15. Sayen MR, Gustafsson AB, Sussman MA, et al. Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. Am J Physiol Cell Physiol 2003,284(2):C562-570.
1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomised trials. Lancet 2003; 361:13-20.
2. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA. Myocardial protection at a crossroads:the need for translation into clinical therapy. Circ Res 2004; 95:125-34.
3. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005; 112:2143-8.
4. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 2003; 60:617-25.
5. Burgdorf C, Richardt D, Kurz T, et al. Adenosine inhibits norepinephrine release in the postischemic rat heart:the mechanism of neuronal stunning. Cardiovasc Res 2001;49: 713-720.
6. Pomblum VJ, Korbmacher B, Cleveland S, et al. Cardiac stunning in the clinic:the full picture. Interact CardioVasc Thorac Surg 2010; 10:86-91.
7. Ito H. No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat Clin Pract Cardiovasc Med 2006; 3:499-506.
8. Majidi M, Kosinski AS, Al-Khatib, SM, et al. Reperfusion ventricular arrhythmia 'bursts'in TIMI 3 flow restoration with primary angioplasty for anterior ST-elevation myocardial infarction:a more precise definition of reperfusion arrhythmias. Europace, 2008,10,988-997.
9. Garcia-Dorado D, Ruiz-Meana M, Piper HM, et al. Lethal reperfusion injury in acute myocardial infarction:facts and unresolved issues Cardiovasc Res.2009; 0: cvp185v2-cvp185
10. Ly HQ, Denault A, Dupuis J, et al. A pilot study:the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 2005; 150:933.
11. Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 2006; 70:181-190.
12. Ishii H, Ichimiya S, Kanashiro M, et al. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 2005; 112:1284-1288.
13. Gumina RJ, Buerger E, Eickmeier C, Moore J, Daemmgen J, Gross GJ. Inhibition of the Na (+)/H (+) exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs. Circulation 1999; 100: 2519-2526.
14. Zeymer U, Suryapranata H, Monassier JP, et al. The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: results of the Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction (ESCAMI) trial. J Am Coll Cardiol 2001; 38:1644-1650.
15. Lemasters JJ, Bond JM, Chacon E, et al. The pH paradox in ischemia-reperfusion injury to cardiac myocytes. EXS; 1996; 76:99-114.
16. Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+overloading, trigger pH-and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia-reperfusion. Am J Physiol Heart Circ Physiol; 2006; 290: H2024-H2034.
17. Avkiran M, Marber MS. Na (+)/H (+) exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol 2002; 39:747-753.
18. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004; 61:481-497.
19. Vakeva AP, Agah A, Rollins SA, Matis LA, Li L, Stahl GL. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion:role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 1998; 97:2259-2267.
20. Mertens P, Maes A, Nuyts J, et al. Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction:the P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial. Am Heart J 2006; 152:125.e1-125.e8.
21. Granger CB, Mahaffey KW, Weaver WD, et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction:the COMplement inhibition in Myocardial infarction treated withAngioplasty (COMMA) trial. Circulation 2003; 108:1184-1190.
22. Armstrong PW, Granger CB, Adams PX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention:a randomized controlled trial. JAMA 2007; 297:43-51.
23. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-Ⅱ). J Am Coll Cardiol 2005; 45:1775-1780.
24. Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction:the AMISTAD-2 trial. Eur Heart J 2006; 27:2400-2405.
25. Apstein CS, Opie LH. A challenge to the metabolic approach to myocardial ischaemia. Eur Heart J 2005; 26:956-959.
26. Mehta SR, Yusuf S, Diaz R, et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction:the CREATE-ECLArandomized controlled trial. JAMA 2005; 293:437-446.
27. Christensen CW, Rieder MA, Silverstein EL, Gencheff NE. Magnesium sulfate reduces myocardial infarct size when administered before but not after coronary reperfusion in a canine model. Circulation 1995; 92:2617-2621.
28. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4:a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345:669-685.
29. Antman E, Cooper H, McKinlay S, et al. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial:a randomised controlled trial. Lancet 2002; 360: 1189-1196.
30. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556.
31. Dae MW, Gao DW, Sessler DI, Chair K, Stillson CA. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol 2002; 282:H1584-H1591.
32. Ly HQ, Denault A, Dupuis J, et al. A pilot study:the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 2005; 150:933-933.
33. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore:its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 2003; 35:339-341.
34. Halestrap A.P. Calcium, mitochondria and reperfusion injury:a pore way to die。 Biochem Soc Trans.2006; 34 (Pt 2):232-7.
35. Yellon DM, Hausenloy DJ. Myocardial Reperfusion Injury. N Engl J Med 2007; 357:1121-35.
36. Vinten-Johansen J, Yellon DM, Opie LH. Postconditioning:a simple, clinically applicable procedure to improve revascularization in acute myocardial infarction. Circulation 2005; 112:2085-2088.
37. Yellon DM, Opie LH. Postconditioning for protection of the infarcting heart. Lancet 2006; 367:456-458.
38. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury:targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res 2004; 61:448-460.
39. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore:its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 2003; 35:339-341.
40. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. [J] Am J Physiol Heart Circ Physiol.2003; 285:H579-H588.
41. Zhao ZQ, Vinten-Johansen J. Postconditioning:reduction of reperfusion-induced injury. Cardiovasc Res 2006; 70:200-211.
42. Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning:staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007; 115:1895-1903.
43. Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway:a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 2005; 15:69-75.
44. Davidson SM, Hausenloy D, Duchen MR, Yellon DM. Signalling via the Reperfusion Injury Signalling Kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem Cell Biol 2006; 38: 414-419.
45. Abdallah Y, Gkatzoflia A, Gligorievski D, et al. Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage. Cardiovasc Res 2006; 70:346-353.
46. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005; 54: 146-151.
47. Bullard AJ, Govewalla P, Yellon DM. Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol 2005; 100:397-403.
48. Bell RM, Yellon DM. Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J Am Coll Cardiol 2003; 41:508-515.
49. Yang XM, Philipp S, Downey JM, Cohen MV. Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. Basic Res Cardiol 2006; 101: 311-318.
50. Lipsic E, van der Meer P, Voors AA, et al. A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction:a randomized feasibility and safety study. Cardiovasc Drugs Ther 2006; 20:135-141.
51. Patti G, Pasceri V, Colonna G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention:results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49:1272-1278.
52. Inagaki K, Churchill E, Mochly-Rosen D. Epsilon protein kinase C as a potential therapeutic target for the ischemic heart. Cardiovasc Res 2006; 70:222-230.
53. Bates E, Bode C, Costa M, et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation; 2008; 117(7):886-896.
54. Hausenloy DJ, Maddock HL, Baxter GF, et al. Inhibiting mitochondrial permeability transition pore opening:a new paradigm for myocardial preconditioning? Cardiovasc Res 2002; 55:534-543.
55. Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005; 434:658-662.
56. Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM. Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Am J Physiol Heart Circ Physiol; 2005; 289:H237-H242.
57. Heusch D, Boengler K, Schulz R. Cardioprotection Nitric Oxide, Protein Kinases, and Mitochondria. Circulation.2008; 118:1915-1919.
58. Zhao ZQ, Nakamura M, Wang NP, et al. Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res 2000; 94:133-144.
59. Doukas J, Wrasidlo W, Noronha G, et al. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc Natl Acad Sci USA,2006; 103:19866-19871.
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium. [J]Circulation.1986; 74:1124-1136.
2. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. [J] Am J Physiol Heart Circ Physiol.2003; 285:H579-H588.
3. Hausenloy DJ., Yellon DM. Survival kinases in ischemic preconditioning and postconditioning Cardiovascular Research.2006; 70:240-253.
4. Gho BC, Schoemaker RG, Vadendel MA, et al. Myocardial protection by brief ischemia in non cardiac tissue [J]. Circulation,1996,94 (9):2193-2200.
5. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. [J]Basic Res Cardiol 2005; 100:404-412.
6. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion [J] Circulation,1993,87:893-899.
7. Dickson EW, Reinhardt CP, Renzi FP, et al. Ischemic preconditioning may Be transferable via whole blood transfusion:preliminary evidence [J]. J Thromb thronmbolysis,1999; 8:123-129.
8. Dickson EW, Lorbar M, Porcaro WA, et al. Rabbit heart can be "preconditioned" via transfer of coronary effluent[J]. Am J Phsiol,1999; 277:H2451-H2457.
9. Pell TJ, Baxter GF, Yellon DM, et al. Renal ischemia preconditions myocardium:role of adenosine receptors and ATP-sensitive potassium channels [J]. Am J Phsiol,1998; 275:H1542-H1547.
10. Takaoka A, Nakae I, Mitsunami K, et al. Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits:effects of "remote preconditioning". [J] J Am Coll Cardiol,1999,33:556-564.
11. Patel HH, Moore J, Hsu AK, et al. Cardioprotection at a distance:Mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism [J]. J Mol Cell Cardiol.2002,34:1317-1323.
12. Tokuno S, HinokiyamA K, Tokuno K, et al. Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia [J]. Arteriosclera Thromb Vasc Biol,2002; 22:995-100.
13. de Zeeuw S, Lameris TW, Duncker DJ, et al. Cardioprotection in pigs by exogenous norepinephrine but not by cerebral ischemia-induced release of endogenous norepinephrine[J]. Stroke.2001; 32:767-74.
14. Oxman T, Arad M, Klein R, et al. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia [J]. Am J Physiol.1997; 273:H1707-1712.
15.Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo [J] Circulation,2002;106:2881-2883.
16. Konstantinov IE, Li J, Cheung MM, et al. Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism [J]. Transplantation.2005; 79:1691-1695.
17. 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 [J]. Cardiovasc Res.2004; 61:591-599.
18. Nakano A, Heusch G, Cohen MV, et al. Preconditioning one myocardial region does not necessarily precondition the whole rabbit heart[J]. Basic Res Cardiol 2002; 97: 35-39.
19. Kharbanda RK, Peters M, Walton B, et al. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo [J]. Circulation.2001; 103:1624-1630.
20. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, et al. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans:role of the autonomic nervous system. [J] J Am Coll Cardiol.2005; 46:450-456.
21. Gunaydin B, Cakici I, Soncul H, et al. Does remote organ ischaemia trigger cardiac preconditioning during coronary artery surgery [J]? Pharmacol Res.2000; 41:493-496.
22. Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery:a randomised controlled trial [J]. Lancet 2007; 370:575-9.
23. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al, Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism[J]. Circulation.2007,18; 116(12):1386-95.
24. Cheung MM. Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans [J]. J Am Coll Cardiol.2006; 47:2277-2282.
25.刘小军,易善永,廖斌,等.肢体缺血预处理对心脏瓣膜置换术心肌保护作用的研究[J].心血管康复医学杂志.2007,16(4)：347-349.
26. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:underlying mechanisms and clinical application [J]. Cardiovasc res,2008,79,377-386.
27. Xiao L, Lu R, Hu CP, et al. Delayed cardioprotection by intestinal preconditioning mediated by calcitonin gene-related peptide [J]. Eur J Phalmacol.2001,427:131-135.
28. Chen YS, Chien CT, Ma MC, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway [J]. J Surg Res.2005; 126:92-101.
29. Schoemaker RG, van Heijningen CL. Bradykinin mediates cardiac preconditioning at a distance [J]. Am J Physiol Heart Circ Physiol,2000; 278:H1571-1576.
30. Singh D, Chopra K. Evidence of the role of angiotensin AT(I) receptors in remote renal preconditioning of myocardial[J]. Methods Find Exp Clin Pharmacol,2004; 26:117-122.
31. Ren X, Wang Y, Jones WK. TNF-alpha is required for late ischemic preconditioning but not for remote preconditioning of trauma [J]. J Surg Res.2004; 121:120-129.
32. Wolfrum S, Nienstedt J, Heidbreder M, et al Calcitonin gene related peptide mediates cardioprotection by remote preconditioning [J]. Regul Pept.2005; 127:217-224.
33. Wang YP, Maeta H, Mizoguchi K, et al. Intestinal ischemia preconditions myocardium: role of protein kinase C and mitochondrial K(ATP) channel[J]. Cardiovasc Res.2002 Aug 15; 55(3):576-82.
34. Wolfrum S, Schneider K, Heidbreder M, et al. Remote preconditioning protects the heart by activating myocardial PKC epsilon-isoform [J]. J Cardiovasc Res,2002; 55:583-589.
35. Li G, Labruto F, Sirsjo A, et al. Myocardial protection by remote preconditioning:the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase [J]. Eur J Cardiothorac Surg.2004; 26:968-73.
36. Guohu L, Fausto L, Allan S, et al. Myocardial protection by remote preconditioning: The role of nuclear factor kappa-B p105 and inducible nitric oxide synthase [J]. Eur J Cardiothorac Surg,2004,26:968-973.
37. Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism [J]. Am J Physiol Heart Circ Physiol.2005; 288:H1252-1256.
38. Davidson SM, Hausenloy D, DuchenMR, et al. Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection[J]. Int J Biochem Cell Biol,2006,38 (3):414-419.
39. Zhang SZ, Wang NF, Xu J, et al. kappa-Opioid receptors mediate cardioprotection by remote preconditioning [J]. Anesthesiology 2006; 105:550-556.
40.刘兴德,袁志柳,黄达枚.双下肢缺血后处理对大鼠心肌缺血再灌注损伤的保护作用[J].贵阳医学院学报.2004；2：7-9.
41.张兴华,李春梅,马晓静,等.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究[J].中华医学杂志.2006,.86：841-845.
42. Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs [J]. Heart 2007; 93: 749-752.
43. Gritsopoulos G, Iliodromitis EK, Zoga A, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits [J]. Cardiovasc Drugs Ther.2009,23(3):193-8.
44. Matteo PS. Remote Postconditioning in patients with acute myocardial infarction treated by primary percutaneous coronary intervention (PCI) (RemPostCon) (Accessed March 18,2009, at http://clinicaltrials.gov.).
45. Lawson Health Research Institute. Remote ischemic postconditioning during percutaneous coronary interventions (RIP-PCI) (Accessed September 2,2009, at http://clinicaltrials.gov.).
46. Zang W, Sun L, Yu X. Cardioprotection of ischemic postconditioning and pharmacological post-treatment with adenosine or acetylcholine [J]. Acta Physiologica Sinica.2007,59 (5):593-600.
47. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury:targeting the reperfusion injury salvage kinase (RISK)-pathway [J].Cardiovasc Res,2004,61(3):448-60.
48. Tsubota H, Marui A, Miwa S, et al. Remote postconditioning may attenuate ischemia-reperfusion injury in a murine hind limb through activation of adenosine receptors[J]. Circulation.2009; 120:S1117.
49.蒋玲玲,张野,翁立军,等.中枢吗啡后处理对在体大鼠缺血后心肌的保护作用.中国药理学通报.2009；25(2)：77-81.
50. Williams RP, Okorie MI, Gill H, et al. Role of the autonomic nervous system in remote postconditioninginhumans[J]. Circulation.2008; 118:S1473.
51. Fang J, Chen L, Wu L, et al. Intra-cardiac remote ischemic post-conditioning attenuates ischemia-reperfusion injury in rats [J]. Scand Cardiovasc J.2009; 43(6):386-94.
52. Schmidt MR, Smerup M, Konstantinov IE, et al:Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism:First demonstration of remote ischemic preconditioning[J]. Am J Physiol Heart Circ Physiol 2007;292 (4):H1883-H1890.
53. Saxena P, Newman M AJ, Shehatha JS, et al. Remote ischemic conditioning:evolution of the concept, mechanisms, and clinical application. J Card Surg 2010; 25:127-134.
54. Kharbanda RK, Li J, Konstantinov IE, et al:Remote ischemic preconditioning protects against cardiopulmonary bypass-induced tissue injury:A preclinical study. Heart 2006; 92:1506-1511.
2. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation, 1993,87(3):893-899.
3. Gho BC, Schoemaker RG, Vadendel MA, et al. Myocardial protection by brief ischemia in non cardiac tissue. Circulation,1996,94 (9):2193-2200
4. Rahman I, Bonser RS. Remote ischaemic preconditioning:the current best hope for improved myocardial protection in cardiac surgery? Heart,2009; 95(19):1553-1555.
5. Venugopal V, Ludman A, Yellon M D, et al.'Conditioning'the heart during surgery. Eur J Cardiothorac Surg,2009,35(6):977-87.
6. 刘秀华.缺血后处理内源性心脏保护的研究进展,生理学报,2007,59(5)：628-634.
7. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. Am J Physiol Heart Circ physiol.2003; 285(2):H579-H588.
8. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation,2005, 112 (14):2143-2148.
9. Ma XJ, Zhang XH, Li CM, et al. Effect of postconditioning on coronary blood flow velocity and endothelial function in patients with acute myocardial infarction. Scand Cardiovasc J 2006; 40(6):327-333.
10. Luo W, Li B, Lin G, Huang R. Postconditioning in cardiac surgery for tetralogy of Fallot. J Thorac Cardiovasc Surg.2007; 133(5):1373-1374.
11. Luo W, Li B, Lin G, Chen R, Huang R. Does cardioplegia leave room for postconditioning in paediatric cardiac surgery? Cardiol Young.2008; 18(3):282-287.
12. Luo W, Li B, Chen R, Huang R, Lin G. Effect of ischemic postconditioning in adult valve replacement. Eur J Cardiothorac Surg.2008,33(2):203-208.
13. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res Cardiol 2005,100(5):404-412.
14.张兴华,李春梅,马晓静,等.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究.中华医学杂志；2006,86(12)：841-845.
15. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al, Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation.2007,116(18):1386-1395.
16. Hausenloy JD, Yellon MD. Preconditioning and postconditioning:United at reperfusion. Pharmacology& Therapeutics,2007,116(2):173-191.
17. Hausenloy JD, Yellon MD. Remote ischaemic preconditioning:underlying mechanisms and clinical application. Cardiovascular Research.2008,79 (3):377-386.
18. Weiss NJ, Korge P, Honda M H, et al. Role of the mitochondrial permeability transition in myocardial disease. Circ Res.2003,93(4):292-301.
19. Schmidt MR, Smerup M, Konstantinov IE, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATp-dependent mechanism:first demonstration of remote ischemic preconditioning. Am J Physiol Heart Circ Physiol,2007,292(4):H1883-H1890.
1.齐志敏.大鼠心肌缺血再灌注损伤模型几种开胸方法评述[J].锦州医学院学报,2004,25(6)：73-74.
2. Bhindi R, Witting PK, McMahon AC, et al. Rat models of myocardial infarction Pathogenetic insights and clinical relevance [J]. Thromb Haemost,2006,96(5): 602-610.
3. Wayman NS, McDonald MC, Chatterjee PK, et al. Models of coronary artery occlusion and reperfusion for the discovery of novel antiischemic and antiinflammatory drugs for the heart [J]. Methods Mol Biol,2003,225(1):199-208.
4. Chimenti S, Carlo E, Masson S, et al. Myocardial infarction:animal models [J]. Methods Mol Med,2004,98(1):217-226.
5. Klocke R, Tian W, Kuhlmann MT, et al. Surgical animal models of heart failure related to coronary heart disease [J]. Cardiovasc Res,2007,74(1):29-38.
6. Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems:an examination of seven scores in an in vivo model of regional myocardial ischemia [J]. Cardiovasc Res,1988,22(9):656-665.
7. 刘付平,姚宏伟,李俊.大鼠心肌缺血再灌注损伤模型的改进[J].安徽医科大学学报,2003,38(3)：234-236.
8. Hale SL, Mehra A, Leeka J, et al. Postconditioning fails to improve no reflow or alter infarct sizein an open-chest rabbit model of myocardial ischemia-reperfusion [J]. Am J Physiol Heart Circ Physiol,2008,294(1):H421-H425.
9. 李崇剑,高润霖,宋来凤,等.用结扎法建立小型猪心肌缺血再灌注损伤模型[J].中国分子心脏病学杂志,2006,6(1)：30-32.
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium. [J]Circulation,1986,74(5):1124-1136.
2. Przyklenk K, Bauer B, Ovize M et al, Regional ischemic "preconditioning" protects remote virgin myocardium from subsequent sustained coronary occlusion. [J] Circulation.1993,87(3):893-899.
3. Gho BCG, Schoemaker RG, Van den Doel MA, et al. Myocardial protection by brief ischemia in noncardiac tissue. [J]Circulation.1996,94(9):2193-2200.
4. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. [J] Am J Physiol Heart Circ Physiol.2003; 285(2):H579-H588.
5. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. [J]. Basic Res Cardiol 2005; 100(5):404-412.
6.张兴华,李春梅,马晓静,等.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究[J].中华医学杂志.2006,86(12)：841-845.
7. Schmidt MR, Smerup M, Konstantinov IE, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism:first demonstration of remote ischemic preconditioning [J]Am J Physiol Heart Circ Physiol,2007.292(4):H1883-H1890.
8. Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems:an examination of seven scores in an in vivo model of regional myocardial ischemia. [J]Cardiovasc Res,1988,22 (9):656-665.
9. Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. [J]Heart 2007; 93(6): 749-752.
10. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning:united at reperfusion. [J] Pharmacol Ther 2007; 116(2):173-191.
11. Liem DA, Verdouw PD, Ploeg H, Sites of action of adenosine in interorgan preconditioning of the heart et al. Sites of action of adenosine in interorgan preconditioning of the heart. Am J Physiol Heart Circ Physiol,2002,283(1):H29-37.
12. Xiao L, Lu R, Hu CP, et al. Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide. Eur J Pharmacol,2001,427(2):131-135.
13. Oxman T, Arad M, Klein R, et al. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia [J]. Am J Physiol.1997; 273(4):H1707-1712.
14. Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo [J]. Circulation,2002;106(23):2881-2883.
15.刘兴德,袁志柳,黄达枚.双下肢缺血后处理对大鼠心肌缺血再灌注损伤的保护作用[J].贵阳医学院学报.2004；29(1)：7-9.
16. Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs [J]. Heart 2007; 93(6):749-752.
17. Gritsopoulos G, Iliodromitis EK, Zoga A, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits [J]. Cardiovasc Drugs Ther.2009,23(3):193-8.
18. David GD. Myocardial reperfusion injury:a new review [J]. Cardiaovasc Res,2004, 61(3):363-4.
19. GalinnanesM, FowlerA G. Role of clinical pathologies inmyocardial injury following ischemia and reperfusion [J]. Cardiaovasc Res,2004,61(3):512-521.
20.王海华,戚仁斌,俞蕾,等.非创伤性预处理在离体心脏抗再灌注损伤中作用机制的探讨.中国病理生理杂志.2002,18(5)：535-539
21. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al, Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism [J]. Circulation.2007,116(12):1386-95.
22. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:underlying mechanisms and clinical application. [J]Cardiovasc Res,2008,79(3):377-386.
1. Ling H, Lou Y. Total flavones from Elsholtzia blanda reduce infarct size during acute myocardial ischemia by inhibiting myocardial apoptosis in rats. J Ethnopharmacol, 2005,101(1):169-175.
2. Das A, Xi L, Kukreja RC, et al. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem,2005,280(13):12944-12955.
3. Hotchkiss RS, Strasser A, McDunn JE, et al. Cell Death. N Engl J Med 2009; 361(16):1570-83.
4. Fliss, H., Gattinger, D. Apoptosis in ischemic and reperfused rat myocardium. Circ Res, 1996,79(5):949-956.
5. Gottlieb, RA, Burleson, KO, Kloner, RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest,1994,94(4):1621-1628.
6. Green DR, Reed JC. Mitochondria and apoptosis [J]. Science,1998,281(5381):
1309-1312.
7. Susin SA, Lorenzo HK, Zamzami N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature,1999,397(6718):441-446.
8. Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature,2001,412(6842):95-99.
9. Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med,2005,11(7): 725-730.
10. Bras M, Queenan B, Susin SA. Programmed cell death via mitochondria:different modles of dying [J]. Biochemistry (Moscow),2005,70 (2):231-239.
11. Black S C, Huang J Q, Rezaiefar P, et al. Co-localization of thecysteine p rotease Caspase-3 with apop totic myocytes after in vivo myocardial ischemia and reperfusion in the rat [J]. JMol Cell Cardiol,1998,30 (4):733-742.
12. Okamura T, Miura T, Takemura G, et al. Effect of Caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation inthe ischemia-reperfused rat heart [J]. Cardiovasc Res,2000,45(3):642-650.
13. Ruixing Y, A12Ghazali R, Wenwu L, et al. Pretreatmentwith probucol attenuates cardiomyocyte apop tosis in a rabbitmodel of ischemia/reperfusion [J]. Scand J Clin Lab Invest,2006,66 (7):549-558.
14. Zhao ZQ, Morris CD, Budde JM, et al. Inhibition f myocardial apoptosis reduces infarct size and improves egional contractile dysfunction during reperfusion. Cardiovasc Res,2003,59(1):132-142.
15. Borutaite V, Jekabsone A, Morkuniene R, et al. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction cytochrome c andapoptosis induced by heart ischemia. J Mol Cell Cardiol,2003,35(4):357-366.
16. Vohra H A, GalinanesM. Effect of the degree of ischaemic injury and reoxygenation time on the type of myocardial cell death in man:role of caspases [J]. BMC Physiol, 2005,5 (3):14.
17.谢俊然,郁丽娜,骆荣华,等.环孢素A对缺血-再灌注大鼠心肌细胞凋亡的影响[J].临床麻醉学杂志,2005,21(12)：838-840.
1. Gho BC, Schoemaker RG, Vadendel MA, et al. Myocardial protection by brief ischemia in non cardiac tissue [J]. Circulation,1996,94 (9):2193-2200.
2. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. [J]Basic Res Cardiol 2005; 100(5):404-412.
3.刘兴德,袁志柳,黄达枚.双下肢缺血后处理对大鼠心肌缺血再灌注损伤的保护作用[J].贵阳医学院学报,2004；29(1)：7-9.
4. Oxman T, Arad M, Klein R, et al. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia [J]. Am J Physiol.1997; 273(4):H1707-1712.
5. Galagudza M, Kurapeev D, Minasian S, et al. Ischemic postconditioning:brief ischemia during reperfusion converts persistent ventricular fibrillation into reglar rhythm [J]. Eur Cardiothorac surg,2004; 25(6):1006-1010.
6. 陶凌,李源,高峰,等.缺血后处理对急性心肌缺血再灌注兔心脏的保护作用[J].第四军医大学学报,2000,21(6)：116-118.
7. Shliakhto EV, GalagudzaMM, Syrenskii AV, et al. Ischemic postconditioning of the myocardium:A new method of heart protection against reperfusion damage [J]. Ter Arkh.2005; 77(5):77-80.
8. Petrishchev NN, Vlasov TD, Galagudza MM, et al. Myocardial ischemic postconditioning:A brief ischemia causes conversion of resistent reperfusion induced ventricular fibrillation into the normal rhythm [J]. Ross Fiziol Zh Im I M Sechenova. 2004,90 (9):1138-44.
1.仇万山,陈亦江.线粒体结构、功能和常用研究办法.麻醉学与复苏杂志,2007,28(3),282-285.
2. Das B, Sarkar C. Is the sarcolemmal or mitochondrial K (ATP) channel activation important in the antiarrhythmic and cardioprotective effects during acute ischemiaP reperfusion in the intact anesthetized rabbit model? [J].Life Sci,2005,77 (11):1226-1248.
3. Davidson SM, Hausenloy D, DuchenMR, et al. Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection[J]. Int J Biochem Cell Biol 2006,38 (3):414-419.
4. Hausenloy DJ, Maddock HL, Baxter GF, el al. Inhibiting mitochondrial permeability transition pore opening:a new paradigm for myocardial preconditioning [J]. Cardiovasc Res,2002,55(3):534-543.
5. Bozdogan O, Gonca E, Suveren E, et al. Mechanisms of glybenclamide-mediated anti-arrhythmia and ischemic conditionining in a rat model of myocardialinfarction: role of yohimbine treatment. Turk J Med Sci 2004,34(1):21-27.
6. Krolikowski JG, Bienengraeber M, Weihrauch D, et al.Inhibition of Mitochondrial Permeability Transition Enhances Isoflurane-Induced Cardioprotection During Early Reperfusion:The Role of Mitochondrial KATP Channels. Anesth Analg 2005; 101(6):1590-1596.
7. Murata M, Akao M, O'Rourke B, et al. Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection [J]. Circ Res,2001,89 (11):891-898.
8. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion:a target for cardioprotection [J]. Cardiovasc Res,2004,61(3):372-385.
9. Yang J, Cortopassi G. Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome c [J]. Free Radic Biol Med,1998, 24(4):624-631.
10. Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism [J]. Am J Physiol Heart Circ Physiol.2005; 288(3):H1252-1256.
11. Zuurbier CJ, Eerbeek O, Meijer AJ. Ischemic preconditioning, insulin, and morphine all cause hexokinase redistribution [J]. Am J Physiol Heart Circ Physiol,2005, 289(1):H496-H499.
12. Wang G, Liem DA,Vondriska TM, et al. Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition[J]. Am J Physiol Heart Circ Physiol,2005,288(3):H1290-H1295.
13. Zhang SZ, Wang NF, Xu J, et al. kappa-Opioid receptors mediate cardioprotection by remote preconditioning [J]. Anesthesiology 2006; 105(3):550-556.
14.李杨,于金凤,张朝颖,等.环孢霉素A诱导的心肌损伤与NO和NOS的关系.哈尔滨医科大学学报,2009,43(3)：241-244,254.
15. Sayen MR, Gustafsson AB, Sussman MA, et al. Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. Am J Physiol Cell Physiol 2003,284(2):C562-570.
1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomised trials. Lancet 2003; 361:13-20.
2. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA. Myocardial protection at a crossroads:the need for translation into clinical therapy. Circ Res 2004; 95:125-34.
3. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005; 112:2143-8.
4. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res 2003; 60:617-25.
5. Burgdorf C, Richardt D, Kurz T, et al. Adenosine inhibits norepinephrine release in the postischemic rat heart:the mechanism of neuronal stunning. Cardiovasc Res 2001;49: 713-720.
6. Pomblum VJ, Korbmacher B, Cleveland S, et al. Cardiac stunning in the clinic:the full picture. Interact CardioVasc Thorac Surg 2010; 10:86-91.
7. Ito H. No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat Clin Pract Cardiovasc Med 2006; 3:499-506.
8. Majidi M, Kosinski AS, Al-Khatib, SM, et al. Reperfusion ventricular arrhythmia 'bursts'in TIMI 3 flow restoration with primary angioplasty for anterior ST-elevation myocardial infarction:a more precise definition of reperfusion arrhythmias. Europace, 2008,10,988-997.
9. Garcia-Dorado D, Ruiz-Meana M, Piper HM, et al. Lethal reperfusion injury in acute myocardial infarction:facts and unresolved issues Cardiovasc Res.2009; 0: cvp185v2-cvp185
10. Ly HQ, Denault A, Dupuis J, et al. A pilot study:the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 2005; 150:933.
11. Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 2006; 70:181-190.
12. Ishii H, Ichimiya S, Kanashiro M, et al. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 2005; 112:1284-1288.
13. Gumina RJ, Buerger E, Eickmeier C, Moore J, Daemmgen J, Gross GJ. Inhibition of the Na (+)/H (+) exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs. Circulation 1999; 100: 2519-2526.
14. Zeymer U, Suryapranata H, Monassier JP, et al. The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: results of the Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction (ESCAMI) trial. J Am Coll Cardiol 2001; 38:1644-1650.
15. Lemasters JJ, Bond JM, Chacon E, et al. The pH paradox in ischemia-reperfusion injury to cardiac myocytes. EXS; 1996; 76:99-114.
16. Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+overloading, trigger pH-and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia-reperfusion. Am J Physiol Heart Circ Physiol; 2006; 290: H2024-H2034.
17. Avkiran M, Marber MS. Na (+)/H (+) exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol 2002; 39:747-753.
18. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004; 61:481-497.
19. Vakeva AP, Agah A, Rollins SA, Matis LA, Li L, Stahl GL. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion:role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 1998; 97:2259-2267.
20. Mertens P, Maes A, Nuyts J, et al. Recombinant P-selectin glycoprotein ligand-immunoglobulin, a P-selectin antagonist, as an adjunct to thrombolysis in acute myocardial infarction:the P-Selectin Antagonist Limiting Myonecrosis (PSALM) trial. Am Heart J 2006; 152:125.e1-125.e8.
21. Granger CB, Mahaffey KW, Weaver WD, et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction:the COMplement inhibition in Myocardial infarction treated withAngioplasty (COMMA) trial. Circulation 2003; 108:1184-1190.
22. Armstrong PW, Granger CB, Adams PX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention:a randomized controlled trial. JAMA 2007; 297:43-51.
23. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-Ⅱ). J Am Coll Cardiol 2005; 45:1775-1780.
24. Kloner RA, Forman MB, Gibbons RJ, Ross AM, Alexander RW, Stone GW. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction:the AMISTAD-2 trial. Eur Heart J 2006; 27:2400-2405.
25. Apstein CS, Opie LH. A challenge to the metabolic approach to myocardial ischaemia. Eur Heart J 2005; 26:956-959.
26. Mehta SR, Yusuf S, Diaz R, et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction:the CREATE-ECLArandomized controlled trial. JAMA 2005; 293:437-446.
27. Christensen CW, Rieder MA, Silverstein EL, Gencheff NE. Magnesium sulfate reduces myocardial infarct size when administered before but not after coronary reperfusion in a canine model. Circulation 1995; 92:2617-2621.
28. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4:a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345:669-685.
29. Antman E, Cooper H, McKinlay S, et al. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial:a randomised controlled trial. Lancet 2002; 360: 1189-1196.
30. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556.
31. Dae MW, Gao DW, Sessler DI, Chair K, Stillson CA. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol 2002; 282:H1584-H1591.
32. Ly HQ, Denault A, Dupuis J, et al. A pilot study:the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 2005; 150:933-933.
33. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore:its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 2003; 35:339-341.
34. Halestrap A.P. Calcium, mitochondria and reperfusion injury:a pore way to die。 Biochem Soc Trans.2006; 34 (Pt 2):232-7.
35. Yellon DM, Hausenloy DJ. Myocardial Reperfusion Injury. N Engl J Med 2007; 357:1121-35.
36. Vinten-Johansen J, Yellon DM, Opie LH. Postconditioning:a simple, clinically applicable procedure to improve revascularization in acute myocardial infarction. Circulation 2005; 112:2085-2088.
37. Yellon DM, Opie LH. Postconditioning for protection of the infarcting heart. Lancet 2006; 367:456-458.
38. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury:targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res 2004; 61:448-460.
39. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore:its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 2003; 35:339-341.
40. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. [J] Am J Physiol Heart Circ Physiol.2003; 285:H579-H588.
41. Zhao ZQ, Vinten-Johansen J. Postconditioning:reduction of reperfusion-induced injury. Cardiovasc Res 2006; 70:200-211.
42. Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning:staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007; 115:1895-1903.
43. Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway:a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 2005; 15:69-75.
44. Davidson SM, Hausenloy D, Duchen MR, Yellon DM. Signalling via the Reperfusion Injury Signalling Kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem Cell Biol 2006; 38: 414-419.
45. Abdallah Y, Gkatzoflia A, Gligorievski D, et al. Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage. Cardiovasc Res 2006; 70:346-353.
46. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005; 54: 146-151.
47. Bullard AJ, Govewalla P, Yellon DM. Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol 2005; 100:397-403.
48. Bell RM, Yellon DM. Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J Am Coll Cardiol 2003; 41:508-515.
49. Yang XM, Philipp S, Downey JM, Cohen MV. Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. Basic Res Cardiol 2006; 101: 311-318.
50. Lipsic E, van der Meer P, Voors AA, et al. A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction:a randomized feasibility and safety study. Cardiovasc Drugs Ther 2006; 20:135-141.
51. Patti G, Pasceri V, Colonna G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention:results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49:1272-1278.
52. Inagaki K, Churchill E, Mochly-Rosen D. Epsilon protein kinase C as a potential therapeutic target for the ischemic heart. Cardiovasc Res 2006; 70:222-230.
53. Bates E, Bode C, Costa M, et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation; 2008; 117(7):886-896.
54. Hausenloy DJ, Maddock HL, Baxter GF, et al. Inhibiting mitochondrial permeability transition pore opening:a new paradigm for myocardial preconditioning? Cardiovasc Res 2002; 55:534-543.
55. Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005; 434:658-662.
56. Shanmuganathan S, Hausenloy DJ, Duchen MR, Yellon DM. Mitochondrial permeability transition pore as a target for cardioprotection in the human heart. Am J Physiol Heart Circ Physiol; 2005; 289:H237-H242.
57. Heusch D, Boengler K, Schulz R. Cardioprotection Nitric Oxide, Protein Kinases, and Mitochondria. Circulation.2008; 118:1915-1919.
58. Zhao ZQ, Nakamura M, Wang NP, et al. Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res 2000; 94:133-144.
59. Doukas J, Wrasidlo W, Noronha G, et al. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc Natl Acad Sci USA,2006; 103:19866-19871.
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium. [J]Circulation.1986; 74:1124-1136.
2. Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. [J] Am J Physiol Heart Circ Physiol.2003; 285:H579-H588.
3. Hausenloy DJ., Yellon DM. Survival kinases in ischemic preconditioning and postconditioning Cardiovascular Research.2006; 70:240-253.
4. Gho BC, Schoemaker RG, Vadendel MA, et al. Myocardial protection by brief ischemia in non cardiac tissue [J]. Circulation,1996,94 (9):2193-2200.
5. Kerendi F, Kin H, Halkos ME, et al. Brief renal ischemic and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. [J]Basic Res Cardiol 2005; 100:404-412.
6. Przyklenk K, Bauer B, Ovize M, et al. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion [J] Circulation,1993,87:893-899.
7. Dickson EW, Reinhardt CP, Renzi FP, et al. Ischemic preconditioning may Be transferable via whole blood transfusion:preliminary evidence [J]. J Thromb thronmbolysis,1999; 8:123-129.
8. Dickson EW, Lorbar M, Porcaro WA, et al. Rabbit heart can be "preconditioned" via transfer of coronary effluent[J]. Am J Phsiol,1999; 277:H2451-H2457.
9. Pell TJ, Baxter GF, Yellon DM, et al. Renal ischemia preconditions myocardium:role of adenosine receptors and ATP-sensitive potassium channels [J]. Am J Phsiol,1998; 275:H1542-H1547.
10. Takaoka A, Nakae I, Mitsunami K, et al. Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits:effects of "remote preconditioning". [J] J Am Coll Cardiol,1999,33:556-564.
11. Patel HH, Moore J, Hsu AK, et al. Cardioprotection at a distance:Mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism [J]. J Mol Cell Cardiol.2002,34:1317-1323.
12. Tokuno S, HinokiyamA K, Tokuno K, et al. Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia [J]. Arteriosclera Thromb Vasc Biol,2002; 22:995-100.
13. de Zeeuw S, Lameris TW, Duncker DJ, et al. Cardioprotection in pigs by exogenous norepinephrine but not by cerebral ischemia-induced release of endogenous norepinephrine[J]. Stroke.2001; 32:767-74.
14. Oxman T, Arad M, Klein R, et al. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia [J]. Am J Physiol.1997; 273:H1707-1712.
15.Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo [J] Circulation,2002;106:2881-2883.
16. Konstantinov IE, Li J, Cheung MM, et al. Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism [J]. Transplantation.2005; 79:1691-1695.
17. 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 [J]. Cardiovasc Res.2004; 61:591-599.
18. Nakano A, Heusch G, Cohen MV, et al. Preconditioning one myocardial region does not necessarily precondition the whole rabbit heart[J]. Basic Res Cardiol 2002; 97: 35-39.
19. Kharbanda RK, Peters M, Walton B, et al. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo [J]. Circulation.2001; 103:1624-1630.
20. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, et al. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans:role of the autonomic nervous system. [J] J Am Coll Cardiol.2005; 46:450-456.
21. Gunaydin B, Cakici I, Soncul H, et al. Does remote organ ischaemia trigger cardiac preconditioning during coronary artery surgery [J]? Pharmacol Res.2000; 41:493-496.
22. Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery:a randomised controlled trial [J]. Lancet 2007; 370:575-9.
23. Loukogeorgakis SP, Williams R, Panagiotidou AT, et al, Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism[J]. Circulation.2007,18; 116(12):1386-95.
24. Cheung MM. Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans [J]. J Am Coll Cardiol.2006; 47:2277-2282.
25.刘小军,易善永,廖斌,等.肢体缺血预处理对心脏瓣膜置换术心肌保护作用的研究[J].心血管康复医学杂志.2007,16(4)：347-349.
26. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning:underlying mechanisms and clinical application [J]. Cardiovasc res,2008,79,377-386.
27. Xiao L, Lu R, Hu CP, et al. Delayed cardioprotection by intestinal preconditioning mediated by calcitonin gene-related peptide [J]. Eur J Phalmacol.2001,427:131-135.
28. Chen YS, Chien CT, Ma MC, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway [J]. J Surg Res.2005; 126:92-101.
29. Schoemaker RG, van Heijningen CL. Bradykinin mediates cardiac preconditioning at a distance [J]. Am J Physiol Heart Circ Physiol,2000; 278:H1571-1576.
30. Singh D, Chopra K. Evidence of the role of angiotensin AT(I) receptors in remote renal preconditioning of myocardial[J]. Methods Find Exp Clin Pharmacol,2004; 26:117-122.
31. Ren X, Wang Y, Jones WK. TNF-alpha is required for late ischemic preconditioning but not for remote preconditioning of trauma [J]. J Surg Res.2004; 121:120-129.
32. Wolfrum S, Nienstedt J, Heidbreder M, et al Calcitonin gene related peptide mediates cardioprotection by remote preconditioning [J]. Regul Pept.2005; 127:217-224.
33. Wang YP, Maeta H, Mizoguchi K, et al. Intestinal ischemia preconditions myocardium: role of protein kinase C and mitochondrial K(ATP) channel[J]. Cardiovasc Res.2002 Aug 15; 55(3):576-82.
34. Wolfrum S, Schneider K, Heidbreder M, et al. Remote preconditioning protects the heart by activating myocardial PKC epsilon-isoform [J]. J Cardiovasc Res,2002; 55:583-589.
35. Li G, Labruto F, Sirsjo A, et al. Myocardial protection by remote preconditioning:the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase [J]. Eur J Cardiothorac Surg.2004; 26:968-73.
36. Guohu L, Fausto L, Allan S, et al. Myocardial protection by remote preconditioning: The role of nuclear factor kappa-B p105 and inducible nitric oxide synthase [J]. Eur J Cardiothorac Surg,2004,26:968-973.
37. Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism [J]. Am J Physiol Heart Circ Physiol.2005; 288:H1252-1256.
38. Davidson SM, Hausenloy D, DuchenMR, et al. Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection[J]. Int J Biochem Cell Biol,2006,38 (3):414-419.
39. Zhang SZ, Wang NF, Xu J, et al. kappa-Opioid receptors mediate cardioprotection by remote preconditioning [J]. Anesthesiology 2006; 105:550-556.
40.刘兴德,袁志柳,黄达枚.双下肢缺血后处理对大鼠心肌缺血再灌注损伤的保护作用[J].贵阳医学院学报.2004；2：7-9.
41.张兴华,李春梅,马晓静,等.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究[J].中华医学杂志.2006,.86：841-845.
42. Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs [J]. Heart 2007; 93: 749-752.
43. Gritsopoulos G, Iliodromitis EK, Zoga A, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits [J]. Cardiovasc Drugs Ther.2009,23(3):193-8.
44. Matteo PS. Remote Postconditioning in patients with acute myocardial infarction treated by primary percutaneous coronary intervention (PCI) (RemPostCon) (Accessed March 18,2009, at http://clinicaltrials.gov.).
45. Lawson Health Research Institute. Remote ischemic postconditioning during percutaneous coronary interventions (RIP-PCI) (Accessed September 2,2009, at http://clinicaltrials.gov.).
46. Zang W, Sun L, Yu X. Cardioprotection of ischemic postconditioning and pharmacological post-treatment with adenosine or acetylcholine [J]. Acta Physiologica Sinica.2007,59 (5):593-600.
47. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury:targeting the reperfusion injury salvage kinase (RISK)-pathway [J].Cardiovasc Res,2004,61(3):448-60.
48. Tsubota H, Marui A, Miwa S, et al. Remote postconditioning may attenuate ischemia-reperfusion injury in a murine hind limb through activation of adenosine receptors[J]. Circulation.2009; 120:S1117.
49.蒋玲玲,张野,翁立军,等.中枢吗啡后处理对在体大鼠缺血后心肌的保护作用.中国药理学通报.2009；25(2)：77-81.
50. Williams RP, Okorie MI, Gill H, et al. Role of the autonomic nervous system in remote postconditioninginhumans[J]. Circulation.2008; 118:S1473.
51. Fang J, Chen L, Wu L, et al. Intra-cardiac remote ischemic post-conditioning attenuates ischemia-reperfusion injury in rats [J]. Scand Cardiovasc J.2009; 43(6):386-94.
52. Schmidt MR, Smerup M, Konstantinov IE, et al:Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism:First demonstration of remote ischemic preconditioning[J]. Am J Physiol Heart Circ Physiol 2007;292 (4):H1883-H1890.
53. Saxena P, Newman M AJ, Shehatha JS, et al. Remote ischemic conditioning:evolution of the concept, mechanisms, and clinical application. J Card Surg 2010; 25:127-134.
54. Kharbanda RK, Li J, Konstantinov IE, et al:Remote ischemic preconditioning protects against cardiopulmonary bypass-induced tissue injury:A preclinical study. Heart 2006; 92:1506-1511.