Realizing the clinical potential of ischemic preconditioning and postconditioning

After an acute myocardial infarction (AMI), early reperfusion by thrombolysis or primary percutaneous coronary intervention remains the most-effective strategy for limiting the size of an evolving infarct. The mortality from AMI, however, remains significant, due partly to the lethal reperfusion injury that occurs on reperfusing the ischemic myocardium. Novel cardioprotective strategies are required to target this form of injury. In ischemic preconditioning transient, nonlethal episodes of myocardial ischemia and reperfusion before the index ischemic episode reduce infarct size. The cardioprotective potential of ischemic preconditioning has not been realized in clinical practice because it necessitates an intervention applied before the onset of AMI, which is difficult to predict. A more-amenable approach to cardioprotection is to intervene at the onset of reperfusion, the timing of which is under the control of the operator. In this regard, ischemic postconditioning, in which transient episodes of myocardial ischemia and reperfusion administered at the onset of reperfusion reduce infarct size, constitutes one such intervention. Interestingly, studies suggest that ischemic preconditioning and postconditioning activate the same signaling pathway at the time of reperfusion, thereby offering a common target for cardioprotection. Therefore, the pharmacologic recruitment of this signaling pathway at the time of myocardial reperfusion might allow one to harness the cardioprotective potential of ischemic preconditioning and postconditioning. In this review, we discuss the potential application of ischemic preconditioning and postconditioning in the clinical arena of myocardial ischemia and reperfusion, and examine the common signaling pathways by which this might be achieved.     

Ischemia/reperfusion injury and cardioprotective mechanisms: Role of mitochondria and reactive oxygen species

Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction(AMI).However reperfusion is responsible for additional myocardial damage,which likely involves opening of the mitochondrial permeability transition pore(mPTP).In reperfusion injury,mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability.Major mechanisms of mitochondrial dysfunction include the long lasting opening of mPTPs and the oxidative stress resulting from formation of reactive oxygen species(ROS).Several signaling cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning,obtained with brief intermittent ischemia or with pharmacological agents.These pathways converge on a common target,the mitochondria,to preserve their function after ischemia/reperfusion.The present review discusses the role of mitochondria in cardioprotection,especially the involvement of adenosine triphosphate-dependent potassium channels,ROS signaling,and the mPTP.Ischemic postconditioning has emerged as a new way to target the mitochondria,and to drastically reduce lethal reperfusion injury.Several clinical studies using ischemic postconditioning during angioplasty now support its protective effects,and an interesting alternative is pharmacological postconditioning.In fact ischemic postconditioning and the mPTP desensitizer,cyclosporine A,have been shown to induce comparable protection in AMI patients.     

缺血后处理减轻心肌线粒体损伤对缝隙连接蛋白43的影响

目的观察缺血后处理对线粒体缝隙连接蛋白43(Cx43)的影响以及心肌保护的可能机制。方法健康新西兰大白兔64只.建立心肌缺血再灌注模型,随机分为4组,假手术组、缺血再灌注组、缺血预处理组、缺血后处理组,每组16只。检测各组心肌梗死面积,透射电镜观察心肌细胞的超微结构,荧光法检测线粒体膜电位,比色法检测线粒体Ca~(2+)和丙二醛浓度及超氧化物歧化酶(SOD)活性,Western blot法检测Cx43含量。结果与缺血再灌注组比较,缺血后处理组和缺血预处理组兔心肌梗死面积明显减少,心肌线粒体形态结构改变明显减轻,跨膜电位、SOD活性、线粒体Cx43明显升高,Ca~(2+)、丙二醛浓度明显降低(P<0.05,P<0.01)。与假手术组比较,缺血再灌注组兔线粒体Cx43明显下调(P<0.05)。结论缺血后处理保护心肌及线粒体可能与提高线粒体跨膜电位、降低线粒体氧自由基水平和减轻线粒体Ca~(2-)超载有关,其机制可能与提高线粒体Cx43表达有关。     

miR-214在大鼠心肌缺血再灌注损伤及缺血后适应中的表达及机制探讨

目的探讨miR-214在心肌缺血再灌注损伤及缺血后适应心脏保护作用中的变化及可能机制。方法 30只雄性SD大鼠随机分为假手术组、缺血再灌注组和缺血后适应组。通过颈动脉插管测定不同组的血流动力学指标,采用伊文思兰和TTC染色法测定缺血和梗死面积,并通过实时定量PCR方法测定再灌注2h缺血心肌miR-214及预测的靶基因HIF1AN(hypoxia-inducible factor1alpha subunit inhibitor)的变化。结果与大鼠心肌缺血再灌注组相比,缺血后适应处理可以显著改善再灌注后左室收缩压(LVSP)、左室舒张末期压(LVEDP)、左室内压最大上升速率(+dp/dtmax)以及最大下降速率(-dp/dtmax),并降低了心肌梗死面积;与假手术组相比,心肌缺血再灌注组大鼠心肌组织缺血区的miR-214表达显著下调,缺血后适应组心肌组织缺血区miR-214的表达较缺血再灌注组明显升高;通过生物信息学分析预测miR-214在HIF1AN的3'-UTR上存在结合位点,与假手术组相比,HIF1AN mRNA水平在缺血再灌注组中显著增加,而缺血后适应组与缺血再灌组相比,HIF1AN的mRNA水平显著减...     

Cardioprotection from ischemia/reperfusion injury: basic and translational research

Because ischemic heart diseases (IHDs) are a major cause of mortality and heart failure, novel therapeutic approaches are expected to improve the clinical outcomes of patients with IHDs such as acute myocardial infarction and ischemic heart failure. Brief episodes of nonlethal ischemia and reperfusion before sustained ischemia or at the onset of reperfusion can reduce ischemia-reperfusion injury. These ischemic conditioning phenomena are termed "ischemic preconditioning" and "ischemic postconditioning", respectively. Furthermore, brief episodes of nonlethal ischemia and reperfusion applied to the organ or tissue distal to the heart reduce myocardial infarct size, known as "remote ischemic conditioning". The cardioprotection afforded by these ischemic conditionings can be used to treat patients with acute myocardial infarction or cardiac operations. Extensive research has determined that autacoids (eg, adenosine, bradykinin opioid) and cytokines, their respective receptors, kinase signaling pathways and mitochondrial modulation are involved in ischemic conditioning. Modification of these factors by pharmacological agents mimics the cardioprotection by ischemic conditioning and provides a novel therapeutic intervention for IHDs. Here, the potential mechanisms of ischemic conditioning and its "proof-of-concept" translational studies are reviewed. In the near future, large, multicenter, randomized, placebo-controlled, clinical trials will be required to determine whether pharmacological and ischemic conditioning can improve the clinical outcomes of patients with IHDs.     

远隔预处理和后处理对兔急性心肌缺血再灌注损伤的作用

目的探讨远隔预处理和后处理是否具有减轻兔心肌缺血再灌注损伤的作用及其机制。方法新西兰大白兔40只，随机平均分为4组：对照组、心肌缺血预处理组、肢体缺血预处理组和肢体缺血后处理组，分组进行干预。测定血浆磷酸肌酸激酶（CK）和丙二醛（MDA）活性及心肌梗死面积并检测组织髓过氧化物酶（MPO）活性。结果心肌缺血预处理组、肢体缺血预处理组和肢体缺血后处理组心肌梗死面积、再灌注末MDA活性、缺血组织MPO活性均明显低于对照组（均P〈0．01）。结论远隔预处理和后处理均有显著的心脏保护作用，其作用可能与减轻活性氧的损伤及抗氧化作用加强有关。     

再灌注心脏保护的新策略:后处理和预处理的比较（英文）

心肌缺血/再灌注引起的损伤（RMMI）是由多种触发物、媒介物和效应器参与的复杂生物反应过程,导致炎症反应、内皮细胞损伤、血流障碍、心功能异常、心肌细胞坏死和凋亡。过去二十多年来,尽管人们开发了多种心脏保护措施（药物性干预）以减少RMMI,但结果并不令人满意。因此,在临床上寻求可行和有效的治疗措施以减轻RMMI有着极大的价值。我们实验室近来报道了在再灌注或恢复供氧早期,快速反复中断冠脉血流或氧供（缺血或缺氧后处理）,可减少心肌组织或细胞内自由基的生成,减轻钙超载,减轻内皮功能的损伤,降低黏附蛋白的表达,减少坏死和凋亡。后处理的这些保护作用可能和内源性生成物如腺苷和一氧化氮增多、蛋白酶（包括PI3KAkt和ERK1/2）的激活、线粒体的ATP依赖性K+通道开放和线粒体通透性转换孔关闭有关。与预处理比较,后处理具有同样的保护效应。在长时间再灌注后仍有减少梗死范围的作用。目前的实验结果和临床观察证实,在缺血后恢复血供时,后处理的应用在治疗缺血/再灌注损伤方面开启了一个新的治疗窗口。     

Preconditioning, postconditioning and their application to clinical cardiology

Ischemic preconditioning is a well-established phenomenon first described in experimental preparations in which brief episodes of ischemia/reperfusion applied prior to a longer coronary artery occlusion reduce myocardial infarct size. There are ample correlates of ischemic preconditioning in the clinical realm. Preconditioning mimetic agents that stimulate the biochemical pathways of ischemic preconditioning and protect the heart without inducing ischemia have been examined in numerous experimental studies. However, despite the effectiveness of ischemic preconditioning and preconditioning mimetics for protecting ischemic myocardium, there are no preconditioning-based therapies that are routinely used in clinical medicine at the current time. Part of the problem is the need to administer therapy prior to the known ischemic event. Other issues are that percutaneous coronary intervention technology has advanced so far (with the development of stents and drug-eluting stents) that ischemic preconditioning or preconditioning mimetics have not been needed in most interventional cases. Recent clinical trials such as AMISTAD I and II (Acute Myocardial Infarction STudy of ADenosine) suggest that some preconditioning mimetics may reduce myocardial infarct size when given along with reperfusion or, as in the IONA trial, have benefit on clinical events when administered chronically in patients with known coronary artery disease. It is possible that some of the benefit described for adenosine in the AMISTAD 1 and 2 trials represents a manifestation of the recently described postconditioning phenomenon. It is probable that postconditioning--in which reperfusion is interrupted with brief coronary occlusions and reperfusion sequences--is more likely than preconditioning to be feasible as a clinical application to patients undergoing percutaneous coronary intervention for acute myocardial infarction.     

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection

Following an acute myocardial infarction (AMI), early coronary artery reperfusion remains the most effective means of limiting the eventual infarct size. The resultant left ventricular systolic function is a critical determinant of the patient’s clinical outcome. Despite current myocardial reperfusion strategies and ancillary antithrombotic and antiplatelet therapies, the morbidity and mortality of an AMI remain significant, with the number of patients developing cardiac failure increasing, necessitating the development of novel strategies for cardioprotection which can be applied at the time of myocardial reperfusion to reduce myocardial infarct size. In this regard, the Reperfusion Injury Salvage Kinase (RISK) Pathway, the term given to a group of pro-survival protein kinases (including Akt and Erk1/2), which confer powerful cardioprotection, when activated specifically at the time of myocardial reperfusion, provides an amenable pharmacological target for cardioprotection. Preclinical studies have demonstrated that an increasing number of agents including insulin, erythropoietin, adipocytokines, adenosine, volatile anesthetics natriuretic peptides and ‘statins’, when administered specifically at the time of myocardial reperfusion, reduce myocardial infarct size through the activation of the RISK pathway. This recruits various survival pathways that include the inhibition of mitochondrial permeability transition pore opening. Interestingly, the RISK pathway is also recruited by the cardioprotective phenomena of ischemic preconditioning (IPC) and postconditioning (IPost), enabling the use of pharmacological agents which target the RISK pathway, to be used at the time of myocardial reperfusion, as pharmacological mimetics of IPC and IPost. This article reviews the origins and evolution of the RISK pathway, as part of a potential common cardioprotective pathway, which can be activated by an ever-expanding list of agents administered at the time of myocardial reperfusion, as well as by IPC and IPost. Preliminary clinical studies have demonstrated myocardial protection with several of these pharmacological activators of the RISK pathway in AMI patients undergoing PCI. Through the use of appropriately designed clinical trials, guided by the wealth of existing preclinical data, the administration of pharmacological agents which are known to activate the RISK pathway, when applied as adjuvant therapy to current myocardial reperfusion strategies for patients presenting with an AMI, should lead to improved clinical outcomes in this patient group.     

缺血后处理对大鼠急性心肌缺血再灌注损伤的影响

目的观察在体条件下缺血后处理对大鼠心肌缺血再灌注损伤的作用及可能的途径。方法建立大鼠在体缺血再灌注模型,将30只大鼠随机分为假手术组、缺血再灌注组、缺血后处理组、缺血预适应组。于再灌注末测定心肌酶,超氧化物歧化酶(SOD)及丙二醛(MDA)的含量,并测定心肌组织梗死面积。结果与缺血再灌注组相比,缺血后处理组与缺血预适应组心肌梗死面积明显减小,血浆肌钙蛋白I及MDA的含量均降低(P<0.05),血浆SOD活性升高(P<0.05)。结论缺血后处理可减轻心肌缺血再灌注损伤,具有心肌保护效应。     

缺血后处理对高血脂大鼠缺血/再灌注心肌的保护作用

目的 观察缺血后处理对高血脂大鼠缺血/再灌注（I/R）心肌的保护作用。方法 选择高血脂SD大鼠36只,随机分为3组,即假手术组、I/R组和缺血后处理组,每组12只。制备大鼠心肌I/R模型。I/R组:收紧结扎线缺血40 min,放松结扎线再灌注240 min。缺血后处理组:缺血40 min后,再灌注10 s,缺血10 s,连续3个循环,然后再灌注240 min。假手术组:开胸后穿线做套环,但不收紧结扎线。用全自动生化仪测定血清肌酸激酶（CK）的含量,黄嘌呤氧化酶法检测超氧化物岐化酶（SOD）的活性。采用硫代巴比妥酸法测定丙二醛（MDA）的含量,用伊文氏蓝-红四氮唑（TTC）染色法测定心肌梗死的范围。结果 ①血清CK活性的测定:再灌注结束后,缺血后处理组和I/R组的活性CK的活性明显高于假手术组［分别为（712.94±20.68）、（946.58±27.43） vs （232.12±18.26）U/L,P<0.05,1 U=16.67 nkat］,缺血后处理组明显低于I/R组(P<0.05)。②血清SOD和MDA的含量:缺血后处理组血清SOD 的含量高于对照组(P<0.05);MDA的含量明显低于对照组(P<0.05)。③心肌梗死范围:再灌注结束后,缺血后处理组和I/R组的心肌缺血区与左室面积的比率无明显差异。缺血后处理组的心肌坏死区与缺血区的比率显著低于I/R组［分别为(25.3±6.6）% vs （39.2±7.1）%,P<0.05］。结论 缺血后处理对高血脂大鼠I/R心肌具有保护作用。     

缺血后处理对心肌缺血再灌注损伤过程中内质网应激的影响研究

目的 探讨缺血后处理(IPostC)对心肌缺血再灌注损伤(MIRI)中细胞凋亡的影响,以及特异性内质网应激(ERS)损伤相关蛋白Grp78(葡萄糖调节蛋白78)和Caspase 12(半胱氨酸蛋白酶12)的蛋白表达水平的变化和意义。方法 Wistar 大鼠24只随机分为假手术组、I/R组(缺血再灌注组)、IPostC组(缺血后处理组)3组,每组8只。分别测定各组心肌缺血和梗死面积、细胞凋亡指数和Caspase12、 Grp78蛋白表达检测。结果 假手术组未见梗死心肌和缺血心肌,IPostC组心肌缺血区面积(46.46±2.13)%和梗死区面积(41.02±2.93)%均明显小于I/R组(53.31±3.87, 52.19±3.44)%,P值均<0.01。假手术组心肌细胞凋亡指数(6.70±2.25)%明显低于I/R组(26.92±1.91)% 、IPostC组(20.54±3.05)%,P值均<0.001。心肌组织Caspase12蛋白表达水平在假手术组(0.11±0.01)明显低于I/R组(0.41±0.06)和IPostC组(0.35±0.06),并且IPostC组低于I/R组,P值均<0.01;心肌组织Grp78蛋白水平在假手术组(0.13±0.03)亦明显低于I/R组(1.04±0.16)和IPostC组(1.17±0.14),并且IPostC组高于I/R组,P值均<0.01。结论 本研究从动物实验证实IPostC能减轻心肌细胞凋亡,而ERS激活参与了大鼠MIRI过程,推测IPostC在大鼠MIRI过程中可能通过调节ERS途径抑制细胞凋亡,改善MIRI。     

Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion

Short non-lethal ischemic episodes administered to hearts prior to (ischemic preconditioning, IPC) or directly after (ischemic postconditioning, IPost) ischemic events facilitate myocardial protection. Transferring coronary effluent collected during IPC treatment to un-preconditioned recipient hearts protects from lethal ischemic insults. We propose that coronary IPC effluent contains hydrophobic cytoprotective mediators acting via PI3K/Akt-dependent pro-survival signaling at ischemic reperfusion. Ex vivo rat hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion. IPC effluent administered for 10 min prior to index ischemia attenuated infarct size by ≥55% versus control hearts (P < 0.05). Effluent administration for 10 min at immediate reperfusion (reperfusion therapy) or as a mimetic of pharmacological postconditioning (remote postconditioning, RIPost) significantly reduced infarct size compared to control (P < 0.05). The IPC effluent significantly increased Akt phosphorylation in un-preconditioned hearts when administered before ischemia or at reperfusion, while pharmacological inhibition of PI3K/Akt-signaling at reperfusion completely abrogated the cardioprotection offered by effluent administration. Fractionation of coronary IPC effluent revealed that cytoprotective humoral mediator(s) released during the conditioning phase were of hydrophobic nature as all hydrophobic fractions with molecules under 30 kDa significantly reduced infarct size versus the control and hydrophilic fraction-treated hearts (P < 0.05). The total hydrophobic effluent fraction significantly reduced infarct size independently of temporal administration (before ischemia, at reperfusion or as remote postconditioning). In conclusion, the IPC effluent retains strong cardioprotective properties, containing hydrophobic mediator(s) < 30 kDa offering cytoprotection via PI3K/Akt-dependent signaling at ischemic reperfusion.     

盐酸法舒地尔后适应对大鼠心肌缺血再灌注损伤的保护作用

目的通过主动脉根部模拟冠状动脉内给药,观察盐酸法舒地尔后适应对大鼠急性心肌缺血再灌注损伤的保护作用。方法选择SD大鼠48只,随机分为假手术组、缺血再灌注组、缺血后适应组、法舒地尔组,每组12只。各组于再灌注3 h后处死大鼠,分别测定心功能参数、血浆心肌酶、心肌梗死范围和心肌细胞凋亡指数。结果与假手术组比较,缺血再灌注组、缺血后适应组和法舒地尔组血浆心肌酶含量明显升高,差异有统计学意义(P<0.01)。与缺血再灌注组比较,法舒地尔组心功能参数明显改善,血浆心肌酶含量、心肌梗死范围、心肌细胞凋亡指数明显下降,差异有统计学意义(P<0.01)。结论盐酸法舒地尔可以模拟缺血后适应效应,减轻心肌缺血再灌注损伤,减少缺血心肌细胞凋亡,缩小心肌梗死范围。     

Pathophysiology of Myocardial Infarction

One or several short cycles of ischemia/reperfusion before (preconditioning) or after (postconditioning) a sustained coronary occlusion with subsequent reperfusion reduce the ultimate infarct size. The protection is potent, but limited to a narrow time frame. In animal experiments, a complex signal transduction cascade was identified which results specifically in a reduction of reperfusion injury. There is evidence for both ischemic pre- and postconditioning in patients with coronary artery disease.     

不同时期无创肢体缺血预适应对急性心肌梗死大鼠的保护作用

目的:探讨急性心肌梗死前、再灌注前及再灌注时等不同时期,无创性肢体缺血预适应在减轻大鼠缺血/再灌注损伤中的作用。方法:所有大鼠随机分为4组(每组10只):心肌缺血/再灌注损伤组(A组)、急性心肌梗死前肢体缺血预适应组(B组)、再灌注前肢体缺血预适应组(C组)和再灌注初期肢体缺血预适应组(D组)。观察各组心电、心肌缺血范围(AAR)、心肌梗死范围(IA)、心肌梗死部位质量与左心室质量(LV)的比值(IA/LV)、梗死范围与缺血范围的比值(IA/AAR)、CK-MB值。结果:与A组相比,B、C、D 3组ST段抬高幅度、CK-MB值、IA/LV和IA/AAR比值均显著降低(P<0.01)。结论:无创性肢体缺血预适应在急性心肌梗死前、再灌注前及再灌注时的各个时期应用,都能明显降低大鼠心肌缺血/再灌注时的ST段抬高幅度,明显降低心肌酶水平,明显缩小心肌坏死面积。     

Brief ischemia-reperfusion performed after prolonged ischemia (ischemic postconditioning) can terminate reperfusion arrhythmias with no reduction of cardiac function in rats

OBJECTIVE: Recently, it has been reported that ischemic postconditioning, a brief episode of ischemia-reperfusion performed after prolonged ischemia, can reduce ischemic myocardial injury. However, the effects of ischemic postconditioning on ischemia/reperfusion injury remain unclear. We investigated the effects of brief ischemia-reperfusion before (ischemic preconditioning) and after (ischemic postconditioning) prolonged ischemia on myocardial ischemia/reperfusion injury, especially reperfusion arrhythmias. METHODS: Adult male Sprague-Dawley rats weighing about 400-500 g were used. The isolated heart was perfused using a working heart method (Krebs-Henseleit bicarbonate buffer). In the control group, after stabilization, diastolic global ischemia for 15 minutes was produced by a one-way ball valve with electrical pacing (330 bpm, 2.0 V). After ischemia, the heart was reperfused for 20 minutes. In the preconditioning and postconditioning groups, 5-minute global ischemia was produced before and after ischemia for 15 minutes with a 1 minute interval. An electrocardiogram was performed and left ventricular pressure (LVP, +dP/dt, -dP/dt) and CK activity in coronary effluent were measured during the protocol. RESULTS: Ischemic preconditioning did not affect the incidence or duration of reperfusion ventricular arrhythmias. Ischemic postconditioning could terminate reperfusion ventricular arrhythmias completely and reduced the duration of reperfusion ventricular arrhythmias significantly (P < 0.01). Furthermore, the recovery ratio of +dP/dt at 20 minutes after initial reperfusion was significantly higher in the postconditioning group than in the other groups. CONCLUSION: These results suggest that ischemic postconditioning can terminate reperfusion arrhythmias with no reduction of cardiac function, and may be useful for correcting stunned myocardium.     

Postconditioning A new link in nature’s armor against myocardial ischemia–reperfusion injury

Reperfusion injury is a complex process involving several cell types (endothelial cells, neutrophils, and cardiomyocytes), soluble proinflammatory mediators, oxidants, ionic and metabolic dyshomeostasis, and cellular and molecular signals. These participants in the pathobiology of reperfusion injury are not mutually exclusive. Some of these events take place during the very early moments of reperfusion, while others, seemingly triggered in part by the early events, are activated within a later timeframe. Postconditioning is a series of brief mechanical interruptions of reperfusion following a specific prescribed algorithm applied at the very onset of reperfusion. This algorithm lasts only from 1 to 3 minutes depending on species. Although associated with re–occlusion of the coronary artery or re–imposition of hypoxia in cell culture, the reference to ischemia has been dropped. Postconditioning has been observed to reduce infarct size and apoptosis as the “end games” in myocardial therapeutics; salvage of infarct size was similar to that achieved by the gold standard of protection, ischemic preconditioning. The cardioprotection was also associated with a reduction in: endothelial cell activation and dysfunction, tissue superoxide anion generation, neutrophil activation and accumulation in reperfused myocardium, microvascular injury, tissue edema, intracellular and mitochondrial calcium accumulation. Postconditioning sets in motion triggers and signals that are functionally related to reduced cell death. Adenosine has been implicated in the cardioprotection of postconditioning, as has e–NOS, nitric oxide and guanylyl cyclase, opening of K_ATP channels and closing of the mitochondrial permeability transition pore. Cardioprotection by postconditioning has also been associated with the activation of intracellular survival pathways such as ERK1/2 and PI3 kinase – Akt pathways. Other pathways have yet to be identified. Although many of the pathways involved in postconditioning have also been identified in ischemic preconditioning, some may not be involved in preconditioning (ERK1/2). The timing of action of these pathways and other mediators of protection in postconditioning differs from that of preconditioning. In contrast to preconditioning, which requires a foreknowledge of the ischemic event, postconditioning can be applied at the onset of reperfusion at the point of clinical service, i.e. angioplasty, cardiac surgery, transplantation.     

后肢远程预处理对心肌缺血再灌注与心交感神经损伤的影响

目的：后肢远程缺血预处理对急性心肌缺血再灌注与心交感神经损伤影响的实验研究。方法：20只雄性新西兰大白兔随机被均分成两组：对照组及远程缺血预处理（RIPC）组。两组均制作心肌缺血模型。RIPC组在心肌缺血前行双后肢短暂缺血预处理2次（充气式压力止血带环扎双后肢腘窝上1／3,压力26．6kPa,每次10min,间隔10min）,最后一次后肢缺血预处理后再灌注60min制作急性心肌缺血模型。其方法为：冠状动脉左前降支完全闭塞45min,于松开结扎圈再灌注2、4h时,分别以碘-间位碘代苄胍（^131-MIBG）、^99m锝-甲氧基异丁基异腈（^99mTc-MIBI）双核素作放射自显影,其后以美蓝、氯化四唑（TTC）作组织染色,分别确定心肌危险梗塞灶与实际梗塞灶。结果：再灌注4h后,预处理组危险梗塞灶与实际梗塞灶均小于对照组（P〈0．01）。^131I-MIBG及^99m～Tc-M1BI自显影在同一区域摄取存在差异性,两组^131I-MIBG显影缺损面积（40．8土3．2）％．均显著比^99mTc-MIBI显影缺损及实际梗塞灶大（P〈0．05）。结论：远程预处理能有效阻断心肌缺血再灌注对交感神经损伤的作用;利用交感神经显影剂MIBG显影能客观监测心肌梗塞病变范围和程度,评价远程预处理的心肌保护效应。