心肌保护新策略--缺血后处理

缺血后处理(ischemic postconditioning)是近年来提出的一种新的心肌保护方法,即再灌注后对缺血心肌反复进行再缺血处理,以减轻缺血再灌注损伤.其机制可能与抑制氧自由基堆积、中性粒细胞黏附、心肌细胞凋亡和细胞内钙超载有关.由于缺血后处理可在不可预见的心肌缺血后进行,且操作方便,因此在临床上可能具有较大的应用价值.     

吸人麻醉药后处理心肌保护作用机制的研究进展

背景 吸入麻醉药后处理（inhalational anesthetics postconditioning,APO）是指在缺血后再灌注早期给予一定浓度吸入麻醉药处理。APO具有心肌保护作用,其作用机制目前尚未完全阐明。目的 对APO心肌保护作用机制的研究进展进行回顾和总结。内容 APO的心肌保护的信号转导机制与缺血后处理有很多相似之处,可能是通过刺激心肌产生触发物,活化相关信号通路,激活效应因子,发挥后处理效应。目前研究已证实APO心肌保护作用与激活再灌注损伤补救激酶（reperfusion injury salvage kinase,RISK）,抑制再灌注心肌细胞凋亡及线粒体等有关。趋向 APO心肌保护作用机制错综复杂,弄清这些复杂的信号转导机制对于揭示APO效应的原理,促进临床推广具有重要的指导意义。     

缺血后处理的关键——延迟再灌注初短暂酸性环境

缺血后处理(ischemic postconditioning,IP0)是近年来提出的一种减轻缺血,再灌(reperfusion injung,I/R)损伤的新方法,即在全面再灌注前进行反复、短暂的再灌注/停灌注.近来认为IPO的关键是通过造成I/R初期的一种短暂的延迟性酸性环境,从而保护缺血心肌免受再灌注损伤.     

心肌保护新策略——缺血后处理

缺血后处理（ischernjc postconditioning）是近年来提出的一种新的心肌保护方法，即再灌注后对缺血心肌反复进行再缺血处理，以减轻缺血再灌注损伤。其机制可能与抑制氧自由基堆积、中性粒细胞黏附、心肌细胞凋亡和细胞内钙超载有关。由于缺血后处理可在不可预见的心肌缺血后进行，且操作方便，因此在临床上可能具有较大的应用价值。     

远隔后处理心肌保护的基础研究和临床应用转化

背景 在远离靶器官的组织(如肢体)实施后处理产生保护性信号(即远隔后处理)是提供内源性组织保护的一种措施.目的 综述远隔后处理的心肌保护效应、作用机制和临床应用转化现状.内容 在包括鼠、兔和猪在内的多个种属动物实验研究中,远隔后处理能够明显减轻心肌缺血/再灌注(ischemia/reperfusion,I/R)损伤、组织坏死和细胞凋亡.与远隔预处理一样,远隔后处理需要通过体液或神经信号转导通路传递或交流保护性因子或信号.靶器官保护机制的触发子包括G蛋白耦联受体配体、缺血代谢物和小分子热敏物质.有关远隔后处理改善临床结果或生物标记的临床研究结果令人鼓舞.趋向 与经典缺血预处理和后处理不同,有关远隔后处理心肌保护作用生理或分子机制的研究目前仍显不足.如果进一步的临床研究证实远隔后处理可改善患者的转归,其实践价值将是巨大的.     

PI3K/Akt和JAK/STAT信号转导通路在α7nAChR激动剂后处理减轻大鼠心肌缺血再灌注损伤中的作用

目的 探讨PI3K/Akt和JAK/STAT信号转导通路在α7亚基烟碱型乙酰胆碱受体(α7nAChR)激动剂后处理减轻大鼠心肌缺血再灌注损伤中的作用.方法 雄性SD大鼠60只,体重290～ 320 g,采用随机数字表法,将其随机分为4组(n=15):缺血再灌注组(I/R组)、缺血预处理组(IPC组)、缺血后处理组(IPOC组)和α7nAChR激动剂后处理组(PNU组).4组采用结扎左冠状动脉前降支30 min时进行再灌注的方法制备心肌缺血再灌注损伤模型.IPC组进行缺血预处理,缺血5min再灌注5min,共3个循环,IPOC组再灌注前进行缺血后处理,再灌注10 s缺血10s,共3个循环.PNU组再灌注前即刻腹腔注射特异性α7nAChR激动剂PNU282987 2.4 mg/kg.再灌注60 min时取5只大鼠,取心肌组织,测定Akt mRNA、STAT3 mRNA、磷酸化Akt(p-Akt)和磷酸化STAT3( p-STAT3)的表达水平.再灌注180 min时取10只大鼠,取心肌组织,测定心肌梗死面积.结果 与I/R组比较,IPC组心肌组织STAT3 mRNA和p-Akt表达上调,IPOC组心肌组织p-Akt和p-STAT3表达上调,PNU组上述指标差异无统计学意义(P＞0.05),IPC组、IPOC组和PNU组心肌梗死面积缩小(P＜0.05).结论 α7nAChR激动剂后处理减轻大鼠心肌缺血再灌注损伤的机制与PI3K/Akt和JAK/STAT两条信号转导通路无关.     

缺血后处理对肝脏缺血再灌注中肝窦内皮细胞损伤的保护作用

目的探讨缺血后处理对肝脏缺血再灌注中肝窦内皮细胞损伤的保护作用.方法建立大鼠局部肝脏缺血再灌注模型,将24只健康雄性Wistar大鼠随机分为假手术、缺血再灌注、缺血后处理3组,以缺血再灌前、反复多次的短暂预再灌、停灌作后处理,观察各组血浆肝酶及透明质酸(HA)水平变化和肝组织中丙二醛(MDA)、超氧化物歧化酶(SOD)、内皮素-1(ET-1)含量,并行肝组织病理形态学检查.结果与缺血再灌注组相比,缺血后处理组肝酶的漏出、血浆HA水平及肝组织中MDA、ET-1的含量明显降低(P＜0.01),而SOD活性则显著升高(P＜0.01),肝组织病理学损伤亦明显减轻.结论缺血后处理可通过抑制再灌注后氧自由基的过量生成而保护肝窦内皮细胞,减轻肝脏缺血再灌注损伤.     

吸入性麻醉药异氟醚对大鼠脑缺血/再灌注损伤的保护作用

目的 研究异氟醚预处理对大鼠脑缺血/再灌注损伤的可能保护机制.方法 采用四动脉结扎法建立大鼠脑缺血模型.分别在缺血前随机分为假手术组、直接脑缺血/再灌注组、吸入2 h 1.5 MAC异氟醚脑缺血/再灌注组和吸入纯氧2h脑缺血/再灌注对照组,全脑缺血15 min后再分别复灌3 d和5 d.复灌3 d的大鼠断头取海马进行JNK3的免疫印迹和免疫沉淀;复灌5 d的大鼠用焦油紫染色法检测海马CA1区的细胞.结果 复灌3 d后,缺血前吸入1.5 MAC异氟醚组的大鼠组其JNl.的活性明显低于直接缺血对照组和吸入纯氧对照组(P<0.05);复灌5 d后,缺血前吸入1.5 MAC异氟醚可有效降低大鼠海马CA1区锥体细胞的死亡(P<0.05).结论 1.5 MAc异氟醚对大鼠脑缺血/再灌注损伤有确切的保护作用;JNK信号通路可能介导了异氟醚对缺血性脑损伤的保护作用.     

单纯缺血预处理对兔未成熟心脏不足以提供保护作用

目的探讨单纯缺血预处理(IPC)对兔未成熟心脏缺血再灌注损伤的影响.方法利用Langendorff模型灌注幼兔(14-21d)离体心脏,5min缺血、10min再灌的IPC处理后,观察其在生理体温(39℃)下接受30min缺血、40min复灌的血液动力学、冠脉流出液心肌酶及心肌能量的变化.结果复灌后IPC组与对照组在心率(HR)、冠脉流出量(CF)、左室发展压(LVDP)、左室最大上升和下降速率(±dp/dt)恢复率及室性心律失常发生率无明显差别,肌酸磷酸激酶同工酶(CK-MB)漏出量有增多趋势.而IPC组在全心停灌后心脏缺血跳动时间明显延长(P＜0.01),再灌注末心肌ATP含量显著减少(P＜0.001).结论单纯缺血预处理不能保护未成熟心脏免受心肌缺血再灌注损伤,反而可导致心肌细胞的损伤;其原因可能与全心缺血后,心脏不能很快停跳而导致能量消耗过多有关.     

七氟烷后处理的心肌保护作用及其机制

背景 大量实验证据表明缺血后处理和药物后处理对心肌再灌注损伤具有确切的保护作用.七氟烷是一种新型的、理想的吸入性麻醉药,被广泛应用于全身麻醉.实验证明七氟烷后处理可以保护心肌对抗缺血/再灌注损伤(ischemia/reperfusion injury,I/RI).目的 通过对近年研究进展的总结对七氟烷后处理的心肌保护作用及机制予以阐述.内容七氟烷后处理可以减少再灌注心肌的梗死面积、线粒体损害和再灌注室性心律失常的发生,改善心脏的血流动力学.七氟烷后处理心肌保护作用复杂且涉及多个方面,如阻断线粒体通透性转运孔(mitochondrial permeability transition pore,mPTP)、激活线粒体ATP敏感性K+通道(mitochondrial KATP-channel,mKATP),激活细胞外信号调节激酶1/2(extracellular signal-regulated kinase 1/2,ERK1/2)以及磷酯酰肌醇-3激酶-丝氨酸/苏氨酸激酶(phosphatidylin ositol-3-kinase-serine/threonine,PI3K-Akt)信号通道等. 趋势 未来的研究除进一步探究七氟烷后处理的心肌保护机制,同时应加强七氟烷后处理的临床应用,为实际工作提供可靠依据.     

麻醉药物后处理心肌的胞内信号转导研究进展

背景 麻醉药物后处理是最近提出的一种心肌保护的新策略,具有很好的临床应用前景.目的 麻醉药物后处理对心肌再灌注损伤的保护是多因素参与的复杂过程,对麻醉药物后处理中心肌胞内信号转导的作用机制及研究进展作一综述.内容 麻醉药物后处理除了通过减少活性氧类物质的产生、抑制线粒体内钙超载、减轻内皮功能失调等被动作用外,还可主动激...     

Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta

BACKGROUND: Postischemic administration of volatile anesthetics activates reperfusion injury salvage kinases and decreases myocardial damage. However, the mechanisms underlying anesthetic postconditioning are unclear. METHODS: Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. Anesthetic postconditioning was induced by 15 min of 2.1 vol% isoflurane (1.5 minimum alveolar concentration) administered at the onset of reperfusion. In some experiments, atractyloside (10 microm), a mitochondrial permeability transition pore (mPTP) opener, and LY294002 (15 microm), a phosphatidylinositol 3-kinase inhibitor, were coadministered with isoflurane. Western blot analysis was used to determine phosphorylation of protein kinase B/Akt and its downstream target glycogen synthase kinase 3beta after 15 min of reperfusion. Myocardial tissue content of nicotinamide adenine dinucleotide served as a marker for mPTP opening. Accumulation of MitoTracker Red 580 (Molecular Probes, Invitrogen, Basel, Switzerland) was used to visualize mitochondrial function. RESULTS: Anesthetic postconditioning significantly improved functional recovery and decreased infarct size (36 +/- 1% in unprotected hearts vs. 3 +/- 2% in anesthetic postconditioning; P < 0.05). Isoflurane-mediated protection was abolished by atractyloside and LY294002. LY294002 inhibited isoflurane-induced phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3beta and opened mPTP as determined by nicotinamide adenine dinucleotide measurements. Atractyloside, a direct opener of the mPTP, did not inhibit phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3beta by isoflurane but reversed isoflurane-mediated cytoprotection. Microscopy showed accumulation of the mitochondrial tracker in isoflurane-protected functional mitochondria but no staining in mitochondria of unprotected hearts. CONCLUSIONS: Anesthetic postconditioning by isoflurane effectively protects against reperfusion damage by preventing opening of the mPTP through inhibition of glycogen synthase kinase 3beta.     

缺血后处理对大鼠移植肝缺血再灌注损伤的保护作用

目的探讨在体条件下缺血后处理对大鼠移植肝缺血再灌注损伤的保护作用及其可能机制。方法采用SD大鼠原位肝移植模型,供肝冷保存时间100min,无肝期控制于18min以内,60只雄性健康SD大鼠随机分为3组,对照组12只,缺血再灌注损伤组和后处理组各24只。对照组开腹后仅游离肝周韧带;缺血再灌注损伤组受体大鼠供肝切除前仅以肝素化生理盐水经门静脉灌注;后处理组供肝植入后完全再灌注前,给予多次短暂复灌复停作为缺血后处理。缺血再灌注损伤组、后处理组受体一半（6只）于再灌注后2h留取血液及肝组织,另一半（6只）于再灌注后6h留取肝组织。对照组于关腹后相应时间留取血液及肝组织。各组分别检测肝功能,采用酶联免疫吸附法测定血清肿瘤坏死因子Or．和中性粒细胞弹性蛋白酶。根据酶促反应原理,利用分光光度仪测定肝脏谷胱甘肽过氧化物酶、丙二醛、髓过氧化物酶、超氧化物歧化酶。肝组织HE染色后光镜下观察组织学变化。结果缺血再灌注损伤组和后处理组血清肝功能指标、炎性细胞因子水平及肝组织过氧化物含量均高于对照组（P〈0．05）,而后处理组较缺血再灌注损伤组则明显低（P〈0．05）;缺血再灌注损伤组和后处理组肝组织抗氧化酶活力显著低于对照组（P〈0．05）,而后处理组较缺血再灌注损伤组则明显高（P〈0．05）。结论缺血后处理对大鼠移植肝的缺血再灌注损伤有明显的保护作用。提高组织的抗氧化能力和降低炎性细胞因子水平可能是缺血后处理保护作用的机制之一。     

Isoflurane Postconditioning Prevents Opening of the Mitochondrial Permeability Transition Pore through Inhibition of Glycogen Synthase Kinase 3β

Background: Postischemic administration of volatile anesthetics activates reperfusion injury salvage kinases and decreases myocardial damage. However, the mechanisms underlying anesthetic postconditioning are unclear.

Methods: Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. Anesthetic postconditioning was induced by 15 min of 2.1 vol% isoflurane (1.5 minimum alveolar concentration) administered at the onset of reperfusion. In some experiments, atractyloside (10 [mu]m), a mitochondrial permeability transition pore (mPTP) opener, and LY294002 (15 [mu]m), a phosphatidylinositol 3-kinase inhibitor, were coadministered with isoflurane. Western blot analysis was used to determine phosphorylation of protein kinase B/Akt and its downstream target glycogen synthase kinase 3[beta] after 15 min of reperfusion. Myocardial tissue content of nicotinamide adenine dinucleotide served as a marker for mPTP opening. Accumulation of MitoTracker Red 580 (Molecular Probes, Invitrogen, Basel, Switzerland) was used to visualize mitochondrial function.

Results: Anesthetic postconditioning significantly improved functional recovery and decreased infarct size (36 +/- 1% in unprotected hearts vs. 3 +/- 2% in anesthetic postconditioning; P < 0.05). Isoflurane-mediated protection was abolished by atractyloside and LY294002. LY294002 inhibited isoflurane-induced phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3[beta] and opened mPTP as determined by nicotinamide adenine dinucleotide measurements. Atractyloside, a direct opener of the mPTP, did not inhibit phosphorylation of protein kinase B/Akt and glycogen synthase kinase 3[beta] by isoflurane but reversed isoflurane-mediated cytoprotection. Microscopy showed accumulation of the mitochondrial tracker in isoflurane-protected functional mitochondria but no staining in mitochondria of unprotected hearts.     

Postconditioning, a series of brief interruptions of early reperfusion, prevents neurologic injury after spinal cord ischemia

OBJECTIVE: We sought to test whether postconditioning, a series of brief mechanical interruptions of reperfusion applied during the onset of reperfusion, can prevent neurologic injury of the spinal cord after transient ischemia. SUMMARY BACKGROUND DATA: Ischemia-reperfusion injury of the spinal cord is the principal mechanism leading to the paraplegia after surgery for descending and thoracoabdominal aortic aneurysms. Postconditioning has recently been demonstrated to confer cardioprotection by attenuating reperfusion injury. METHODS: Spinal cord ischemia was induced in rabbits by infrarenal aorta occlusion for 25 minutes. Control animals underwent no additional intervention. Two groups of animals underwent postconditioning consisting of 4 or 6 cycles of 1-minute occlusion/1-minute reperfusion, respectively, which were applied 1 minute after the start of reperfusion. In 2 additional groups, 6 cycles of postconditioning started 5 or 10 minutes after the onset of reperfusion, respectively. Hind-limb motor function was assessed during a 10-day recovery period using the modified Tarlov criteria. Histologic examination of the spinal cord was performed, and the number of intact motor neurons was counted. RESULTS: Compared with controls, 4 cycles of postconditioning significantly increased the Tarlov score and the number of intact motor neurons. Six cycles of postconditioning did not further improve the neuroprotection. Postconditioning starting 5 minutes after reperfusion still resulted in powerful neuroprotection, but the neuroprotection disappeared completely when postconditioning was delayed for 10 minutes. CONCLUSIONS: Postconditioning prevents neurologic injury of the spinal cord after ischemia, and the first few minutes of reperfusion are crucial to neuroprotection by postconditioning.     

缺血后处理和预处理对大鼠骨骼肌缺血-再灌注损伤的作用

目的 探讨缺血后处理( IPost)和缺血预处理(IPC)对大鼠骨骼肌缺血再灌注(IR)损伤的影响.方法 将40只大鼠随机分成缺血再灌注组(A组)、缺血后处理组(B组)、缺血预处理组(C组)、缺血预处理加缺血后处理组(D组)以及对照组(E组),采用切断患肢全部皮肤、肌肉和神经,保留患肢股动、静脉的动物模型,通过夹闭和开放股动、静脉造成骨骼肌缺血再灌注损伤,通过测定骨骼肌缺血4h、再灌注1h后血清丙二醛(MDA)和骨骼肌髓过氧化物酶(MPO),以及再灌注6h后骨骼肌的坏死程度来观察缺血后处理.缺血预处理及缺血预处理加缺血后处理对大鼠骨骼肌缺血再灌注损伤的影响.结果 B组、C组和D组再灌注1 h MDA和MPO水平以及再灌注6h骨骼肌坏死程度均低于A组(P＜ 0.05),但是高于E组(P＜0.05);B组和D组再灌注1 h MDA和MPO水平以及再灌注6h骨骼肌坏死程度基本相同(P＞0.05);B组和D组再灌注1 h MDA和MPO水平低于C组(P＜0.05),但再灌注6h骨骼肌坏死程度基本相同(P＞0.05).结论 应用缺血后处理和缺血预处理对大鼠骨骼肌缺血再灌注损伤有一定的保护效果,联合应用缺血后处理和缺血预处理,对骨骼肌缺血再灌注损伤的保护作用并没有明显增强.     

药物后处理对心肌缺血/再灌注损伤保护作用的研究与展望

背景随着心肌缺血/再灌注损伤（ischemia/reperfusion injury,I/RI）机制及心肌保护机制研究的深入,药物后处理作为一种更具有临床实用价值的心肌保护方法成为了研究热点。 目的阐述药物后处理用于心肌保护时,相关药物所模拟内源性保护机制的主要环节以及近年来药物后处理的研究概况和前瞻。 内容介绍药物后处理用于心肌保护时,主要途径、作用靶点以及相关药物。趋势药物后处理心肌保护机制的研究和深入将会发现更多的药物靶点,独特的操作便利性,必将更好的应用于临床服务于患者。