Riksen N P, Smits P, Rongen G A
Departments of Pharmacology-Toxicology and General Internal Medicine, University Medical Centre St Radboud, Nijmegen, the Netherlands.
Neth J Med. 2004 Nov;62(10):353-63.
Ischaemic preconditioning is defined as an increased tolerance to ischaemia and reperfusion induced by a previous sublethal period of ischaemia. Since this is the most powerful mechanism for limiting infarct size, other than timely reperfusion, an overwhelming number of studies have addressed the way in which this form of protection occurs. During the short preconditioning period of ischaemia, several trigger substances are released (adenosine, bradykinin, norepinephrine, opioids). By activation of membrane-bound receptors, these substances activate a complex intracellular signalling cascade, which converges on mitochondrial end-effectors, including the ATP-sensitive potassium channel and the mitochondrial permeability transition pore. Activation of this pathway protects cardiomyocytes against both necrosis and apoptosis during a subsequent more prolonged ischaemic episode. The protection afforded by preconditioning lasts only two to three hours, but reappears 24 hours after the preconditioning stimulus. This 'delayed preconditioning' requires synthesis of new proteins, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and heat shock proteins. Additionally, preconditioning is not confined to one organ, but can also limit infarct size in remote, non-preconditioned organs ('remote preconditioning'). Knowledge of these mechanisms mediating ischaemic preconditioning is essential to understand which drugs are able to mimic preconditioning or interfere with pre-conditioning in patients at risk for myocardial ischaemia. This review aims to summarise current knowledge regarding the different forms and mechanisms of ischaemic preconditioning.
缺血预处理的定义是，先前短暂的亚致死性缺血所诱导的对缺血和再灌注耐受性增强。由于这是除及时再灌注外限制梗死面积的最有效机制，因此大量研究探讨了这种保护形式的发生方式。在短暂的缺血预处理期间，会释放几种触发物质（腺苷、缓激肽、去甲肾上腺素、阿片类物质）。通过激活膜结合受体，这些物质激活复杂的细胞内信号级联反应，该反应汇聚于线粒体终效应器，包括ATP敏感性钾通道和线粒体通透性转换孔。激活该途径可保护心肌细胞在随后更长时间的缺血发作期间免受坏死和凋亡。预处理所提供的保护仅持续两到三个小时，但在预处理刺激后24小时会再次出现。这种“延迟预处理”需要合成新的蛋白质，包括诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）和热休克蛋白。此外，预处理并不局限于一个器官，还可限制远处未预处理器官的梗死面积（“远程预处理”）。了解这些介导缺血预处理的机制对于理解哪些药物能够模拟预处理或干扰心肌缺血风险患者的预处理至关重要。本综述旨在总结关于缺血预处理的不同形式和机制的当前知识。
