Ischaemic preconditioning: from molecular characterisation to clinical application--part I.
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.
Riksen
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NP
Departments of Pharmacology-Toxicology and General Internal Medicine, University Medical Centre St Radboud, Nijmegen, the Netherlands. N.Riksen@aig.umcn.nl
Smits
P
P
Rongen
G A
GA
D000241:Adenosine / Q000502:physiology; D001920:Bradykinin / Q000502:physiology; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000517:prevention & control; D009638:Norepinephrine / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013997:Time Factors
D015221:Potassium Channels; D017382:Reactive Oxygen Species; D000241:Adenosine; D001920:Bradykinin; D009638:Norepinephrine