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. 2000 Apr;83(4):381–387. doi: 10.1136/heart.83.4.381

Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality?

D Yellon 1, G Baxter 1
PMCID: PMC1729364  PMID: 10722532

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Modification of several molecular targets presents new therapeutic possibilities for limitation or delay of myocyte death during ischaemia and/or reperfusion. The figure summarises three promising approaches to infarct limitation during ischaemia and/or reperfusion. Top Intracellular accumulation of protons during ischaemia leads to the activation of the sarcolemmal sodium-hydrogen exchanger (NHE). Consequent intracellular sodium overload causes the activation of the sarcolemmal sodium-calcium exchanger (NCE) and predisposes to intracellular calcium overload. Inhibitors of NHE attenuate this mechanism of injury and can limit infarct size in experimental models. Bottom Preconditioning is an endogenous adaptive response in myocytes. Mediators released in ischaemic tissue include adenosine, noradrenaline, bradykinin, and opioid peptides. These mediators act via seven transmembrane G-protein coupled receptors on myocytes, (adenosine A1 and A3 receptors, δ-opioid receptors, and bradykinin B2 receptors) and initiate a complex kinase signalling cascade, which opens the KATP channel in the mitochondrial inner membrane (mt-KATP). These channels are the likely end effector of preconditioning. Opening of the channel enhances myocyte viability during ischaemia through a mechanism that is likely to involve preservation of mitochondrial integrity and ATP generating capacity. There are several possibilities for exploitation of pharmacological preconditioning ("preconditioning mimetics"). Adenosine A1 and A3 receptor agonists and δ-opioid receptor agonists activate the preconditioning signal cascade and limit infarct size in experimental models. Potentiation of endogenously generated bradykinin during ischaemia is possible with angiotensin converting enzyme (ACE) inhibitors and neutral endopeptidase (NEP) inhibitors. These agents prevent the breakdown of bradykinin and augment its protective effects on myocytes. Centre The predominant pathological feature of infarction is myocyte death by necrosis. However, apoptosis is now recognised as an additional mechanism of cell death which may be activated, particularly during reperfusion. Regulation of apoptotic pathways is extremely complex and incompletely understood, but inhibition of apoptosis may be a therapeutic route to salvage myocytes during ischaemia and/or reperfusion. Caspase inhibitors and counter regulatory growth factors limit infarct size when administered during the early reperfusion period.    

Selected References

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