Sarcolemmal permeability changes during ischaemia and reperfusion: release of survival factors.

Enzyme release by ischaemic myocardium has been used as a hallmark of the infarction process for several decades: in the clinical setting, deterioration of cell membrane integrity, as evidenced by the release of macromolecules such as creatine kinase and lactate dehydrogenase, has been used as quantitative indication of myocardial infarction. Leakage of membrane-impermeable molecules due to sarcolemmal rupture is considered to be the most prominent feature of irreversible injury, and the main mechanisms proposed to underlie this phenomenon are energy deficiency and calcium overload. However, changes in sarcolemmal permeabililty have been demonstrated to occur after exposure of the heart to relatively short periods of ischaemia. Using NMR spectroscopy, Askenasy et al. showed that sarcolemmal integrity deteriorated as a function of the duration of ischaemia and that even after as short a period as 10 min ischaemia cellular membrane permeability to osmolytes increased, although myocytes remained impermeable to polar and large molecules. Interestingly, before the onset of irreversible injury, enzyme release by the ischaemic perfused heart can be manipulated by the substrate present: for example, glucose reduces fatty acid-induced enzyme release, possibly via provision of glycolytic ATP. With the discovery of the phenomenon of ischaemic pre-conditioning, attention was again drawn to the potential of the myocardium to release a variety of substances (autocoids) after exposure to very short periods of ischaemia and reperfusion (e.g. 5 min), which may have either beneficial or detrimental effects on the heart. However, the causal stimulus for and the exact mechanism whereby the cardiomyocyte changes its sarcolemmal permeability properties during very short periods of ischaemia have not been resolved yet. It is now well-established that the release of molecules such as adenosine, bradykinin, opioids, and catecholamines during the short episodes of ischaemia/reperfusion of a pre-conditioning protocol elicits, via their respective G-protein-coupled receptors and subsequent intracellular signalling processes, an adaptive response leading to resistance to a subsequent period of sustained ischaemia. In this regard, the significant involvement of adenosine, a breakdown product of ATP, in the response of the heart to ischaemia/reperfusion has been demonstrated in both preand post-conditioning. The copious amounts of catecholamines, particularly norepinephrine, which are released during reperfusion of the ischaemic myocardium have dual effects: both a1-adrenergic 8 and b-adrenergic receptor stimulation may act as triggers during an ischaemic preconditioning protocol, while excessive accumulation during long periods of ischaemia aggravate the progression of cell injury and development of arrhythmias. Other substances of interest released by the ischaemic myocardium are the natriuretic peptides, atrial natriuretic peptide (ANP), and brain natriuretic peptide, e.g. an almost 3-fold increase in ANP release was reported after 5 min of ischaemia of the rat heart. The reduction in infarct size by these peptides was attributed to, amongst others, an increase in cyclic guanosine monophosphate levels and opening of the KATP channels. In contrast to the above beneficial effects exerted by some substances released by the ischaemic myocardium, it is well-established that myocardial ischaemia also triggers the release of harmful substances such as the cytokines, tumour necrosis factor-a, interleukin-1b (IL-1b), and IL-6 and the platelet activating factor which depress myocardial contractility (for a review, see Stangl et al.). However, in general, this seems to be a slower process, occurring during reperfusion after relatively longer periods of ischaemia. In this edition of Cardiovascular Research, the release of a novel survival factor from an embryonic rat heart-derived cell line H9c2 during simulated ischaemia/reperfusion is described. Interestingly, it appears that this substance is released by a mechanism other than via a damaged membrane, since the rate of cell death among cells exposed to ischaemia/reperfusion in this study was almost equal to that of control cells. These cells were exposed to simulated The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.