Endothelin and the Ischaemic Heart 1 Cardioprotective Effects of Et-1 Mediated by the Et a Receptor

2 Introduction It has been widely documented that plasma ET-1 and big ET-1 levels are increased in patients within a day of onset of acute myocardial infarction [1,2,3,4]. Similar changes in systemic plasma ET-1 are seen in animal models of myocardial ischaemia [5,6]. The source of the released ET-1 appears to be the area subjected to ischaemic damage, since in a study in anaesthetised pigs both short and long periods of left anterior descending (LAD) coronary artery occlusion were found to enhance overflow of ET-1 from the area of myocardium subjected to the ischaemia/reperfusion insult [7]. The myocardial tissue level of ET-1 has been found to be increased by 3 to 7 fold in the ischaemic area compared to the non-ischaemic myocardium, suggesting an increased biosynthesis of ET-1 during ischaemia/reperfusion [5,7]. Indeed, the demonstration of increased ET-1 mRNA levels in cardiomyocytes subjected to ischaemia [8], supports this notion that that the raised circulating levels of endothelin are not simply due to release of stored peptide. The observation that ischaemia and reperfusion increases 125 I-labelled ET-1 binding sites in rat cardiac membranes [9] further supports the view that the endothelin system is up-regulated during these events, although the observation that there is no difference in ET-1 mRNA levels between animals subjected to ischaemia only and hearts subjected to ischaemia followed by reperfusion, implies that it is ischaemia that stimulates enhanced ET-1 production. Taken together, these observations have led to the concept that endothelin may play an important role in determining the outcome of myocardial ischaemia/reperfusion. Based on our knowledge that ET-1 is a potent vasoconstrictor peptide, early hypotheses focused on the role of ET-1 as a detrimental factor in the 3 ischaemic/reperfused heart. However, over the last decade or so, as our understanding of the cellular effects of endothelin has extended beyond that of vasoconstriction, evidence is emerging that endothelin may play a very complex role in the setting of the ischaemic heart, with the potential to both contribute to cellular injury and cellular repair. The aim of this review therefore is to provide an overview of the effects of endothelin on the cardiomyocyte, in the setting of myocardial ischaemia, and within this to consider not only its actions mediated through vasoconstriction, but also through its effects on ion channels, cellular integrity and inflammatory cells. Contribution of endothelin to ischaemia/reperfusion-induced myocardial injury. The possibility that the coronary vasoconstrictor effects of endothelin …