ENDOTHELIN IN MYOCARDIAL-ISCHEMIA AND REPERFUSION

Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide der ived from vascular endothelial cells. ET-1 can also be produced by oth er cell types such as smooth muscle cells and cardiomyocytes. Plasma l evels of ET-1 are elevated during several different cardiovascular dis orders like atherosclerosis, myocardial infarction and congestive hear t failure. During and following myocardial ischaemia and reperfusion, the myocardial production and release of ET-1 is stimulated and the co rollary constrictor response to ET-1 is enhanced. These findings all f avour a pathophysiological role for ET-1 in the development of ischaem ia/reperfusion injury. Accordingly, by using different pharmacological tools (monoclonal antibody, ET converting enzyme inhibitor or ET rece ptor antagonists) that block the biological actions of ET-1, myocardia l ischaemia/reperfusion injury has been demonstrated to be reduced in experimental animal models, in terms of both reduction in final infarc t size and improved recovery of myocardial performance and coronary fl ow. However, some studies have shown no cardioprotective effects of ET receptor antagonists. Possible explanations for these apparently conf licting results are differences in animal species used, route and timi ng of drug administration, experimental protocol and chemical nature o f the antagonists. The potential mechanisms underlying the cardioprote ctive effects of ET antagonists an discussed and include prevention of no-reflow, inhibition of ET-induced neutrophil activation, abolishmen t of direct pro-ischaemic actions of ET on myocytes, and interruption of interference of ET with the renin-angiotensin system.