Abstract

Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide derived from vascular endothelial cells. ET-1 can also be produced by other cell types such as smooth muscle cells and cardiomyocytes. Plasma levels of ET-1 are elevated during several different cardiovascular disorders like atherosclerosis, myocardial infarction and congestive heart failure. During and following myocardial ischaemia and reperfusion, the myocardial production and release of ET-1 is stimulated and the coronary constrictor response to ET-1 is enhanced. These findings all favour a pathophysiological role for ET-1 in the development of ischaemia/reperfusion injury. Accordingly, by using different pharmacological tools (monoclonal antibody, ET converting enzyme inhibitor or ET receptor antagonists) that block the biological actions of ET-1, myocardial ischaemia/reperfusion injury has been demonstrated to be reduced in experimental animal models, in terms of both reduction in final infarct size and improved recovery of myocardial performance and coronary flow. However, some studies have shown no cardioprotective effects of ET receptor antagonists. Possible explanations for these apparently conflicting results are differences in animal species used, route and timing of drug administration, experimental protocol and chemical nature of the antagonists. The potential mechanisms underlying the cardioprotective effects of ET antagonists are discussed and include prevention of no-reflow, inhibition of ET-induced neutrophil activation, abolishment of direct pro-ischaemic actions of ET on myocytes, and interruption of interference of ET with the renin-angiotensin system.

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