THE CLINICAL POTENTIAL OF ENDOTHELIN RECEPTOR ANTAGONISTS IN CARDIOVASCULAR MEDICINE

The endothelin family of peptides are extremely potent endogenous vaso constrictor and presser agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET(A) and ET(B). Both receptor subtypes are found on smooth m uscle cells and mediate the vasoconstrictor and presser actions of end othelin. The ET(B) receptor is also found on vascular endothelial cell s and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endo thelins have been the subject of intense research on their physiologic al function and potential pathophysiological role in cardiovascular di sease. There is now good evidence that endothelin regulates vascular t one and blood pressure, and studies to support the development of endo thelin receptor antagonists in conditions associated with chronic vaso constriction, such as hypertension and heart failure, as well as in va sospastic disorders, such as subarachnoid haemorrhage and Raynaud's di sease. There are now a number of selective ET(A) and combined ET(A/B) receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic v alue. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel th erapeutic approach to a fundamental and newly discovered endogenous va soconstrictor mechanism. The results of the current clinical trials ar e awaited with considerable interest.