Endothelin: From molecule to man

Endothelin-1 is an endothelium-derived vasoconstrictor and co-mitogenic agent which acts as a local paracrine and autocrine mediator; and is the most potent and sustained vasoconstrictor and presser substance yet identified. On the basis of studies in healthy man, endothelin-1 is now known to play an important physiological role in maintaining peripheral vascular tone and blood pressure. Endothelin-1 also has actions which might influence the function of the heart, kidney and nervous system. However, their physiological importance remains to be determined. Abnormalities of the endothelin system are now recognised to occur in a range of diseases associated with vasoconstriction, vasospasm and vascular hypertrophy and it appears that endothelin-1 may be causal, or at least contributory, in some of these pathophysiological processes. The use of endothelin receptor antagonists in experimental models of cardiovascular disease and in human clinical pharmacology studies has indicated a number of conditions - including hypertension, heart failure, acute renal failure, subarachnoid haemorrhage, and pulmonary hypertension - in which further clinical studies would be worthwhile. A number of peptide and orally-active non-peptide endothelin receptor antagonists are now under clinical investigation and further studies are now required in specific diseases to determine whether selective ET(A) or combined ET(A/B) receptor antagonists would be more effective. The discovery of endothelin-1, and the design of endothelin antagonists, has been among the most promising developments in cardiovascular medicine since the launch of ACE inhibitors 15 years ago. Major clinical trials are now needed to confirm the predicted benefits for endothelin antagonists in patients with cardiovascular disease.