In 1988 Yanagisawa described endothelins, a new class of vasoconstrictor agents produced by endothelial cells. Further biological effects of these peptides have subsequently been demonstrated, for example, induction of cell proliferation and fibrosis. Two types of endothelin receptors have been described: ETA are responsible for endothelininduced vasoconstriction whereas ETB induce endothelial cells to release nitric oxide (NO) and prostacyclin. Many antagonists of endothelin receptors have been synthesized and evaluated in animal models and in humans. Satisfactory results have been obtained in animal models of arterial hypertension, pulmonary hypertension, stroke and heart failure but clinical trials have failed to demonstrate that these drugs have a beneficial effect in the treatment of heart failure and a dose-dependent reversible hepatic toxicity has been observed. However, the efficacy of bosentan, a mixed antagonist of endothelin receptors, in the treatment of primary pulmonary hypertension has been demonstrated and the drug is now marketed worldwide for this condition. Further studies are ongoing to evaluate other clinical applications of these drugs. Recently it has been reported that atrasentan, a selective ETA antagonist, delayed the progression of hormone-refractory prostate cancer in humans. This review describes the results of the studies performed in animals and in humans and their potential future clinical applications.
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