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Letters to Nature
Nature 365, 759 - 761 (21 October 1993); doi:10.1038/365759a0

Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist

Martine Clozel, Volker Breu, Kaspar Burri, Jean-Marie Cassal, Walter Fischli, Gillian A. Gray, Georges Hirth, Bernd-Michael Löffier, Marcel Müller, Werner Neidhart & Henri Ramuz

Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4002 Basel, Switzerland

SINCE its discovery1, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors2. Plasma concentrations of endothelin-1 are low3 and its release by endothelial cells is polarized towards the basolateral side4,5, suggesting that it is a paracrine factor and not a hormone. Consequently, the effect of injected endothelin-1 may not reflect the effect of endogenous endothelin-1. In contrast, blockade of the action of endogenous endothelin-1 using receptor antagonists should be a valuable means of investigating its physiological and pathological effects. We report here evidence for the pathophysiological role of endothelin-1 as brought by the first synthetic orally active non-peptide antagonist of endothelin receptors, Ro 46-2005.

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