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

Since its discovery, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. Plasma concentrations of endothelin-1 are low and its release by endothelial cells is polarized tow...

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Bibliographic Details
Published in:Nature (London) 1993-10, Vol.365 (6448), p.759-761
Main Authors: Clozel, Martine, Breu, Volker, Burri, Kaspar, Cassal, Jean-Marie, Fischli, Walter, Gray, Gillian A, Hirth, Georges, Löffier, Bernd-Michael, Müller, Marcel, Neidhart, Werner, Ramuz, Henri
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biochemistry
Biological and medical sciences
Cardiovascular system
Endothelin Receptor Antagonists
Endothelins - physiology
Genetics
Humans
In Vitro Techniques
Male
Medical sciences
Molecular Structure
Muscle Contraction - drug effects
Pharmacology. Drug treatments
Proteins
Pyrimidines - blood
Pyrimidines - pharmacology
Rats
Rats, Wistar
Sulfonamides - blood
Sulfonamides - pharmacology
Vasoconstriction - drug effects
Vasodilator agents. Cerebral vasodilators
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Summary:Since its discovery, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. Plasma concentrations of endothelin-1 are low and its release by endothelial cells is polarized towards the basolateral side, 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 nonpeptide antagonist of endothelin receptors, Ro 46-2005.
ISSN:0028-0836
1476-4687
DOI:10.1038/365759a0