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 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.
Clozel
M
M
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Breu
V
V
Burri
K
K
Cassal
J M
JM
Fischli
W
W
Gray
G A
GA
Hirth
G
G
Löffler
B M
BM
Müller
M
M
Neidhart
W
W
D000284:Administration, Oral; D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D000096926:Benzenesulfonamides
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011743:Pyrimidines; D013449:Sulfonamides; C083751:Ro 46-2005; D000096926:Benzenesulfonamides