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

Nature. 1993 Oct 21;365(6448):759-61. doi: 10.1038/365759a0.


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.

MeSH terms

  • Administration, Oral
  • Animals
  • Endothelin Receptor Antagonists*
  • Endothelins / physiology*
  • Humans
  • In Vitro Techniques
  • Male
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Pyrimidines / blood
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Sulfonamides / blood
  • Sulfonamides / pharmacology*
  • Vasoconstriction / drug effects


  • Endothelin Receptor Antagonists
  • Endothelins
  • Pyrimidines
  • Sulfonamides
  • Ro 46-2005