title: Conversion of big-endothelin-1 elicits an endothelin ETA receptor-mediated response in endothelial cells.
abstract: Functional conversion of big-endothelin-1 to endothelin-1 and characterization of endothelin receptor subtype were investigated in cultured rat aortic endothelial cells. Exogenous endothelin-1 and big-endothelin-1 both increased arachidonic acid release and inositol phosphate production dose dependently. Endothelin-1 was more potent than big-endothelin-1 as indicated by EC50 values: 0.5 +/- 0.1 nM and 10.0 +/- 2.0 nM for endothelin-1-induced arachidonic acid release and inositol phosphate formation, respectively, versus 1.0 +/- 0.4 nM and 35.0 +/- 6.0 nM for big-endothelin-1-induced responses. Big-endothelin-1, but not endothelin-1 actions were inhibited by phosphoramidon. Comparative studies of endothelin receptor agonists and antagonists showed that endothelin-3 but not sarafotoxin S6c stimulated arachidonic acid release and inositol phosphate formation. The responses to big-endothelin-1 and endothelin-1 were specifically inhibited by the selective endothelin ETA receptor antagonist, [cyclo-D-Trp-D-Asp-Pro-D-Val-Leu] (BQ-123) but not by the selective endothelin ETB receptor antagonist [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma- methyl-Leu-D-Trp-(COMe)-D-NLeu-ONa] (BQ-788). [125I]Endothelin-1 binding was inhibited by endothelin-1, endothelin-3 and BQ-123 but not by BQ-788. These results indicate that the pharmacological responses to big-endothelin-1 in aortic endothelial cells are due to the extracellular phosphoramidon-sensitive conversion to endothelin-1. Endothelin effects are mediated through endothelin ETA receptors in these cells.
authors.affiliation: INSERM U460, Faculté de Médecine Xavier Bichat, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: N'Diaye
authors.forename: M E
authors.initials: ME
authors.lastname: Pueyo
authors.forename: T
authors.initials: T
authors.lastname: Battle
authors.forename: C
authors.initials: C
authors.lastname: Ossart
authors.forename: D
authors.initials: D
authors.lastname: Guédin
authors.forename: J B
authors.initials: JB
authors.lastname: Michel
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006020:Glycopeptides / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D011498:Protein Precursors / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D007295:Inositol Phosphates; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D016718:Arachidonic Acid; C008890:phosphoramidon