title: Cellular mechanism of endothelin-1 release by angiotensin and vasopressin.
abstract: Release of endothelin-1, a novel potent vasoconstrictor peptide originally isolated from endothelial cells, from cultured bovine endothelial cells has been shown to be stimulated by arginine vasopressin and angiotensin II. To elucidate the cellular mechanism by which endothelin-1 is released by these vasoconstrictors, we tested the effects of several compounds on the agonist-induced endothelin-1 release and studied the changes of cytosolic free Ca2+ concentrations and phosphoinositide breakdown by these agonists in cultured bovine endothelial cells. Protein kinase C inhibitors (H-7, staurosporine), an intracellular Ca2+ chelator, and an inhibitor of phospholipase C (neomycin), all abolished the agonist-induced endothelin-1 release, whereas the Ca2+ channel blocker nicardipine was ineffective. Although synthetic 1,2-diglyceride (diolein) dose dependently stimulated endothelin-1 release, downregulation of protein kinase C after pretreatment with phorbol ester resulted in decreased effects to increase endothelin-1 release by the agonists. Both arginine vasopressin and angiotensin II induced immediate and transient increases in intracellular Ca2+ levels of fura-2-loaded endothelial cells as well as formation of inositol trisphosphate; the agonist-induced intracellular Ca2+ increases were not affected either by nicardipine or by chelating extracellular Ca2+. The arginine vasopressin- and angiotensin II-induced intracellular Ca2+ increases, inositol trisphosphate formation, and endothelin-1 release were completely abolished by V1-receptor antagonist and saralasin, respectively. It is concluded that arginine vasopressin and angiotensin II stimulate the release of endothelin-1 by a common mechanism, involving receptor-mediated mobilization of intracellular Ca2+ and activation of protein kinase C in endothelial cells.
authors.affiliation: Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Emori
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
authors.forename: K
authors.initials: K
authors.lastname: Ohta
authors.forename: K
authors.initials: K
authors.lastname: Kanno
authors.forename: S
authors.initials: S
authors.lastname: Eguchi
authors.forename: T
authors.initials: T
authors.lastname: Imai
authors.forename: M
authors.initials: M
authors.lastname: Shichiri
authors.forename: F
authors.initials: F
authors.lastname: Marumo
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004075:Diglycerides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004533:Egtazic Acid / Q000494:pharmacology / Q000031:analogs & derivatives; D016232:Endothelins / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D009529:Nicardipine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D019311:Staurosporine
chemical_list: D000470:Alkaloids; D004075:Diglycerides; D016232:Endothelins; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; D001127:Arginine Vasopressin; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015544:Inositol 1,4,5-Trisphosphate; D009529:Nicardipine; D011493:Protein Kinase C; D019311:Staurosporine; D009355:Neomycin; D002118:Calcium; C013965:diolein