title: Heparin suppresses cyclosporine-induced endothelin-1 synthesis in rat endothelial cells.
abstract: Cyclosporine stimulates vasoconstrictor endothelin-1 (ET-1) synthesis. This study examined the effect of heparin on cyclosporine-induced ET-1 synthesis in Wistar rat aortic endothelial cells in culture. Cyclosporine (0.01-5 mumol/L) stimulated ET-1 mRNA expression in a dose-dependent manner. A nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA) (10(-5) mol/L), did not affect cyclosporine-induced ET-1 mRNA expression. Heparin (1-20 U/ml) suppressed cyclosporine-induced ET-1 mRNA expression in a dose-dependent manner. The inhibitory effect of heparin was blunted in the presence of either L-NMMA (10(-5) mol/L) or calmodulin inhibitors such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (5 x 10(-5) mol/L) or calmidazolium (5 x 10(-5) mol/L) in the presence of the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (0.1 mmol/L). These results suggest that heparin suppresses cyclosporine-induced ET-1 mRNA expression via both NO- and calmodulin-dependent pathways.
authors.affiliation: First Department of Internal Medicine, Osaka City University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yokokawa
authors.forename: M
authors.initials: M
authors.lastname: Kohno
authors.forename: M
authors.initials: M
authors.lastname: Minami
authors.forename: K
authors.initials: K
authors.lastname: Yasunari
authors.forename: A K
authors.initials: AK
authors.lastname: Mandal
authors.forename: J
authors.initials: J
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D003864:Depression, Chemical; D019332:Endothelin-1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000925:Anticoagulants; D002147:Calmodulin; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016572:Cyclosporine; D006493:Heparin; D019001:Nitric Oxide Synthase