title: Cyclosporine A-induced acute hepatotoxicity in guinea pigs is associated with endothelin-mediated decrease in local hepatic blood flow.
abstract: OBJECTIVE
  To bring further insight into the mechanism of cyclosporine A (CsA)-induced hepatotoxicity, the acute effect of CsA on local hepatic blood flow (LHBF) and its association with systemic hemodynamics, histopathological and biochemical indicators of liver toxicity were studied in guinea pigs in vivo. The association of endothelin (ET) and/or Cremophor-EL (C-EL, vehicle in parenteral CsA preparation) with CsA effects was also investigated.
  
  
  METHODS
  Animals were assigned into five groups; control, CsA, C-EL, Bosentan (non-selective ET receptor antagonist)+CsA, and BQ-123 (ET(A) receptor antagonist)+CsA. CsA was infused intravenously (i.v.) at 20 and 10mg/kg doses by 15 min interval. Antagonists were administered 15 min before CsA infusion. LHBF and mean arterial blood pressure (MAP) changes were simultaneously recorded. Blood and liver samples were collected for biochemical and histopathological examinations.
  
  
  RESULTS
  CsA, but not C-EL, decreased LHBF by 53.3% at the end of 30 min. Although being non-significant, CsA slightly increased MAP suggesting that, CsA-induced acute decrease in LHBF was likely independent of MAP changes. Bosentan (5mg/kg, i.v.) and BQ-123 (1mg/kg, i.v.) pre-treatments prevented the CsA-induced decrease in LHBF suggesting that CsA decreases LHBF through an ET-related mechanism. Additionally, CsA, but not its vehicle C-EL, caused marked acute pathological changes in the liver morphology.
  
  
  CONCLUSIONS
  CsA-induced findings of acute hepatotoxicity were prevented by bosentan and BQ-123 pre-treatments. Thus, CsA seems to exert acute hepatotoxic effect through ET-related mechanisms.
authors.affiliation: Başkent University, Faculty of Medicine, Department of Pharmacology, Baglica Kampusu, Eskisehir Yolu 20 km, Ankara, Turkey. rerdem@baskent.edu.tr
authors.forename: S Remzi
authors.initials: SR
authors.lastname: Erdem
authors.forename: Selda
authors.initials: S
authors.lastname: Emre-Aydıngöz
authors.forename: Pergin
authors.initials: P
authors.lastname: Atilla
authors.forename: A Nur
authors.initials: AN
authors.lastname: Cakar
authors.forename: Turgay
authors.initials: T
authors.lastname: Dalkara
authors.forename: Hayrunnisa
authors.initials: H
authors.lastname: Bolay
authors.forename: Meral
authors.initials: M
authors.lastname: Tuncer
mesh_terms: D000818:Animals; D000077300:Bosentan; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000502:physiology*; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016232:Endothelins; D010456:Peptides, Cyclic; D013449:Sulfonamides; C000515:cremophor EL; D016572:Cyclosporine; D005990:Glycerol; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)