PMID- 21356218
OWN - NLM
STAT- MEDLINE
DCOM- 20110615
LR  - 20181201
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 88
IP  - 17-18
DP  - 2011 Apr 25
TI  - Cyclosporine A-induced acute hepatotoxicity in guinea pigs is associated with 
      endothelin-mediated decrease in local hepatic blood flow.
PG  - 753-60
LID - 10.1016/j.lfs.2011.02.015 [doi]
AB  - AIMS: 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. MAIN 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. KEY 
      FINDINGS: 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. SIGNIFICANCE: 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Erdem, S Remzi
AU  - Erdem SR
AD  - Baskent University, Faculty of Medicine, Department of Pharmacology, Baglica 
      Kampusu, Eskisehir Yolu 20 km, Ankara, Turkey. rerdem@baskent.edu.tr
FAU - Emre-Aydingoz, Selda
AU  - Emre-Aydingoz S
FAU - Atilla, Pergin
AU  - Atilla P
FAU - Cakar, A Nur
AU  - Cakar AN
FAU - Dalkara, Turgay
AU  - Dalkara T
FAU - Bolay, Hayrunnisa
AU  - Bolay H
FAU - Tuncer, Meral
AU  - Tuncer M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110226
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Endothelins)
RN  - 0 (Peptides, Cyclic)
RN  - 0 (Sulfonamides)
RN  - 6D4M1DAL6O (cremophor EL)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - PDC6A3C0OX (Glycerol)
RN  - Q326023R30 (Bosentan)
RN  - S2A8YZM151 (cyclo(Trp-Asp-Pro-Val-Leu))
SB  - IM
MH  - Animals
MH  - Bosentan
MH  - Cyclosporine/antagonists & inhibitors/pharmacology/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Endothelins/*physiology
MH  - Female
MH  - Glycerol/analogs & derivatives/pharmacology
MH  - Guinea Pigs
MH  - Liver/blood supply/*drug effects/enzymology/pathology
MH  - Liver Circulation/*drug effects/physiology
MH  - Male
MH  - Peptides, Cyclic/pharmacology
MH  - Sulfonamides/pharmacology
EDAT- 2011/03/02 06:00
MHDA- 2011/06/16 06:00
CRDT- 2011/03/02 06:00
PHST- 2010/10/12 00:00 [received]
PHST- 2011/01/13 00:00 [revised]
PHST- 2011/02/03 00:00 [accepted]
PHST- 2011/03/02 06:00 [entrez]
PHST- 2011/03/02 06:00 [pubmed]
PHST- 2011/06/16 06:00 [medline]
AID - S0024-3205(11)00090-7 [pii]
AID - 10.1016/j.lfs.2011.02.015 [doi]
PST - ppublish
SO  - Life Sci. 2011 Apr 25;88(17-18):753-60. doi: 10.1016/j.lfs.2011.02.015. Epub 2011 
      Feb 26.