Document Detail

Methylprednisolone inhibits low-flow hypoxia-induced mitochondrial dysfunction in isolated perfused rat liver.
MedLine Citation:
PMID:  12771620     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: To investigate the mechanism by which methylprednisolone protects the liver from hypoxia-induced injury. DESIGN: Prospective control study using the isolated rat liver. SETTING: Animal research facility. SUBJECTS: Male, fasted, pathogen-free Sprague-Dawley rats. INTERVENTIONS: Low-flow hypoxia was produced by reducing afferent perfusate pressure from 10 to 2.5 cm H(2)O; isolated livers were portally perfused for 2 hrs. MEASUREMENTS AND MAIN RESULTS: We measured mitochondrial membrane potential and hydrogen peroxide production by imaging rhodamine 123 and 2'-7'-dichlorofluorescein fluorescence, respectively. Leakage of mitochondrial enzymes was also monitored by assaying mitochondrial aspartate aminotransferase activity in the outflow perfusate, and the radical-scavenging effect of methylprednisolone was assessed by measuring luminol-dependent hydrogen peroxide chemiluminescence. Apoptosis in liver cells was determined by using terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling. Rhodamine 123 fluorescence was significantly diminished in the hypoxic liver, especially in the region of the terminal hepatic venules, which is indicative of membrane depolarization in the mitochondria in those areas. Hypoxia-induced mitochondrial dysfunction was indicated by leakage of aspartate aminotransferase into the outflow perfusate, and increased 2'-7'-dichlorofluorescein fluorescence indicated increased hydrogen peroxide levels, particularly in the midzone. Pretreatment with 30, 10, or 3 mg/kg of methylprednisolone inhibited the hypoxia-induced mitochondrial membrane depolarization and enzyme leakage, although hydrogen peroxide levels and apoptosis in sinusoidal endothelial cells were unaffected. CONCLUSIONS: Methylprednisolone does not protect the liver from hypoxia-induced injury by suppressing hydrogen peroxide production. Instead, the beneficial effect of methylprednisolone seems to be related to its ability to protect against mitochondrial membrane depolarization under hypoxic conditions.
Satoru Motoyama; Satoshi Saito; Yoshihiro Minamiya; Reijiro Saito; Masakatsu Nakamura; Manabu Okuyama; Hiroshi Imano; Jun-ichi Ogawa
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Critical care medicine     Volume:  31     ISSN:  0090-3493     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2003 May 
Date Detail:
Created Date:  2003-05-28     Completed Date:  2003-06-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1468-74     Citation Subset:  AIM; IM    
Second Department of Surgery, Akita University School of Medicine, Akita City, Japan.
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MeSH Terms
Anoxia / enzymology,  etiology,  prevention & control*
Anti-Inflammatory Agents / pharmacology,  therapeutic use*
Aspartate Aminotransferase, Mitochondrial / analysis
Chemiluminescent Measurements
Disease Models, Animal*
Drug Evaluation, Preclinical
Free Radical Scavengers / pharmacology,  therapeutic use
Hydrogen Peroxide / analysis
In Situ Nick-End Labeling
Liver / blood supply*
Membrane Potentials / drug effects
Methylprednisolone / pharmacology,  therapeutic use*
Mitochondria, Liver*
Mitochondrial Diseases / enzymology,  etiology,  prevention & control*
Prospective Studies
Rats, Sprague-Dawley
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Free Radical Scavengers; 7722-84-1/Hydrogen Peroxide; 83-43-2/Methylprednisolone; EC 2.6.1.-/Aspartate Aminotransferase, Mitochondrial

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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