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Research ArticleTOXICOLOGY

Oxidant Stress in Rat Liver after Lipopolysaccharide Administration: Effect of Inducible Nitric-Oxide Synthase Inhibition

Chaojie Zhang, Lisa M. Walker, Jack A. Hinson and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 968-972;
Chaojie Zhang
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Lisa M. Walker
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Jack A. Hinson
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Philip R. Mayeux
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Abstract

The role of inducible nitric-oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced hepatic oxidant stress was evaluated using the iNOS inhibitor l-iminoethyl-lysine (l-NIL). Male rats were divided into three groups. One group received LPS (Salmonella minnesota) 2 mg/kg i.v. A second group received LPS plus l-NIL (3 mg/kg i.p.) at the time of LPS administration followed by a second dose 3 h later. A third group received saline i.v. At 6 h, blood and liver tissue were collected. Serum nitrate/nitrite (metabolic products of nitric oxide) levels were increased from 5.4 ± 1.5 nmol/ml in the saline group to 360 ± 48 nmol/ml in the LPS group (n = 5). Values for the LPS + l-NIL group were significantly reduced to 35 ± 7 nmol/ml. Tissue malondialdehyde levels were increased from 0.20 ± 0.02 nmol/mg (n = 4) in the saline group to 0.41 ± 0.03 nmol/mg (n = 4) in the LPS group.l-NIL significantly reduced the values in the LPS group to 0.29 ± 0.02 nmol/mg (n = 4). 4-Hydroxynonenal-protein adducts levels were increased 3.6-fold by LPS treatment as compared with saline. l-NIL significantly reversed the levels to 1.6-fold (n = 4). Intracellular GSH levels were decreased from 8.49 ± 0.64 nmol/mg (n = 4) in the saline group to 5.63 ± 0.51 nmol/mg in the LPS group (n = 7).l-NIL significantly increased the levels in the LPS group to 7.04 ± 0.46 nmol/mg (n = 7). These data indicate that LPS-induced nitric oxide generation can result in oxidant stress in the liver, and that inhibitors of iNOS may offer some protection in LPS-induced hepatic toxicity.

Footnotes

  • Send reprint requests to: Philip R. Mayeux, Ph.D., Dept. of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 611, Little Rock, AR 72205. E-mail:mayeuxphilipr{at}exchange.uams.edu

  • ↵1 This work was supported by National Institutes of Health Grants DK44716 to P.R.M. and GM58884 to J.A.H.

  • Abbreviations:
    LPS
    lipopolysaccharide
    NO
    nitric oxide
    iNOS
    inducible NO synthase
    ONOO−
    peroxynitrite
    l-NIL
    l-iminoethyl-lysine
    TBARS
    thiobarbituric acid-reactive substances
    PAGE
    polyacrylamide gel electrophoresis
    ALT
    alanine aminotransferase
    • Received December 7, 1999.
    • Accepted February 17, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleTOXICOLOGY

Oxidant Stress in Rat Liver after Lipopolysaccharide Administration: Effect of Inducible Nitric-Oxide Synthase Inhibition

Chaojie Zhang, Lisa M. Walker, Jack A. Hinson and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 968-972;

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Research ArticleTOXICOLOGY

Oxidant Stress in Rat Liver after Lipopolysaccharide Administration: Effect of Inducible Nitric-Oxide Synthase Inhibition

Chaojie Zhang, Lisa M. Walker, Jack A. Hinson and Philip R. Mayeux
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 968-972;
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