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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Inhibition of Nitric Oxide Synthase Attenuates Peroxynitrite Generation, but Augments Neutrophil Accumulation in Hepatic Ischemia-Reperfusion in Rats

Peitan Liu, Kingsley Yin, Robert Nagele and Patrick Y-K Wong
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 1139-1146;
Peitan Liu
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Kingsley Yin
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Robert Nagele
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Patrick Y-K Wong
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Abstract

The role of nitric oxide (NO) and peroxynitrite in the process of neutrophil adhesion and infiltration was investigated in a model of hepatic ischemia-reperfusion. Male Fischer rats were subjected to 30 min of hepatic no-flow ischemia followed by 4 h of reperfusion (I/R). I/R induced liver injury as evidenced by a 13.7-fold increase in plasma alanine aminotransferase activity. Induction of liver injury was associated with an increase in neutrophil accumulation in ischemic lobes of livers [215 ± 27 polymorphonuclear neutrophil leukocytes/50 high-power field (HPF), P < .05 compared with sham control] and 8-fold augmentation of inducible NO synthase (NOS) activity. However, NO levels in the liver decreased; this decrease may be caused by peroxynitrite formation by the reaction of NO with superoxide. Sections of ischemic lobes of the liver tissue of I/R animals exhibited marked immunoreactivity with anti-nitrotyrosine antibody, which indicates the presence of nitrotyrosine. Administration of Nw-nitro-l-arginine methyl ester (10 mg/kg i.v. before reperfusion) attenuated total and inducible NOS activity in both ischemic and nonischemic lobes of liver, and reduced NO levels in plasma and liver. However, NOS inhibition aggravated liver injury as alanine aminotransferase increased by 61% compared with rats subjected to reperfusion injury. Neutrophil accumulation was enhanced in ischemic (436 ± 48/50 HPF, P < .05 compared with I/R animal) and nonischemic lobes of livers (34 ± 3.2/50 HPF, P < .05 compared with sham control). NOS inhibition also attenuated immunohistochemically detected nitrotyrosine formation, but increased superoxide production in the liver. The NO-dependent regulation of neutrophil accumulation in the liver may be linked closely to P-selectin and intracellular adhesion molecule-1 expression because inhibition of NOS resulted in significant increases in gene expression of these two adhesion molecules (determined by reverse transcription-polymerase chain reaction analysis). These results suggest that NO is important in attenuating neutrophil accumulation and liver damage in ischemia-reperfusion injury. Inhibition of NOS activity reduces peroxynitrite formation but aggravates liver injury and increases neutrophil accumulation, which suggests that the anti-inflammatory function of NO is more important than the cytotoxic potential of peroxynitrite in acute inflammation.

Footnotes

  • Send reprint requests to: Patrick Y-K Wong, Ph.D., Department of Cell Biology, UMDNJ-School of Osteopathic Medicine, 2 Medical Center Drive, Stratford, NJ 08084.

  • ↵1 This work was supported by grants DDK-41747, NIHLB-25316–14 to P Y-K W, AHA 95–6-28 to KY, and AHA NJ-97-GS-16 to PL.

  • Abbreviations:
    ALT
    alanine aminotransferase
    NO
    nitric oxide
    I/R
    ischemia-reperfusion
    NOS
    nitric oxide synthase
    l-NAME
    NW-nitro-l-arginine methyl ester
    HPF
    high-power field
    ICAM-1
    intracellular adhesion molecule-1
    EDTA
    ethylenediaminetetraacetic acid
    HEPES
    N-2-hydroxyethylpiperazine-N′-ethanesulfonic acid
    iNOS
    inducible NOS
    PBS
    phosphate-buffered saline
    PMN
    polymorphonuclear neutrophil leukocytes
    RT-PCR
    reverse transcription polymerase chain reaction
    GSH
    glutathione
    NOA
    Nitric Oxide Analyzer
    ROS
    reactive oxygen species
    MPO
    myeloperoxidase
    • Received July 31, 1997.
    • Accepted November 24, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Inhibition of Nitric Oxide Synthase Attenuates Peroxynitrite Generation, but Augments Neutrophil Accumulation in Hepatic Ischemia-Reperfusion in Rats

Peitan Liu, Kingsley Yin, Robert Nagele and Patrick Y-K Wong
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1139-1146;

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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Inhibition of Nitric Oxide Synthase Attenuates Peroxynitrite Generation, but Augments Neutrophil Accumulation in Hepatic Ischemia-Reperfusion in Rats

Peitan Liu, Kingsley Yin, Robert Nagele and Patrick Y-K Wong
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1139-1146;
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