Gastroenterology

Gastroenterology

Volume 109, Issue 3, September 1995, Pages 899-907
Gastroenterology

Nitric oxide production in experimental alcoholic liver disease in the rat: Role in protection from injury

https://doi.org/10.1016/0016-5085(95)90400-XGet rights and content

Abstract

Background & Aims: Regulation of blood flow and oxygen supply are important pathogenetic factors in alcoholic liver disease. Because nitric oxide may have an important role, its effects on alcoholic liver injury were investigated. Methods: Rats were fed ethanol intragastrically with either saturated fat or corn oil. Spontaneous production of NO by liver nonparenchymal cells was compared in the two dietary groups. Two additional groups of rats fed corn oil and ethanol were treated with either an NO inhibitor (l-NAME) or supplemented with l-arginine. Liver pathology and plasma NO production were evaluated. Results: In the corn oil and ethanol group, a progressive decrease in liver nonparenchymal cell NO production and increased plasma NO levels were associated with liver injury. Reduced nicotinamide adenine dinucleotide phosphate diaphorase staining showed increased centrilobular staining of hepatocytes in the corn oil and ethanol group and l-NAME-treated group. Moreover, l-NAME increased the severity, whereas l-arginine supplementation completely prevented liver injury. In the saturated fat and ethanol group, in which there was no liver injury, the levels of NO2 in nonparenchymal supernatant were 5–10-fold higher than in the corn oil and ethanol group. Conclusions: Decreased NO production by nonparenchymal cells may contribute to liver injury in ethanol-fed rats, and the compensatory increase in hepatocyte NO production may contribute to centrilobular liver injury.

References (62)

  • TT Ma et al.

    Endotoxin stimulated nitric oxide production increases liver injury and reduces rat liver chemiluminescence during reperfusion

    Gastroenterology

    (1995)
  • CJ Lowenstein et al.

    Nitric oxide: a novel biological messenger

    Cell

    (1992)
  • J Kanner et al.

    Nitric oxide as an antioxidant

    Arch Biochem Biophys

    (1991)
  • JS Stamler

    Redox signaling-nitrosylation and related target interactions of nitric oxide

    Cell

    (1994)
  • J Bernstein et al.

    Metabolic alterations produced in the liver by chronic ethanol administration: changes related to energy parameters of the cell

    Biochem J

    (1973)
  • L Videla et al.

    Metabolic alterations produced in the liver by chronic ethanol administration: increased oxidative capacity

    Biochem J

    (1973)
  • T Yuki et al.

    The swift increase in alcohol metabolism: time course for increase in hepatic oxygen uptake and the involvement of glycolysis

    Biochem J

    (1980)
  • H Tsukamoto et al.

    Incomplete compensation of enhanced hepatic oxygen consumption in rats with alcoholic centrilobular necrosis

    Hepatology

    (1989)
  • JE Bredfelt et al.

    Compensatory mechanisms in response to an elevated hepatic oxygen consumption in chronically ethanol-fed rats

    Am J Physiol

    (1985)
  • A Mendneloff

    Effects of intravenous infusions of ethanol upon estimated hepatic blood flow in man

    J Clin Invest

    (1954)
  • JS Stamler et al.

    Biochemistry of nitric oxide and its redox-activated forms

    Science

    (1992)
  • JB Hibbs et al.

    Macrophage cytotoxicity: role for l-arginine deaminase activity and amino nitrogen oxidation to nitrite

    Science

    (1987)
  • RMJ Palmer et al.

    Vascular endothelial cells synthesize nitric oxide from l-arginine

    Nature

    (1988)
  • T Gaillard et al.

    Regulation of nitric oxide production by stimulated rat Kupffer cells

    Pathobiology

    (1991)
  • AA Nanji et al.

    Beef fat prevents alcoholic liver disease in the rat

    Alcohol Clin Exp Res

    (1989)
  • H Tsukamoto et al.

    Insights into the pathogenesis of alcoholic liver necrosis and fibrosis: status report

    Hepatology

    (1989)
  • SW French et al.

    Ethanol-induced hepatic fibrosis in the rat

    Alcohol Clin Exp Res

    (1986)
  • AA Nanji et al.

    Protective effects of a novel quinone derivative, (2E)-3-[5-(2,3 dimethoxy-6-methyl-1,4 benzoquinoyl)]-2-nonyl-2-propenoic acid on experimental alcoholic liver injury

    J Pharmacol Exp Ther

    (1993)
  • SW French et al.

    Pathology of alcoholic liver disease

    Semin Liver Dis

    (1993)
  • L Kobzik et al.

    Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization

    Am J Respir Cell Mol Biol

    (1993)
  • A Leeflang-de-Pijper et al.

    Pitfalls in histochemical localization studies of NADPH generating enzymes or enzyme systems in rat small intestine

    Histochemistry

    (1972)
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    Supported in part by Nitromed. Dr. Stamler is a Pew Scholar in the Biomedical Sciences and the recipient of a Clinical Investigator Award from the National Institues of Health (HL 02582).

    The authors thank Dr. Peter Thomas, Robert Miller-Cassman, Vincent Bird, Vincenzo Barletta, and Marianne Slaney for assistance.

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