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Endothelially Derived Nitric Oxide Affects the Severity of Early Acetaminophen‐induced Hepatic Injury in Mice
Author(s) -
Salhanick Steven D.,
Orlow Daniel,
Holt Doug E.,
Pavlides Stavros,
Reenstra Wende,
Buras Jon A.
Publication year - 2006
Publication title -
academic emergency medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.221
H-Index - 124
eISSN - 1553-2712
pISSN - 1069-6563
DOI - 10.1197/j.aem.2005.11.082
Subject(s) - enos , nitric oxide , nitric oxide synthase , nitrite , toxicity , medicine , endocrinology , acetaminophen , western blot , nitric oxide synthase type iii , liver injury , endothelial nos , pharmacology , chemistry , biochemistry , nitrate , organic chemistry , gene
Objectives:The precise mechanism of hepatocellular toxicity following acetaminophen (APAP) poisoning remains unclear. Nitric oxide is implicated in APAP toxicity as an inflammatory signaling molecule and as a precursor to the free radical peroxynitrate. The effects of inducible nitric oxide synthase (iNOS)‐derived NO in APAP toxicity are known; however, the role of endothelial nitric oxide synthase (eNOS)‐derived NO is unknown. The authors sought to evaluate the effect of eNOS‐derived NO during APAP toxicity.Methods:C57BL6/J mice deficient in eNOS (eNOS KO) or iNOS (iNOS KO) and wild‐type mice (WT) were treated with 300 mg/kg APAP. Alanine aminotransferase levels and plasma nitrate and nitrite levels were measured. Hypoxia inducible factor (HIF)‐1α and Glucose Transporter 1 (Glut‐1) levels were determined by Western blot.Results:Alanine aminotransferase levels were significantly elevated in all treated animals. Alanine aminotransferase levels were significantly lower in eNOS KO and iNOS KO than in treated WT animals. Plasma nitrate/nitrite levels were significantly higher in WT animals than in iNOS KO and eNOS KO animals. HIF‐1α expression was increased in WT mice and decreased in iNOS KO mice. Glut‐1 is a downstream, indirect marker of HIF function. Glut‐1 expression was increased in WT and eNOS KO mice.Conclusions:Deficiency of either iNOS or eNOS results in decreased NO production and is associated with reduced hepatocellular injury following APAP poisoning. HIF‐1α and Glut‐1 levels are increased following APAP poisoning, implying that HIF‐1α is functional during the pathogenic response to APAP poisoning.