Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

Abstract

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

• Authors: Wen-Hong Kan, Jun-Te Hsu, Martin G Schwacha, Mashkoor A Choudhry, Raghavan Raju, Kirby I Bland, Irshad H Chaudry
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 105 Issue 4 Pg. 1076-82 (Oct 2008) ISSN: 8750-7587 [Print] United States
• PMID: 18635878 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amidines
• Benzylamines
• Chemokines
• Cytokines
• Enzyme Inhibitors
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Isoenzymes
• N-(3-(aminomethyl)benzyl)acetamidine
• Nitrates
• Nitrites
• Intercellular Adhesion Molecule-1
• 3-nitrotyrosine
• Tyrosine
• Peroxidase
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, rat
• Nos3 protein, rat
• Glutathione Transferase
• glutathione S-transferase alpha
• NG-Nitroarginine Methyl Ester

Topics

• Amidines (pharmacology)
• Animals
• Benzylamines (pharmacology)
• Blood Pressure (drug effects)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Fluid Therapy (adverse effects)
• Glutathione Transferase (blood)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Intercellular Adhesion Molecule-1 (metabolism)
• Isoenzymes (blood)
• Liver (drug effects, enzymology)
• Liver Diseases (enzymology, etiology, physiopathology, prevention & control)
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitrates (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type III
• Nitrites (metabolism)
• Peroxidase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Resuscitation (adverse effects)
• Shock, Hemorrhagic (enzymology, physiopathology, therapy)
• Tyrosine (analogs & derivatives, metabolism)
• Wounds and Injuries (enzymology, physiopathology, therapy)