Exogenous and endogenous nitric oxide but not iNOS inhibition improves function and survival of ischemically injured livers

J Invest Surg. Sep-Oct 2001;14(5):267-73. doi: 10.1080/089419301753170048.

Abstract

The role of nitric oxide (NO) in liver ischemia/reperfusion (I/R) injury remains controversial and few works have shed more information regarding the effect of exogenous (EX) and/or endogenous NO (EN) under conditions of I/R of the liver. We investigated the role of exogenous and endogenous NO and inducible nitric oxide synthase (iNOS) inhibition in liver function, neutrophil infiltration, and animal survival after liver I/R. Sprague-Dawley rats were subjected to total hepatic ischemia for 90 min using an extracorporeal porto-systemic shunt. The animals were divided into five groups, including the sham porto-systemic shunt with no ischemia, the control ischemic group, the L-arginine-treated group, the sodium nitroprusside (SNP or NaNP)-treated group, and the L-N6-(1-iminoethyl) lysine hydrochloride (L-NIL) (selective iNOS inhibitor)-treated group. The animal survival was followed for 7 days. Liver injury tests, tissue myeloperoxidase (MPO), and histology were analyzed at 6 h postreperfusion. L-Arginine- and sodium nitroprusside-treated groups demonstrated significant improvement in 7 days survival in comparison to the control (20%) (p < .05). The best overall survival was obtained with SNP (70%), followed by survival in the L-arginine treated group (60%). The iNOS inhibitor group (40%) did not show any statistical significance when compared to the control group (p > .05). Liver injury tests and histology scores in the SNP- and L-arginine-treated groups showed significant improvement when compared to the control group (p < .01 and p < .05, respectively). The iNOS group demonstrated only a slight improvement in these parameters. The liver MPO (as a measurement of neutrophil migration into the liver parenchyma) was significantly decreased only in the SNP and L-arginine groups (p < .05) but not in the iNOS group (p > .5). We conclude that NO exogenous donors and substrates for the endogenous pathway are beneficial for the liver after severe I/R and could be important therapeutic targets to prevent damage following this phenomenon.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Arginine / pharmacology
  • Aspartate Aminotransferases / blood
  • Enzyme Inhibitors / pharmacology
  • L-Lactate Dehydrogenase / blood
  • Liver / enzymology*
  • Lysine / analogs & derivatives*
  • Lysine / pharmacology
  • Male
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Nitroprusside / pharmacology
  • Peroxidase / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / mortality
  • Survival Rate

Substances

  • Enzyme Inhibitors
  • N(6)-(1-iminoethyl)lysine
  • Nitric Oxide Donors
  • Nitroprusside
  • Nitric Oxide
  • Arginine
  • L-Lactate Dehydrogenase
  • Peroxidase
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Lysine