Exogenous and endogenous nitric oxide but not iNOS inhibition improves function and survival of ischemically injured livers.
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.
Rivera-Chavez
F A
FA
Department of Surgery, Michigan State University, East Lansing, USA.
Toledo-Pereyra
L H
LH
Dean
R E
RE
Crouch
L
L
Ward
P A
PA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D015996:Survival Rate
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D001120:Arginine; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008239:Lysine