Hepatocellular damage in porcine endotoxemia: beneficial effects of selective versus non-selective nitric oxide synthase inhibition?
While nitric oxide (NO) is implicated as an important mediator of hypotension in sepsis and endotoxemia, its role as a mediator of tissue injury in shock is controversial. During porcine endotoxemia (lipopolysaccharide (LPS) 1.7 microg kg(-1) x h(-1) i.v. for 6 h), we compared circulatory and morphological changes in the liver induced by two different NO synthase inhibitors (N(G)-nitro-L-arginine methyl ester, L-NAME, 25 mg x kg(-1) i.v. and aminoethyl-isothiourea, AE-ITU, 10 mg x kg(-1) i.v.), both given after 3 h. LPS induced time-dependent tissue reactions with edema, sinusoidal dilation, packing of red cells and leukocyte infiltration, progressing to endothelial cell and hepatocyte damage, formation of thrombi, and at 6 h widespread necrosis. These changes were similar in all pigs receiving LPS, regardless of treatment with NOS inhibitors. LPS caused significant increases in aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alpha glutathione S-transferase (alpha-GST), L-NAME caused further increases in AST, ALP and alpha-GST, while AE-ITU prevented the late increase in ALP and alpha-GST observed in the other LPS groups. LPS reduced liver blood flow by approximately 40%. L-NAME further reduced flow by approximately 50%, while AE-ITU restored liver blood flow to baseline values.


CONCLUSIONS
L-NAME in endotoxemia had detrimental effects on liver circulation, while AE-ITU improved liver blood flow and attenuated the late increase in liver enzymes. Liver morphology was unaffected within the 3-h observation time after NOS inhibition.
Saetre
T
T
Institute for Surgical Research, Rikshospitalet, The National Hospital, Oslo, Norway. torunn.satre@ioks.uio.no
Hovig
T
T
Røger
M
M
Gundersen
Y
Y
Aasen
A O
AO
D000818:Animals; D019446:Endotoxemia / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000098:blood supply / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D008111:Liver Function Tests; D008297:Male; D008854:Microscopy, Electron; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D013552:Swine
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester