Differential effects of nitric oxide synthase inhibitors on endotoxin-induced liver damage in rats.
OBJECTIVE
During endotoxemia, expression of inducible nitric oxide synthase (iNOS) and nitric oxide production in the liver is increased. NO has been suggested to have a hepatoprotective function. The aim of this study was to investigate the distribution of iNOS and the effect of different NO synthase inhibitors on liver damage and hemodynamics during endotoxemia.


METHODS
Rats were injected with lipopolysaccharide (LPS) and received the NOS-inhibitor S-methylisothiourea (SMT) or NG-nitro-L-arginine methyl ester (L-NAME). iNOS induction was assessed by Western blot, immunohistochemistry, and measurement of NO metabolites in plasma and bile. Liver damage was determined by aspartate aminotransferase and alanine aminotransferase and by histology. The effects of both inhibitors on systemic and portal pressure were measured in normal and LPS-treated rats.


RESULTS
LPS treatment strongly induced iNOS in inflammatory cells, macrophages, bile duct epithelium, and hepatocytes, especially at the canalicular membrane. LPS-induced liver damage strongly increased after L-NAME. SMT caused a similar reduction of NO production without enhancing liver damage. In LPS-treated rats, SMT increased the systemic and portal pressure significantly more than L-NAME.


CONCLUSIONS
During endotoxemia, administration of the NOS-inhibitor L-NAME aggravates liver damage. This liver damage does not seem to be caused by hemodynamic changes. In contrast, SMT caused significant hemodynamic changes but did not increase LPS-induced liver damage.
Vos
T A
TA
Groningen Institute for Drug Studies, The Netherlands. T.A.Vos@med.rug.nl
Gouw
A S
AS
Klok
P A
PA
Havinga
R
R
van Goor
H
H
Huitema
S
S
Roelofsen
H
H
Kuipers
F
F
Jansen
P L
PL
Moshage
H
H
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D001646:Bile / Q000378:metabolism; D001648:Bile Canaliculi / Q000473:pathology; D001652:Bile Ducts / Q000473:pathology; D019446:Endotoxemia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004848:Epithelium / Q000473:pathology; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects*; D007150:Immunohistochemistry; D007249:Inflammation; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar
D000906:Antibodies; D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D010446:Peptide Fragments; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; D019331:NG-Nitroarginine Methyl Ester