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Department of Pathology, Washington University School of
Medicine, St. Louis, Missouri 63110
Aspirin and aspirin-like drugs are the most commonly indicated agents
for the treatment of inflammation. Mechanisms of action for these
drugs, however, are not clearly understood. In this study, we examined
the effects of aspirin on production of nitric oxide (NO), a
proinflammatory mediator, and show that aspirin inhibits NO production
by transformed pancreatic 
cells (RINm5F) and rat islets in a
concentration-dependent manner with an IC50 value of ~3
mM. Therapeutic concentrations of aspirin (1-5
mM) that block NO production affected neither nuclear
factor-
B activation nor inducible NO synthase (iNOS) mRNA
transcription but potently inhibited iNOS protein expression by both
RINm5F cells and rat islets. The effects of aspirin on islet function
were examined by measuring glucose-stimulated insulin secretion in the
presence of various concentrations of aspirin. Aspirin (1-5
mM) did not affect insulin secretion at basal or
glucose-stimulated conditions, whereas higher concentrations of aspirin
(10-20 mM) significantly increased basal insulin
secretion. Aspirin at high concentrations of 10 and 20 mM
inhibited de novo protein synthesis as demonstrated by
inhibition of [35S]methionine incorporation into total
islet protein and by inhibition of rabbit reticulocyte expression by
Brome mosaic virus mRNA, suggesting that inhibition of iNOS expression
at these high concentrations of aspirin may be due to the impairment of
the translational machinery. These findings indicate that inhibition of
iNOS expression and NO production may explain, in part, the beneficial
effects of aspirin as an anti-inflammatory agent at therapeutic
concentrations, whereas inhibition of de novo protein
synthesis may possibly explain clinical and side effects of aspirin in
the inflamed tissues and organs such as stomach and kidney that may
accumulate high concentrations of aspirin.
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