Effects of aspirin on nitric oxide formation and de novo protein synthesis by RINm5F cells and rat islets.
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 beta cells (RINm5F) and rat islets in a concentration-dependent manner with an IC50 value of approximately 3 mM. Therapeutic concentrations of aspirin (1-5 mM) that block NO production affected neither nuclear factor-kappaB 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.
Kwon
G
G
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Hill
J R
JR
Corbett
J A
JA
McDaniel
M L
ML
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity; D001241:Aspirin / Q000494:pharmacology* / Q000633:toxicity; D002461:Cell Line, Transformed / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007340:Insulinoma / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D007700:Kinetics; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001241:Aspirin