The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase.

DOI Web Site 被引用文献11件
  • A R Amin
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
  • P Vyas
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
  • M Attur
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
  • J Leszczynska-Piziak
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
  • I R Patel
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
  • G Weissmann
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.
  • S B Abramson
    Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003, USA.

書誌事項

公開日
1995-08-15
DOI
  • 10.1073/pnas.92.17.7926
公開者
Proceedings of the National Academy of Sciences

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説明

<jats:p>Nitric oxide synthesized by inducible nitric oxide synthase (iNOS) has been implicated as a mediator of inflammation in rheumatic and autoimmune diseases. We report that exposure of lipopolysaccharide-stimulated murine macrophages to therapeutic concentrations of aspirin (IC50 = 3 mM) and hydrocortisone (IC50 = 5 microM) inhibited the expression of iNOS and production of nitrite. In contrast, sodium salicylate (1-3 mM), indomethacin (5-20 microM), and acetaminophen (60-120 microM) had no significant effect on the production of nitrite at pharmacological concentrations. At suprapharmacological concentrations, sodium salicylate (IC50 = 20 mM) significantly inhibited nitrite production. Immunoblot analysis of iNOS expression in the presence of aspirin showed inhibition of iNOS expression (IC50 = 3 mM). Sodium salicylate variably inhibited iNOS expression (0-35%), whereas indomethacin had no effect. Furthermore, there was no significant effect of these nonsteroidal anti-inflammatory drugs on iNOS mRNA expression at pharmacological concentrations. The effect of aspirin was not due to inhibition of cyclooxygenase 2 because both aspirin and indomethacin inhibited prostaglandin E2 synthesis by > 75%. Aspirin and N-acetylimidazole (an effective acetylating agent), but not sodium salicylate or indomethacin, also directly interfered with the catalytic activity of iNOS in cell-free extracts. These studies indicate that the inhibition of iNOS expression and function represents another mechanism of action for aspirin, if not for all aspirin-like drugs. The effects are exerted at the level of translational/posttranslational modification and directly on the catalytic activity of iNOS.</jats:p>

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