THE MODE OF ACTION OF ASPIRIN-LIKE DRUGS - EFFECT ON INDUCIBLE NITRIC-OXIDE SYNTHASE
THE MODE OF ACTION OF ASPIRIN-LIKE DRUGS - EFFECT ON INDUCIBLE NITRIC-OXIDE SYNTHASE
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DOI：
10.1073/pnas.92.17.7926
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发表时间：
1995-08-15
影响因子：
11.1
通讯作者：
ABRAMSON, SB
中科院分区：
文献类型：
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作者：
AMIN, AR;VYAS, P;ABRAMSON, SB
由诱导型一氧化氮合酶 (iNOS) 合成的一氧化氮被认为是风湿病和自身免疫性疾病中炎症的介质。我们报道，脂多糖刺激的小鼠巨噬细胞暴露于治疗浓度的阿司匹林（IC50 = 3 mM）和氢化可的松（IC50 = 5 μM）会抑制iNOS的表达和亚硝酸盐的产生。相反，水杨酸钠（1-3 mM）、吲哚美辛（5-20 μM）和对乙酰氨基酚（60-120 μM）在药理学浓度下对亚硝酸盐的产生没有显着影响。在超药理学浓度下，水杨酸钠 (IC50 = 20 mM) 显着抑制亚硝酸盐的产生。阿司匹林存在下 iNOS 表达的免疫印迹分析显示 iNOS 表达受到抑制（IC50 = 3 mM）。水杨酸钠不同程度地抑制 iNOS 表达 (0-35%)，而吲哚美辛则没有效果。此外，这些非甾体抗炎药在药理学浓度下对 iNOS mRNA 表达没有显着影响。阿司匹林的作用并非由于抑制环氧合酶 2，因为阿司匹林和吲哚美辛均抑制前列腺素 E(2) 合成 >75%。阿司匹林和 N-乙酰咪唑（一种有效的乙酰化剂）也直接干扰无细胞提取物中 iNOS 的催化活性，但水杨酸钠或吲哚美辛不受影响。这些研究表明，iNOS 表达和功能的抑制代表了阿司匹林的另一种作用机制（即使不是所有阿司匹林类药物）。这些影响在翻译/翻译后修饰水平上发挥作用，并直接影响 iNOS 的催化活性。
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 mu M) inhibited the expression of iNOS and production of nitrite. In contrast, sodium salicylate (1-3 mM), indomethacin (5-20 mu M), and acetaminophen (60-120 mu M) 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 antiinflammatory 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 E(2) 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.