Inhibition of activation of nuclear factor κB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root

作     者：Kang, YJ Lee, YS Lee, GW Lee, DH Ryu, JC Choi, HSY Chang, KC 

作者机构：Gyeongsang Natl Univ Dept Pharmacol Coll Med Chinju 660751 South Korea Gyeongsang Natl Univ Cardiovasc Res Inst Coll Med Chinju 660751 South Korea Sogang Univ Dept Chem Seoul 121742 South Korea Seoul Natl Univ Inst Nat Prod Res Seoul South Korea Inst Sci & Technol Seoul South Korea 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第291卷第1期

页      面：314-320页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

主　　题：乌头属/药理学 生物碱类/药理学 细胞 培养的 内毒素血症/药物疗法 内毒素类/药理学 杂交细胞 低血压/化学诱导 低血压/预防和控制 脂多糖类/药理学 NF-κB/拮抗剂和抑制剂 NF-κB/代谢 一氧化氮/代谢 一氧化氮合酶/拮抗剂和抑制剂 一氧化氮合酶/生物合成 一氧化氮合酶/遗传学 一氧化氮合酶Ⅱ型 植物根/化学 RNA 信使/代谢 大鼠 Sprague-Dawley 四氢异喹啉类 动物 人类 男(雄)性 小鼠 大鼠 

摘      要：Effects of higenamine on nitric oxide (NO) production and inducible NO synthase (iNOS) mRNA expression (RAW 264.7 cells), on vascular reactivity in vitro and in vivo (rats), and on survival rates (mice) and serum nitrite/nitrate levels (rats) were investigated by using last lipopolysaccharide (LPS) plus interferon (IFN)-gamma. Higenamine concentration-dependently inhibited NO production and inducible NO synthase mRNA in RAW 264.7 cells, in which the IC50 was 53 mu M. Higenamine (10 mg/kg i.p.) administered 90 min before LPS (5 mg/kg i.v.) prevented not only LPS-induced hypotension but also pressor response to norepinephrine (1 mg/kg) in rats. Incubation of thoracic aorta with LPS (300 ng/ml) for 8 h in vitro resulted in suppression of the vasoconstrictor effects to phenylephrine, which was prevented by coincubation with higenamine. The survival rate to endotoxin in mice was significantly (P.01) increased by the presence of higenamine in the LPS-treated group up to 48 h. Serum nitrite/nitrate levels were significantly (P .05) reduced by higenamine in LPS-treated rats. Finally, higenamine inhibited the activation of nuclear factor kappa B in RAW 264.7 cells due to LPS + IFN-gamma by mobility shift assays. Taken together, these data strongly suggest that higenamine inhibits iNOS expression by inhibiting nuclear factor kB activation by LPS + IFN-gamma, which may be beneficial in inflammatory diseases in which enhanced formation of NO is the main causative factor. Furthermore, due to positive inotropic action, higenamine may be more effective in a condition where myocardial contractility is likely to depress, such as in septic shock and/or endotoxin-induced inflammatory disorders.