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

Abstract

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 IC(50) was 53 microM. 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 microgram/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 kappaB 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 kappaB 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.

• Authors: Y J Kang, Y S Lee, G W Lee, D H Lee, J C Ryu, H S Yun-Choi, K C Chang
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 291 Issue 1 Pg. 314-20 (Oct 1999) ISSN: 0022-3565 [Print] United States
• PMID: 10490919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Endotoxins
• Lipopolysaccharides
• NF-kappa B
• RNA, Messenger
• Tetrahydroisoquinolines
• Nitric Oxide
• Interferon-gamma
• NOS2 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Nos2 protein, rat
• higenamine

Topics

• Aconitum (pharmacology)
• Alkaloids (pharmacology)
• Animals
• Cells, Cultured
• Endotoxemia (drug therapy)
• Endotoxins (pharmacology)
• Humans
• Hybrid Cells
• Hypotension (chemically induced, prevention & control)
• Interferon-gamma (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• NF-kappa B (antagonists & inhibitors, metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors, biosynthesis, genetics)
• Nitric Oxide Synthase Type II
• Plant Roots (chemistry)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Tetrahydroisoquinolines