RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 314
OP 320
VO 291
IS 1
A1 Kang, Young Jin
A1 Lee, Young Soo
A1 Lee, Goun Woo
A1 Lee, Duck Hyung
A1 Ryu, Jae Chun
A1 Yun-Choi, Hye Sook
A1 Chang, Ki Churl
YR 1999
UL http://jpet.aspetjournals.org/content/291/1/314.abstract
AB 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)-γ. Higenamine concentration-dependently inhibited NO production and inducible NO synthase mRNA in RAW 264.7 cells, in which the IC50 was 53 μM. 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 μg/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 κB in RAW 264.7 cells due to LPS + IFN-γ by mobility shift assays. Taken together, these data strongly suggest that higenamine inhibits iNOS expression by inhibiting nuclear factor κB activation by LPS + IFN-γ, 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. The American Society for Pharmacology and Experimental Therapeutics