Thaliporphine selectively inhibits expression of the inducible, but not the constitutive, nitric oxide synthase.
Formation of nitrites/nitrates caused by lipopolysaccharide (LPS) in J774.2 macrophages was inhibited by thaliporphine, an aporphine derivative isolated from the plant Neolitsea konishii K. This inhibition of nitrite synthesis in LPS-stimulated macrophages by thaliporphine was similar to that by cycloheximide, NG-methyl-L-arginine (MeArg) and dexamethasone. Thaliporphine, but not MeArg, inhibited expression of inducible NO synthase without directly affecting enzyme activity. However, thaliporphine did not inhibit nitrite production by NO synthase that had already been induced by prior exposure to LPS for which any possible further induction was inhibited by cycloheximide. In endothelial cells, nitrite formation induced by bradykinin (in the presence of 0.2 mM Ca2+) was inhibited by MeArg. However, incubation of endothelial cells with dexamethasone, cycloheximide and thaliporphine did not affect this Ca(2+)-dependent nitrite production. Thaliporphine (0.1-100 microM) dose-dependently inhibited nitrite accumulation in macrophages stimulated by interleukin-1 beta (IL-1 beta) whereas nitrite formation induced by tumour necrosis factor alpha was not inhibited. LPS-stimulated IL-1 beta synthesis in macrophages was significantly inhibited by thaliporphine, but thaliporphine had only minimal effect on LPS-stimulated IL-1 beta synthesis in endothelial cells. These results demonstrate that thaliporphine inhibits LPS induction of NO synthase expression, and that the mechanism of action of thaliporphine is via inhibition of LPS-stimulated IL-1 beta synthesis in macrophages. In anaesthetized rats subjected to LPS, pretreatment with thaliporphine partially restored the fall in mean arterial pressure and the vascular hyporeactivity to noradrenaline 3 h after LPS injection. In conclusion, thaliporphine selectively inhibited expression of inducible NO synthase, and may thus hold potential for the treatment of endotoxaemia.
Yu
S M
SM
Department of Pharmacology, Chang Gung Medical College, Kwei-San, Tao-Yuan, Taiwan.
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000209:etiology / Q000517:prevention & control; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D019001:Nitric Oxide Synthase; D009638:Norepinephrine / Q000494:pharmacology; D010936:Plant Extracts; D011651:Pulmonary Artery; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D001060:Aporphines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D002956:Citrulline; C080702:thaliporphine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D002118:Calcium; D009638:Norepinephrine