Cloricromene inhibits the induction of nitric oxide synthase.
The effect of cloricromene, a coumarin derivative, was investigated on the lipopolysaccharide-stimulated nitric oxide (NO) synthase induction in intact aortas from endotoxin shocked rats and in the murine macrophage cell line J774. Rings of thoracic aortas from lipopolysaccharide (4 mg/kg, i.v.)-shocked rats, contracted with phenylephrine, showed a progressive decrease in tone, that was of a greater magnitude than that of aortas from naive rats. Moreover, a decreased response to the constrictor effect of phenylephrine was observed in aortas from shocked rats. In vivo treatment with cloricromene (2 mg/kg, i.v.) 30 min before lipopolysaccharide administration partially prevented the loss in tone of aortic rings and improved their reactivity to phenylephrine. Murine J774 macrophages activated with lipopolysaccharide (100 ng/ml) produced significant amounts of nitrites (NO2-; 28.2 +/- 3.5 nmol/10(6) cells per 24 h). Cloricromene (2, 20 or 200 microM) added to the cells concomitantly with lipopolysaccharide inhibited NO2- production in a concentration-dependent manner. Maximum inhibition (84.0 +/- 8.0%) was observed when cloricromene (200 microM) was added to the cells 6 h before lipopolysaccharide, whereas it was ineffective when given 6 h after endotoxin. These results demonstrate that cloricromene inhibits the expression but not the activity of the inducible NO synthase.
Zingarelli
B
B
Department of Experimental Farmacology, University of Naples, Federico II, Italy.
Carnuccio
R
R
Di Rosa
M
M
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002460:Cell Line; D002866:Chromonar / Q000031:analogs & derivatives* / Q000494:pharmacology; D003864:Depression, Chemical; D004731:Endotoxins / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000201:enzymology
D004731:Endotoxins; D010656:Phenylephrine; D009569:Nitric Oxide; C025945:cloricromen; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D002866:Chromonar