Effect of a nitric oxide releasing derivative of paracetamol in a rat model of endotoxaemia.
OBJECTIVE
Nitroparacetamol is a nitric oxide-releasing paracetamol with novel anti-inflammatory properties compared to the parent compound. This study has investigated the anti-inflammatory activity of nitroparacetamol in a model of endotoxaemia in rats to probe the mechanisms underlying this effect.


METHODS
Nitroparacetamol (92 mg kg(-1)), paracetamol (50 mg kg(-1)) or vehicle were administered to male, Wistar rats 15 min prior to or 3 h after lipopolysaccharide (0.5 mg kg(-1), serotype 0127:B8). Mean arterial pressure and heart rate were measured for 5 h and plasma and organs were then obtained to determine organ dysfunction, inducible nitric oxide synthase and cyclooxygenase-2 expression (lung, liver and kidney tissue) and plasma nitrate/nitrite. In separate experiments, nitroparacetamol, paracetamol or vehicle was administered 1 h before acetylcholine (0.1 microg kg(-1)) or sodium nitroprusside (0.25 microg kg(-1)) to determine if nitroparacetamol desensitizes responses to exogenous/endogenous nitric oxide.


RESULTS
Nitroparacetamol prevented but did not reverse the lipopolysaccharide-induced hypotension. There was no effect on heart rate or plasma markers of organ dysfunction. Nitroparacetamol prevented the increased plasma nitrate/nitrite and expression of COX-2 and iNOS, whereas paracetamol exerted partial inhibition of COX-2 in lung alone. Nitroparacetamol also reduced responses to acetylcholine and sodium nitroprusside.


CONCLUSIONS
NO is the active component of nitroparacetamol in this model of endotoxaemia. Pro-inflammatory processes targeted by nitroparacetamol have been shown to include iNOS/COX-2 induction and possibly vascular soluble guanylyl cyclase. Precise mechanisms underlying the NO effect are unclear but inhibition of cytokine formation may be important.
Marshall
M
M
King's College London, Cardiovascular Division, UK. melanie.marshall@kcl.ac.uk
Keeble
J
J
Moore
P K
PK
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009573:Nitrites / Q000097:blood; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology
D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D000082:Acetaminophen; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D001219:Aspartate Aminotransferases; C478738:4-(nitroxy)butanoic acid 4-acetylaminophenyl ester; D000109:Acetylcholine