title: Sodium salicylate inhibits prostaglandin formation without affecting the induction of cyclooxygenase-2 by bacterial lipopolysaccharide in vivo.
abstract: The mechanisms underlying the anti-inflammatory properties of salicylate are not well understood. In particular, while salicylate inhibits prostaglandin production in vivo it only weakly inhibits cyclooxygenase (COX)-1 or -2 activity in vitro. Thus, it has often been suggested that in vivo salicylate may inhibit the expression rather than the activity of COX, particularly COX-2. Using a model of acute COX-2 expression in the rat, we show that salicylate inhibits COX-2 activity in vivo without affecting COX-2 expression. In anesthetized rats LPS (6 mg kg(-1), i.p.) increased the expression of COX-2 as evidenced by increased circulating levels of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha), a stable breakdown product of PGI(2)), greatly exaggerated formation of 6-keto-PGF(1alpha) following arachidonic acid (AA) challenge (3 mg kg(-1), i.v.), and increased expression of COX-2, but not COX-1, protein. Diclofenac (3 mg kg(-1), i.p.) or the COX-2 selective agent diisopropyl fluorophosphate (10 mg kg(-1), i.p.) decreased the LPS-induced increase in circulating 6-keto-PGF(1alpha) and the exaggerated 6-keto-PGF(1alpha) production following AA challenge. Sodium salicylate (20 or 120 mg kg(-1), i.p.) (administered either 1 h prior, or once per day for 3 days prior, to LPS injection) reduced only the LPS-induced increase in circulating 6-keto-PGF(1alpha), but not the exaggerated 6-keto-PGF(1alpha) production following AA challenge or the expression of COX-2. Thus, salicylate inhibits LPS-induced COX-2 activity in a manner that is overcome by provision of excess substrate and independent of effects on COX-2 expression. In conclusion, our results exclude mechanisms other than direct enzyme inhibition as responsible for the anti-COX effects of salicylate.
authors.affiliation: Department of Cardiac, Vascular and Inflammation Research, The William Harvey Research Institute, St. Bartholomew's and the Royal London Queen Mary's School of Medicine and Dentistry, University of London, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Giuliano
authors.forename: J A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: T D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002319:Cardiovascular System / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000096:biosynthesis*; D007531:Isoflurophate / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012980:Sodium Salicylate / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011453:Prostaglandins; D007531:Isoflurophate; D004008:Diclofenac; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012980:Sodium Salicylate