title: Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib.
abstract: 1. Exposure of tissues to endotoxin (LPS) and/or cytokines leads to the induction of both inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). It has previously been reported that there is 'cross-talk' between these two systems. However, such previous studies have been limited by the availability of highly selective inhibitors. Here we have investigated the interactions between iNOS and COX-2 in vivo using 1400W, an iNOS-selective inhibitor, and celecoxib, a COX-2-selective inhibitor. 2. Infusion of LPS to rats for 6 h caused a time-dependent increase in the plasma concentrations of 6 keto-prostaglandin F1alpha (6 keto-PGF1alpha) and nitrite/nitrate (NO2/NO3), consistent with the induction of iNOS and COX-2. Bolus injection of arachidonic acid (AA) at t=6 h resulted in a further increase of circulating levels of 6 keto-PGF1alpha in LPS-treated animals. 3. Treatment of rats with 1400W or the non-selective NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) inhibited the increase in plasma NO2/NO3 but were both without effect on the plasma concentration of 6 keto-PGF1alpha before or after AA. 4. Treatment with the non-steroidal anti-inflammatory drugs (NSAIDs), A771726 or diclofenac, or with celecoxib significantly reduced the increase in circulating 6 keto-PGF1alpha caused by LPS, and the large increase in 6 keto-PGF1alpha following injection of AA. None of the COX inhibitors affected the increase in plasma NO2/NO3. Dexamethasone, however, significantly inhibited both the increase in 6 keto-PGF1alpha and the increase in NO2/NO3. 5. In conclusion, the use of selective inhibitors does not support the concept of cross talk in vivo between iNOS and COX-2.
authors.affiliation: Vascular Inflammation, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry.
authors.forename: L C
authors.initials: LC
authors.lastname: Hamilton
authors.forename: T D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000578:Amidines / Q000494:pharmacology*; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology*; D000068579:Celecoxib; D003437:Crotonates; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006885:Hydroxybutyrates / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009570:Nitriles; D009573:Nitrites / Q000097:blood; D009585:Nitrogen Dioxide / Q000097:blood; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D014052:Toluidines; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000578:Amidines; D000814:Aniline Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001596:Benzylamines; D003437:Crotonates; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D007527:Isoenzymes; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009570:Nitriles; D009573:Nitrites; D011720:Pyrazoles; D013449:Sulfonamides; D014052:Toluidines; D004008:Diclofenac; C527525:teriflunomide; D019323:omega-N-Methylarginine; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D009585:Nitrogen Dioxide