Interactions between inducible isoforms of nitric oxide synthase and cyclo‐oxygenase in vivo : investigations using the selective inhibitors, 1400W and celecoxib

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 F 1α (6 keto‐PGF 1α ) and nitrite/nitrate (NO 2 /NO 3 ), 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‐PGF 1α 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 NO 2 /NO 3 but were both without effect on the plasma concentration of 6 keto‐PGF 1α 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‐PGF 1α caused by LPS, and the large increase in 6 keto‐PGF 1α following injection of AA. None of the COX inhibitors affected the increase in plasma NO 2 /NO 3 . Dexamethasone, however, significantly inhibited both the increase in 6 keto‐PGF 1α and the increase in NO 2 /NO 3 . 5 In conclusion, the use of selective inhibitors does not support the concept of cross talk in vivo between iNOS and COX‐2.British Journal of Pharmacology (1998) 125 , 335–340; doi: 10.1038/sj.bjp.0702077