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 F_1α (6 keto-PGF_1α) 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-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 NO₂/NO₃ 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 NO₂/NO₃. Dexamethasone, however, significantly inhibited both the increase in 6 keto-PGF_1α 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.

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