Cyclo-oxygenase-2 contributes to constitutive prostanoid production in rat kidney and brain\

Cyclo-oxygenases (COXs) catalyse the synthesis of PGH(2) (prostaglandin H-2), which serves as the common substrate for the production of PGE,, PGD,, PGF2., prostacyclin (or PG12) and TXs (thromboxanes). While COX-1 is the major isoform responsible for prostanoid synthesis in healthy tissues, little information is available on the contribution of constitutive COX-2 to the various prostanoid synthetic pathways under non-inflammatory conditions. To evaluate further the role of COX-2 in prostanoid biosynthesis, rats were acutely treated with the selective COX-11 inhibitor SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] or the selective COX-2 inhibitors MF tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulphonyl)phenyl)2-(5H)-furanone] and DFU [5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulphonyl)phenyl-2-(5H)-furanone]. Selected tissues were then processed for a complete analysis of their prostanoid content by liquid chromatography MS. Whereas the treatment with SC-560 caused a 60-70% inhibition in the total prostanoid content of most tissues examined, a significant decrease (35-50%) in total prostanoid content following selective COX-2 inhibition was solely detected for kidney and brain tissues. Analysis of the individual prostanoids reveals significant inhibition of 6-oxo-PGF(1 alpha), PGE(2), PGD(2), PGF(2 alpha), and TXB2 in the kidney and inhibition of all these prostanoids with the exception of PGD(2) in the forebrain. These results demonstrate that constitutively expressed COX-2 contributes to the production of prostanoids; in kidney and brain for each of the PGE(2), PGI(2) and TXB2 pathways under non-inflammatory conditions. Approaches to modulate inflammation through specific inhibition of terminal synthases, such as mPGES-1 (microsomal PGE, synthase-1), thus have the potential to differ from COX-2 inhibitors and non-selective non-steroidal anti -inflammatory drugs with regard to effects on constitutive prostanoid synthesis and on renal function.