DIFFERING PROFILES OF PROSTAGLANDIN FORMATION INHIBITION BETWEEN SELECTIVE PROSTAGLANDIN-H SYNTHASE-2 INHIBITORS AND CONVENTIONAL NSAIDS ININFLAMMATORY AND NONINFLAMMATORY SITES OF THE RAT

The present study examined the inhibitory profiles of NS-398 and nimes ulide against prostaglandin (PG) formation in inflammatory and non-inf lammatory sites, and compared them with those of aspirin and indometha cin. In vitro, indomethacin inhibited PGH synthase (PGHS)-1 and PGHS-2 almost equally, while NS-398 and,nimesulide inhibited only PGHS-2. NS -398 (1, 10 mg/kg) and nimesulide (3 mg/ kg) slowed the rate of plasma exudation and thus the exudate accumulation in rat carrageenin-induce d pleurisy. Aspirin (30, 100 mg/kg) and indomethacin (20 mg/kg) also r educed this rate. NS-398 and nimesulide reduced the PGE(2) more potent ly than TXB2 and 6-ketoPGF(1 alpha) in the exudate. However, aspirin a nd indomethacin did not exhibit this selectivity. The levels of PGE(2) correlated significantly with the plasma exudation rate. Moreover, ni mesulide (3 mg/kg) did not affect PGE(2) formation in rat stomachs inj ected with 1 M NaCl solution, while indomethacin (10 mg/kg) reduced it . Thus, NS-398 and nimesulide exhibit different inhibitory profiles fr om aspirin and indomethacin against PG formation. These results sugges t that PGE(2) may be produced by PGHS-2 in the inflammatory site, and may play a more prominent role than PGI(2) in plasma exudation.