INHIBITION OF THE PRODUCTION OF PLATELET-ACTIVATING-FACTOR AND OF LEUKOTRIENE B-4 IN ACTIVATED NEUTROPHILS BY NIMESULIDE DUE TO AN ELEVATION OF INTRACELLULAR CYCLIC ADENOSINE-MONOPHOSPHATE

Nimesulide (CAS 51803-78-2) has been shown to exert a marked anti-infl ammatory effect in several in vivo models of inflammation. Recent stud ies indicate that nimesulide not only inhibits prostaglandin synthesis in certain cell types, but also has pleiotropic effects on neutrophil functions, including the respiratory burst, integrin-mediated adheren ce and synthesis of platelet-activating factor (PAF). In the present s tudy, the effect of nimesulide on PAF synthesis was compared with its effect on the production of leukotriene B-4 (LTB(4)). Nimesulide dose- dependently inhibited both processes in neutrophils stimulated by seru m-treated zymosan (STZ) with a comparable efficacy (IC50 values betwee n 10 and 20 mu mol/l). In formyl-methionyl-leucyl-phenylalanine-stimul ated neutrophils (treated with cytochalasin B), these IC50 values were 30 and 50 mu mol/l for PAF and LTB(4) synthesis, respectively. These results indicate an inhibition by nimesulide of a common step in the r elease of these lipid mediators, ie. the activation of phospholipase A (2), possibly by elevating intracellular cAMP. In support of this latt er hypothesis it was observed that nimesulide increased the level of c AMP almost 3-fold after STZ stimulation whereas in fMLP-stimulated neu trophils these changes in cAMP levels were more dramatic Furthermore, the inhibitory effects of nimesulide on PAP and LTB(4) production coul d largely be prevented by addition of H89, an inhibitor of cAMP-depend ent protein kinase (PK-A). It is concluded that an increase in intrace llular cAMP is instrumental in the observed effects of nimesulide on t he release of PAF and LTB, by activated neutrophils and that limited a vailability of arachidonic acid, also the substrate for the cyclo-oxyg enase pathway, may very well contribute to the effects of nimesulide o n prostaglandin synthesis observed in other cell types.