NIMESULIDE DECREASES SUPEROXIDE PRODUCTION BY INHIBITING PHOSPHODIESTERASE TYPE-IV

Nimesulide, the prototype of a new class of anti-inflammatory drugs, dose-dependently decreases the production of the superoxide anion (O-2(-)) in N-formyl-methionyl-leucyl-phenylalanine (fMLP)-and in phorbol myristate acetate (PMA)-stimulated polymorphonuclear leukocytes. The inhibition of O-2(-) is possibly related to its inhibitory effect on polymorphonuclear leukocyte cytosolic phosphodiesterase type IV (IC50 = 39 +/- 2 mu M), to the related increase in cAMP (P < 0.01 at 1 mu M) and the subsequent increase in protein kinase A activity. In fact H-89, a specific protein kinase A inhibitor, counteracts the inhibitory effect of nimesulide on O-2(-) production by fMLP and PMA. The activation of protein kinase A may prompt the phosphorylation of a number of substrates, thus inhibiting the assembly of NADPH-oxidase in the plasma membrane. Accordingly, nimesulide decreases PMA-induced assembly of NADPH-oxidase in polymorphonuclear leukocytes plasma membranes by about 35%. Protein kinase A activation may also interfere with chemotaxis. Nimesulide inhibits stimulated chemotaxis and the effect is decreased by H-89. Inhibition of phosphodiesterase type IV may explain many of nimesulide's effects.