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 (O2-.) in N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and in phorbol myristate acetate (PMA)-stimulated polymorphonuclear leukocytes. The inhibition of O2-. is possibly related to its inhibitory effect on polymorphonuclear leukocyte cytosolic phosphodiesterase type IV (IC50 = 39 +/- 2 microM), to the related increase in cAMP (P < 0.01 at 1 microM) 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 O2-. 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.
Bevilacqua
M
M
Servizio di Endocrinologia, Ospedale Luigi Sacco (Vialba), Milano, Italy.
Vago
T
T
Baldi
G
G
Renesto
E
E
Dallegri
F
F
Norbiato
G
G
D000262:Adenylyl Cyclases / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D009247:NADH, NADPH Oxidoreductases; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate; C012655:nimesulide