Inhibition of neutrophil function in vitro by nimesulide. Preliminary evidence of an adenosine-mediated mechanism.
Nimesulide (CAS 51803-78-2) is a methane sulphoanilide derivative provided with specific anti-inflammatory activity. In human polymorphonuclear leucocytes (PMNs), the activity of nimesulide has been suggested to be based on the inhibition of the oxidative burst. However, the effect of the compound on PMNs function seems to be very complex. In order to give a major insight into the mechanism of action of nimesulide, the effect of the drug was studied in vitro on human PMNs functions, such as free radical generation and enzyme release, and on cytosolic free calcium levels, following the activation with specific stimuli. Moreover, the hypothesis that nimesulide could act by interfering with the adenosine cell receptor system was also evaluated. Nimesulide (1-50 mumol/l showed a dose-dependent inhibitory activity on superoxide anion and chemiluminescence production from PMNs stimulated with the oligopeptide fMLP, the ionophore A23187, and the phorbol ester PMA. Enzyme release was significantly reduced, when fMLP and A23187 represented the stimulating agents, while no effect at all was observed with PMA. Studies with the fluorescent calcium chelating dye FURA 2/AM showed that nimesulide was able to reduce free cytosolic calcium increase produced by fMLP and the ionophore ionomycin. The preincubation of cells with the specific adenosine receptor antagonist theophylline was able to significantly reverse the inhibitory activity of nimesulide, either on free radical production and enzyme release, and on free cytosolic calcium increase sustained by fMLP and the ionophores.(ABSTRACT TRUNCATED AT 250 WORDS)
Capecchi
P L
PL
Institute of Clinical Medicine, University of Siena School of Medicine, Italy.
Ceccatelli
L
L
Beermann
U
U
Laghi Pasini
F
F
Di Perri
T
T
D000241:Adenosine / Q000502:physiology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D009113:Muramidase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005609:Free Radicals; D018047:Receptors, Purinergic P1; D013449:Sulfonamides; D013481:Superoxides; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013806:Theophylline; D009113:Muramidase; D005966:Glucuronidase; D000241:Adenosine; D002118:Calcium; C012655:nimesulide