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 prov ided with specific anti-inflammatory activity. In human polymorphonucl ear leucocytes (PMNs), the activity of nimesulide has been suggested t o be based on the inhibition of the oxidative burst. However, the effe ct 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, t he effect of the drug was studied in vitro on human PMNs functions, su ch as free radical generation and enzyme release, and on cytosolic fre e calcium levels, following the activation with specific stimuli. More over, the hypothesis that nimesulide could act by interfering with the adenosine cell receptor system was also evaluated Nimesulide (1-50 mu mol/l showed a dose-dependent inhibitory activity on superoxide anion and chemiluminescence production from PMNs stimulated with the oligope ptide fMLP the ionophore A23187, and the phorbol ester PMA. Enzyme rel ease was significantly reduced, when fMLP and A23187 represented the s timulating agents, while no effect at all was observed with PMA. Studi es with the fluorescent calcium chelating dye FURA 2/A M showed that n imesulide was able to reduce free cytosolic calcium increase produced by fMLP and the ionophore ionomycin. The preincubation of cells with t he specific adenosine receptor antagonist theophylline was able to sig nificantly reverse the inhibitory, activity of nimesulide, either on f ree radical production and enzyme release, and on free cytosolic calci um increase sustained by fMLP and the ionophores. Evidence arises from these studies that a novel mechanism of action of nimesulide exists, other than scavenging, and that it could consist in a direct interfere nce with the adenosine receptor system on the cell membrane.