DUAL EFFECTS OF NIMESULIDE, A COX-2 INHIBITOR, IN HUMAN PLATELETS

Nimesulide (CAS 51803-78-2) has been shown to exert marked anti-inflam matory effect in several in vivo models of inflammation. Since nimesul ide is considered to be a selective inhibitor of COX-2, it has not bee n studied in detail in relation to its mechanistic effects on platelet s, which express COX-1. This study was conducted to investigate the ef fects of nimesulide in platelet aggregation. We show that nimesulide ( 1-100 mu M) inhibited platelet aggregation induced by adrenaline (20-2 00 mu M). It also inhibited thromboxane A(2) (TXA(2)) formation by pla telets at low concentration (IC50; 1 mu M). However, much lower concen trations of nimesulide (0.01-0.1 mu M) potentiated the aggregatory res ponse of subthreshold concentrations of adrenaline (0.2-2 mu M). Such an effect was blocked by Ca2+-channel blockers, verapamil and diltiaze m (IC50: 7 and 46 mu M, respectively), nitric oxide donor, SNAP (IC50; 2 mu M) and cinchonine (10 nM) but not by genistein (up to 10 mu M). These results are indicative of the concentration-dependent dual effec ts of nimesulide on human platelet aggregation. The synergistic effect of low doses of nimesulide and adrenaline seems to be mediated throug h inhibition of multiple signalling pathways.