NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes

NCX4016 (2 acetoxy‐benzoate 2‐(2‐nitroxymethyl)‐phenyl ester, NicOx S.A., France) is an anti‐thrombotic agent, chemically related to acetylsalicylic acid (ASA) and able to release NO. We tested the effects of NCX4016 and ASA on the release of the thromboxane (TX) A 2 metabolite TXB 2 , tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), expression and activity of tissue factor (TF) in stimulated, adherent human monocytes. Both ASA and NCX4016 1 – 1000 μmol l −1 dose‐dependently reduced TXB 2 concentration, measured by RIA in the supernatant of 10 μg ml −1 LPS‐stimulated cells. NCX4016 activity was comparable to that of equimolar ASA when incubation lasted 6 h (NCX4016 30 μmol l −1 : −86.0±10.1%, NCX4016 300 μmol l −1 : −92.2±9.0%, ASA 30 μmol l −1 : −92.3±7.5%, ASA 300 μmol l −1 : −97.3±1.0%, n =6, M±s.d.). Most of the activity of NCX4016 up to 100 μmol l −1 was prevented by 10 μmol l −1 ODQ, inhibitor of cyclic GMP. NCX4016 100 – 300 μmol l −1 reduced TNF‐α (NCX4016 300 μmol l −1 =−77.2±19.9%, n =6) and IL‐6 (NCX4016 300 μmol l −1 : −61.9±15.2%, n =6) in LPS stimulated monocytes while ASA had no significant effects. TF activity (NCX4016 300 μmol l −1 : 53.7±39.9%, n =4) and immunoreactive TF (NCX4016 300 μmol l −1 : −93.9±7.9%, n =7), measured in the supernatant of stimulated cells, were also dose‐dependently inhibited by NCX4016 but not by ASA. The present results indicate that NCX4016 inhibits TXA 2 generation as well as cytokine release and TF in human monocytes partly via NO‐dependent mechanisms. NCX4016 may have a favourable profile of activities in the clinical setting of athero‐thrombosis.British Journal of Pharmacology (2001) 134 , 905–911; doi: 10.1038/sj.bjp.0704326