Recent studies have suggested that the protective anti-ischemic effects of acetylsalicylic
acid are stronger than the inhibition of platelet thromboxane A2 synthesis. Since
ischemic events still occur in acetylsalicylic acid-treated patients, the development
of new drugs with more powerful protective effects is needed. We compared the effects
of a new platelet antiaggregating drug, 2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal)
and of acetylsalicylic acid on the interaction between human neutrophils and platelets,
examining the capability of neutrophils to generate nitric oxide (NO). Triflusal,
in the presence of neutrophils, showed a greater antiplatelet potency than acetylsalicylic
acid to inhibit thrombin-induced platelet activation. Significant stimulation of NO-mediated
mechanisms in the presence of acetylsalicylic acid or triflusal was demonstrated by
the following findings: (1) increased metabolism of arginine to citrulline, (2) increase
of cGMP in the platelet/neutrophil system and (3) the inhibitory action of the L-arginine
(L-Arg) competitive analogue, NG-nitro-L-arginine-methyl ester (L-NAME), which was
reversed by L-Arg. Triflusal increased the stimulation of NO synthesis by neutrophils
more than did of acetylsalicylic acid. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic
acid (HTB), alone or in combination with acetylsalicylic acid, did not modify NO production
by neutrophils. Therefore, the whole molecule of triflusal is needed to stimulate
NO production by neutrophils. Our results show that, in the presence of neutrophils,
triflusal exerts an antiplatelet effect greater than that of acetylsalicylic acid,
demonstrating a more powerful stimulation of the NO/cGMP system. The present results
indicate that it is possible to develop new and more potent acetylsalicylic acid-related
antiplatelet drugs for the prevention of the myocardial ischemic/reperfusion processes.