Background N‐acetyl‐l‐cysteine, a thiol compound, has been shown to potentiate the inhibition of platelet aggregation exerted by organic nitrates and to increase the anti‐aggregating effect of l‐arginine, which promotes endogenous synthesis of nitric oxide (NO) acting as substrate of platelet constitutive nitric oxide synthase (NOS). It is not known whether this thiol can exert direct effects on platelet aggregability.

Materials and methods 14 healthy male volunteers provided platelet samples to investigate whether N‐acetyl‐l‐cysteine directly influences platelet function and intraplatelet levels of 3′,5′ cyclic guanosine monophosphate (cGMP), which represents the second messenger involved in NO‐induced antiaggregation. Some experiments were repeated in the presence of NOS inhibitor N^G‐monomethyl‐l‐arginine (L‐NMMA), of nitric oxide‐sensitive guanylyl cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), of the selective cGMP phosphodiesterase inhibitor zaprinast and of calcium ionophores (A₂₃₁₈₇, ionomycin).

Results N‐acetyl‐l‐cysteine at 3000–6000 µmol L⁻¹ decreases the responses of human platelets both in platelet‐rich plasma (aggregation induced by adenosine 5‐diphosphate) and in whole blood (aggregation induced by collagen). The anti‐aggregating effect was prevented by preincubation with L‐NMMA and guanylyl cyclase inhibitor ODQ. In resting platelets, N‐acetyl‐l‐cysteine increased the levels of cGMP starting from a concentration of 3000 µmol L⁻¹. Permeabilized platelets exhibited an increased sensitivity to the anti‐aggregating effect of N‐acetyl‐l‐cysteine. Also, cGMP phosphodiesterase inhibition or the increase in calcium availability, enhanced N‐acetyl‐l‐cysteine effects on platelets.

Conclusion N‐acetyl‐l‐cysteine exerts direct anti‐aggregating effects through an increased bioavailability of platelet nitric oxide.