Summary
Despite the proven efficacy of current antithrombotic therapy in preventing ischemic
heart disease (IHD), vascular events still occur. Our aims were i) to evaluate if
combined oral treatment of clopidogrel and LA419, a novel nitric oxide donor with
antiischemic and antiplatelet properties, provides additional antiplatelet effects
to those of the blockade of P2Y12 receptor; and ii) to gain insight into the mechanism behind LA419 antiplatelet effects.
Pigs (n=16) were randomized into four groups: 1) placebocontrol; 2) LA419; 3) clopidogrel;
and 4) LA419+clopidogrel. Both compounds were administered orally: LA419 0.9 mg kg-1 twice daily for 10 days; clopidogrel 10 mg kg-1 day the three last days. Antithrombotic effects were assessed by measuring platelet
deposition (PD) triggered by denuded and disrupted vessel wall placed on the Badimon
chamber. LA419 effects on platelet aggregation, hemodynamic parameters, and platelet
protein expression upon in vitro thrombin stimulation were also evaluated. Total PD on denuded vessels was similarly
reduced by all treatments with respect to placebo (p<0.05). However, combination of
LA419+clopidogrel largely reduced PD triggered by disrupted vessel wall by 80% versus
placebo (p<0.005), 15% versus clopidogrel alone (p<0.01), and 30% versus LA419 alone
(p<0.005). All treatments inhibited collagen- and ADP-induced platelet aggregation,
and no variations were detected in hemodynamic parameters. Proteomic analysis revealed
that LA419 was associated with an increase in membrane protein disulphide isomerase
(protein implicated in nitric oxide release).Treatment with LA419 may result in additional
antiplatelet effect to that of clopidogrel in addition to restoring impaired endothelial
dependent vasodilation without hemodynamic side effects. Further studies in IHD patients
seem warranted.
Keywords
Thrombosis - platelets - nitric - oxide
