Question: 

Hydrogen sulfide (H₂S)-releasing NSAIDs in animal experiments have been shown to cause less gastric mucosal damage and to have stronger anti-inflammatory effects. H₂S is described to mediate vasorelaxation and platelet inhibition. We investigated whether the hydrogen sulfide-releasing aspirin ACS14 has stronger antiplatelet effects than acetylsalicylic acid (ASA).

Methods: 

Platelet aggregation was measured in platelet-rich-plasma (PRP) and whole blood by turbidimetric- and impedance-aggregometry (Multiplate-Analyzer). Different signalling pathways for platelet activation were analyzed by stimulation with Thrombin-receptor-activating-peptide (TRAP), Arachidonic acid, ADP, Collagen and Ristocetin. Plasmatic coagulation was investigated by thrombelastometry. In vivo arterial occlusion time after light-dye-induced endothelial injury was assessed by intravital microscopy in the dorsal skinfold chamber mouse model. Bleeding time was measured by tail-bleeding.

Results: 

H₂S concentration-dependently inhibited platelet aggregation in human PRP and whole blood. Incubation of whole blood with ACS14 (500mM) led to a stronger inhibition of collagen-induced platelet aggregation than ASA (equimolar concentration) and additionally inhibited the TRAP- and ADP-dependent pathways (n=15, each; P<0.05). Plasmatic coagulation was not influenced by ACS14. In vivo thrombotic arterial vessel occlusion time in C57BL6 mice was markedly prolonged after 5 days of oral treatment with ACS14 compared to ASA (n=6, P<0.05). The bleeding time was not different between the two groups.

Conclusions: 

ACS14 compared to ASA additionally inhibits the for platelet activation and aggregation important ADP- and Thrombin-dependent pathways. These effects lead to stronger antithrombotic effects in vivo without prolonging the bleeding-time. Therefore hydrogen sulfide releasing aspirin could be used in the treatment of cardiovascular diseases in the future.