Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo
Objective—Hydrogen sulfide (H2S)–releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H2S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets.
Methods and Results—In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid–induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led both, for a significantly longer time, to arteriolar occlusion after light-dye–induced endothelial injury and a decreased thrombus formation after ferric chloride injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25–500 µmol/L) inhibited arachidonic acid–induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor–activating peptide–, ADP-, and collagen-dependent aggregations. In washed human platelets, ACS14 (500 µmol/L) attenuated αIIbβ3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator-stimulated phosphoprotein phosphorylation.
Conclusion—The H2S-releasing aspirin derivative ACS14 exerts strong antiaggregatory effects by impairing the activation of the fibrinogen receptor by mechanisms involving increased intracellular cyclic nucleotides. These additional antithrombotic properties result in a more efficient inhibition of thrombus formation in vivo as achieved with aspirin alone.
- Received February 8, 2012.
- Accepted September 4, 2012.
- © 2012 American Heart Association, Inc.