title: Hydrogen sulfide-releasing aspirin derivative ACS14 exerts strong antithrombotic effects in vitro and in vivo.
abstract: OBJECTIVE
  Hydrogen sulfide (H(2)S)-releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H(2)S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets.
  
  
  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 to a significantly longer arterial occlusion time after light-dye-induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced 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 aggregation. 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 (VASP) phosphorylation.
  
  
  CONCLUSIONS
  The H(2)S-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.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der LMU, München, Germany. joachim.pircher@med.uni-muenchen.de
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.forename: Franziska
authors.initials: F
authors.lastname: Fochler
authors.forename: Thomas
authors.initials: T
authors.lastname: Czermak
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
authors.forename: Bjoern F
authors.initials: BF
authors.lastname: Kraemer
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
authors.forename: Florian
authors.initials: F
authors.lastname: Krötz
mesh_terms: D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D066298:In Vitro Techniques; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism / Q000517:prevention & control
chemical_list: C577776:2-acetyloxybenzoic acid 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl ester; D004220:Disulfides; D005343:Fibrinolytic Agents; D016023:Integrins; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D006862:Hydrogen Sulfide