Inhibition of ADP-Evoked Platelet Aggregation by Selected Poly(ADP-Ribose) Polymerase Inhibitors

Tamas Alexy, Ambrus Toth, Zsolt Marton, Beata Horvath, Katalin Koltai, Gergely Feher, Gabor Kesmarky, Tamas Kalai, Kalman Hideg, Balazs Sumegi, Kalman Toth

Research output: Article

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Abstract

Pathologic platelet activation has been implicated in the pathogenesis of ischemic heart disease. Since cardiomyocytes can be protected from ischemia-reoxygenation injury by poly(ADP-ribose) polymerase (PARP) inhibitors mimicking the adenine/ADP part of NAD+, their structural resemblance to ADP may also enable the blockade of platelet aggregation via binding to ADP receptors. Blood samples drawn from healthy volunteers were pre-incubated with different concentrations of PARP inhibitors: 4-hydroxyquinazoline, 2-mercapto-4(3H)-quinazolinone, or HO-3089. ADP-, collagen- and epinephrine-induced platelet aggregation was evaluated according to the method described by Born. The effect of PARP inhibitors on thrombocyte aggregation was also examined when platelets were sensitized by heparin and in the presence of incremental concentrations of ADP. All examined PARP inhibitors reduced the ADP-induced platelet aggregation in a dose-dependent manner (significant inhibition at 20 μM for HO-3089 and at 500 μM for the other agents; P < 0.05), even if platelets were sensitized with heparin. However, their hindrance on platelet aggregation waned as the concentration of ADP rose (no effect at 40 μM ADP). PARP inhibitors had minimal effect on both collagen- and epinephrine-induced platelet aggregation. Our study first demonstrates the feasibility of a design for PARP inhibitors that does not only protect against ischemia-reperfusion-induced cardiac damage but may also prevent thrombotic events.

Original languageEnglish
Pages (from-to)423-431
Number of pages9
JournalJournal of cardiovascular pharmacology
Volume43
Issue number3
DOIs
Publication statusPublished - márc. 1 2004

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ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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