Inhibition of ADP-evoked platelet aggregation by selected poly(ADP-ribose) polymerase inhibitors.
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(3 H)-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 microM for HO-3089 and at 500 microM 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 microM 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.
Alexy
Tamas
T
First Department of Medicine, Division of Cardiology, University of Pecs, Medical School, Pecs, Hungary.
Toth
Ambrus
A
Marton
Zsolt
Z
Horvath
Beata
B
Koltai
Katalin
K
Feher
Gergely
G
Kesmarky
Gabor
G
Kalai
Tamas
T
Hideg
Kalman
K
Sumegi
Balazs
B
Toth
Kalman
K
D001792:Blood Platelets / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines