Deaggregation is an integral component of the response of platelets to ADP in vitro: kinetic studies of literature and original data.
Adenosine diphosphate (ADP) is recognized as an important mediator of platelet aggregation. Transient aggregation at low (< or =1 microM), and sustained aggregation at higher ADP concentrations are consistently observed. Dissociation of platelet aggregates has been described and may explain the reversible component of the aggregation response. We hypothesized that the net aggregation response to ADP in vitro results from the concurrent activation of two opposing processes, aggregation and deaggregation. Different purinergic receptor subtypes may mediate these effects. To test this hypothesis and its generalizability, we performed a kinetic analysis of representative published ADP-induced aggregation responses supplemented with original data from our laboratory. A four-compartment kinetic model was used to estimate k(3), a rate constant of deaggregation. Two model-independent parameters, the magnitude of the aggregation response (DeltaOD) and the time to reach maximal aggregation (t(peak)) were also assessed. Greater sustained aggregation at higher ADP concentrations was consistently associated with increased DeltaOD and t(peak) but decreased k(3) values. These relationships were independent of type of platelet preparation or experimental conditions and not due to ADP receptor desensitization. Conversely, blockade of the P2Y(12) receptor subtype (ticlopidine, clopidogrel or 2-MeS-AMP) decreased DeltaOD and t(peak) but increased k(3) values. This supports the presence of active deaggregation which is decelerated by activation of the P2Y(12) receptor subtype.
Maayani
S
S
Department of Anesthesiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1010, New York, NY 10029, USA. saul.maayani@mssm.edu
Tagliente
T M
TM
Schwarz
T
T
Craddock-Royal
B
B
Alcala
C
C
Marrero
G
G
Martinez
R
R
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins; D008962:Models, Theoretical; D009391:Nephelometry and Turbidimetry; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism / Q000502:physiology; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine