Activation of the alpha(2A)-adrenoceptor mediates deceleration of the deaggregation component of the response to ADP or 5-HT in human platelets in vitro.
Platelet aggregation requires the concomitant activation of at least one G(i)- and one G(q)-coupled receptor. Epinephrine (EPI) amplifies the response elicited by a number of agonists for platelet aggregation. This study tested the hypothesis that platelet alpha(2A)-adrenoceptor activation causes deceleration of the deaggregation component of the platelet aggregation response when activated concomitantly with the G(q)-coupled adenosine diphosphate (ADP) P2Y(1) or 5-hydroxytryptamine(2A) receptor. The time course of the aggregation response of human platelet-rich plasma following activation of combinations of two or three receptors was assessed by turbidometry using lepirudin anticoagulation. Simultaneous activation of specific two- and three-receptor combinations was achieved using selective antagonists for the P2Y(12) and P2Y(1) receptor subtypes. Steady-state and kinetic parameters, obtained using a four-compartment kinetic model, were used to assess the effects on the net aggregation response. Graded alpha(2A)-adrenoceptor activation was associated with a concentration-dependent decrease of the rate constant of deaggregation. Activation of both ADP receptor subtypes and the alpha(2A)-adrenoceptor produced a concentration-dependent, mutual amplification of the aggregation response. In addition, when three receptors were simultaneously activated, mutual amplification of the aggregation response was observed at physiologically relevant concentrations of epinephrine or norepinephrine (NE) and ADP. We propose that similar to the P2Y(12) receptor, activation of the alpha(2A)-adrenoceptor decelerates the deaggregation component shifting the balance toward increased net aggregation. The effects of EPI and NE on the aggregation response may contribute to the mechanism of increased thrombotic risk present in certain pathophysiological and disease states.
Maayani
S
S
The Basic Research Laboratory, Department of Anesthesiology, The Mount Sinai School of Medicine, New York, NY 10029-6574, USA. saul.maayani@mssm.edu
Schwarz
T
T
Craddock-Royal
B
B
Tagliente
T M
TM
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000378:metabolism* / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists; D000328:Adult; D000368:Aged; D019483:Disintegrins; D004837:Epinephrine / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013872:Thionucleosides / Q000378:metabolism / Q000494:pharmacology; D014757:Viper Venoms
C547768:ADRA2A protein, human; D058647:Adrenergic alpha-2 Receptor Agonists; D019483:Disintegrins; C415464:EC6 protein, Echis carinatus sochureki; D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D011985:Receptors, Serotonin; D013872:Thionucleosides; D014757:Viper Venoms; D012701:Serotonin; C021714:2-methylthioadenosine; D000244:Adenosine Diphosphate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D000241:Adenosine; D009638:Norepinephrine; D004837:Epinephrine