Activation of the α_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 α_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) P2Y₁ 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 P2Y₁₂ and P2Y₁ 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 α_2A-adrenoceptor activation was associated with a concentration-dependent decrease of the rate constant of deaggregation. Activation of both ADP receptor subtypes and the α_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 P2Y₁₂ receptor, activation of the α_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.