INHIBITION OF PLATELET-AGGREGATION BY ADENOSINE RECEPTOR AGONISTS

2-(Ar)alkoxyadenosines, which are agonists selective for the A(2A)AR i n PC12 cell and rat striatum membranes, are also agonists at the A(2)A R coupled to adenylate cyclase (AC) that mediates the inhibition of pl atelet aggregation. A panel of twelve well-characterized adenosine ana logues stimulated human platelet AC and inhibited ADP-induced platelet aggregation at sub- to low-micromolar concentrations with a potency r anking CGS 21680 > adenosine > R-PIA. There were significant correlati ons between the EC(50) Of anti-aggregatory activity and either the EC( 50) Of stimulation of platelet and PC12 cell AC (r(2) = 0.66 and 0.67, respectively) or the K-i of inhibition of [H-3]NECA binding to the ra t striatum membranes (r(2) = 0.75). Likewise, platelet AC stimulation correlated well with stimulation of PC12 cell AC and with [H-3]NECA bi nding (r(2) = 0.94 and 0.91, respectively). Ten 2-(ar)alkoxyadenosines stimulated platelet AC at EC(50)s ranging between 0.16 and 2.3 mu M a nd inhibited platelet aggregation at EC(50)s ranging between 2 and 30 mu M. There were no correlations between the EC(50)s of anti-aggregato ry activity and either the EC(50)s of the stimulation of platelet or P C12 AC (r(2) = 0.08 and 0.06, respectively) or with the K-i of the inh ibition of [H-3]NECA binding to the A(2a)AR in rat striatum (r(2) = 0. 02). The EC(50)s Of the stimulation of platelet AC correlated with tho se of the stimulation of PC 12 C (r(2) = 0.48), and also with the K-i of [H-3]NECA binding (r(2) = 0.71). Each of the 23 adenosines complete ly inhibited platelet aggregation and thus, functionally, all behaved as full agonists. As stimulants of PC12 cell AC, Group A and B analogu es were equally efficacious. As stimulants of platelet AC, however, th e efficacy relative to NECA (=1.0) of Group B analogues was significan tly less than that of Group A analogues, 0.49+/-0.2 vs. 0.72+/-0.05, P <0.01. The partial agonist activity of Group B analogues at the platel et A(2)AR but full agonist activity at the PC12 cell A(2),AR, as well as the relatively low correlations between platelet AC stimulation and other indices of A(2a)AR agonist activity, suggest the platelet recep tor is not a typical A(2a)AR. Further, the lack of a correlation betwe en the platelet anti-aggregatory and AC stimulatory activity suggests that (a) the 2-(ar)alkoxyadenosines might affect platelet aggregation by mechanisms other than AC stimulation or (b) that the stimulation of the platelet membrane AC by 2-(ar)alkoxy-adenosines does not correspo nd to the accumulation of cyclic AMP in intact platelets.