ISSN:
1432-1912
Keywords:
Key words: Platelet aggregation – 2-Aralkoxyadenosines – Platelet adenosine receptor
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract. 2-(Ar)alkoxyadenosines, which are agonists selective for the A2AAR in PC12 cell and rat striatum membranes, are also agonists at the A2AR coupled to adenylate cyclase (AC) that mediates the inhibition of platelet aggregation. A panel of twelve well-characterized adenosine analogues stimulated human platelet AC and inhibited ADP-induced platelet aggregation at sub- to low-micromolar concentrations with a potency ranking CGS 21680〈adenosine〈R-PIA. There were significant correlations between the EC50 of anti-aggregatory activity and either the EC50 of stimulation of platelet and PC12 cell AC (r 2=0.66 and 0.67, respectively) or the Ki of inhibition of [3H]NECA binding to the rat striatum membranes (r 2=0.75). Likewise, platelet AC stimulation correlated well with stimulation of PC12 cell AC and with [3H]NECA binding (r 2=0.94 and 0.91, respectively). Ten 2-(ar)alkoxyadenosines stimulated platelet AC at EC50s ranging between 0.16 and 2.3 μM and inhibited platelet aggregation at EC50s ranging between 2 and 30 μM. There were no correlations between the EC50s of anti-aggregatory activity and either the EC50s of the stimulation of platelet or PC12 AC (r 2=0.08 and 0.06, respectively) or with the Ki of the inhibition of [3H]NECA binding to the A2aAR in rat striatum (r 2=0.02). The EC50s of the stimulation of platelet AC correlated with those of the stimulation of PC12 AC (r 2=0.48), and also with the Ki of [3H]NECA binding (r 2=0.71). Each of the 23 adenosines completely inhibited platelet aggregation and thus, functionally, all behaved as full agonists. As stimulants of PC12 cell AC, Group A and B analogues were equally efficacious. As stimulants of platelet AC, however, the efficacy relative to NECA (=1.0) of Group B analogues was significantly 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 platelet A2AR but full agonist activity at the PC12 cell A2aAR, as well as the relatively low correlations between platelet AC stimulation and other indices of A2aAR agonist activity, suggest the platelet receptor is not a typical A2aAR. Further, the lack of a correlation between 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 correspond to the accumulation of cyclic AMP in intact platelets.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/PL00004904
Permalink