PURINOCEPTORS ON BLOOD-PLATELETS - FURTHER PHARMACOLOGICAL AND CLINICAL-EVIDENCE TO SUGGEST THE PRESENCE OF 2 ADP RECEPTORS

Platelet aggregation by ADP plays a major role in the development and extension of arterial thrombosis. The antithrombotic thienopyridine compounds ticlopidine and clopidogrel have proved useful tools to investigate the mechanisms of ADP-induced platelet activation. In essence, although clopidogrel has been shown to completely and selectively block ADP-induced platelet aggregation, G protein activation and inhibition of adenylyl cyclase, this drug does not affect shape change and Ca2+ influx. Binding studies, using the non-hydrolysable ligand [P-33]2MeSADP, have shown that human platelets contain about 600 high-affinity binding sites for 2MeSADP (K-d approximate to 5 nM). These sites present pharmacological characteristics of a PLT receptor. Clopidogrel treatment reduces the number of sites by 70% on rat platelets (from 1200 to 450) and leaves the residual binding sites resistant to clopidogrel, Moreover, patients with congenital impairment of ADP-induced platelet aggregation but normal shape change display very low levels of [P-33]2MeSADP binding sites. he current data thus strongly suggest the presence of two ADP receptors, one responsible for shape change and rapid Ca2+ influx and the other a Gi protein-coupled receptor responsible for Ca2+ mobilization from internal stores, inhibition of adenylyl cyclase and platelet aggregation.