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 co mpounds ticlopidine and clopidogrel have proved useful tools to invest igate the mechanisms of ADP-induced platelet activation. In essence, a lthough 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 Ca2influx. Binding studies, using the non-hydrolysable ligand [P-33]2MeSA DP, have shown that human platelets contain about 600 high-affinity bi nding sites for 2MeSADP (K-d approximate to 5 nM). These sites present pharmacological characteristics of a PLT receptor. Clopidogrel treatm ent reduces the number of sites by 70% on rat platelets (from 1200 to 450) and leaves the residual binding sites resistant to clopidogrel, M oreover, patients with congenital impairment of ADP-induced platelet a ggregation but normal shape change display very low levels of [P-33]2M eSADP binding sites. he current data thus strongly suggest the presenc e of two ADP receptors, one responsible for shape change and rapid Ca2 + influx and the other a Gi protein-coupled receptor responsible for C a2+ mobilization from internal stores, inhibition of adenylyl cyclase and platelet aggregation.