IN-VIVO AND EX-VIVO EFFECTS OF ADENOSINE A(1) AND A(2) RECEPTOR AGONISTS ON PLATELET-AGGREGATION IN THE RABBIT

We have investigated both in vivo and ex vivo antiaggregatory activity of three adenosine receptor agonists in the anesthetized rabbit: the non-selective, 5'-N-ethyl-carboxamidoadenosine (NECA), the selective adenosine A(1) receptor agonist, 2-chloro-N-6-cyclopentyladenosine (CCPA) and the new selective A(2) receptor agonist, 2-hexynyl-NECA. The drugs were administered by 30-min intravenous infusion at a dose reducing mean blood pressure by 40-50%. NECA and CCPA also markedly decreased heart rate. In ex vivo experiments, NECA (10 mu g/kg) and 2-hexynyl-NECA (10 mu g/kg) maximally inhibited adenosine 5'-diphosphate (ADP)-induced platelet aggregation at the end of drug infusion by 26.7 +/- 2.9% and 25.2 +/- 3.5%, respectively. In in vivo studies, the inhibition of platelet aggregation was evaluated using the technique based on selective accumulation of In-111-labeled platelets in pulmonary microcirculation upon challenge with ADP 100 mu g/kg. NECA (10 mu g/kg) and 2-hexynyl-NECA (10 mu g/kg) decreased peak values for platelet accumulation by 35.3 +/- 6.9% and 52.5 +/- 5.9% and the area under curve values by 37.7 +/- 8.7% and 41.2 +/- 12.0%, respectively. In comparison, CCPA (100 mu g/kg) did not affect platelet responses to ADP in either of the experimental models. Thus, the present study clearly demonstrates for the first time the in vivo antiplatelet activity of adenosine A(2) receptor agonists, whereas the adenosine A(1) receptor agonist was inactive, in consonance with the in vitro data.