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 a denosine A(1) receptor agonist, 2-chloro-N-6-cyclopentyladenosine (CCP A) and the new selective A(2) receptor agonist, 2-hexynyl-NECA. The dr ugs were administered by 30-min intravenous infusion at a dose reducin g 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-N ECA (10 mu g/kg) maximally inhibited adenosine 5'-diphosphate (ADP)-in duced 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 sel ective accumulation of In-111-labeled platelets in pulmonary microcirc ulation upon challenge with ADP 100 mu g/kg. NECA (10 mu g/kg) and 2-h exynyl-NECA (10 mu g/kg) decreased peak values for platelet accumulati on 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 t he experimental models. Thus, the present study clearly demonstrates f or the first time the in vivo antiplatelet activity of adenosine A(2) receptor agonists, whereas the adenosine A(1) receptor agonist was ina ctive, in consonance with the in vitro data.