In vivo and ex vivo effects of adenosine A1 and A2 receptor agonists on platelet aggregation in the rabbit.

ABSTRACT

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 A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA) and the new selective A2 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 micrograms/kg) and 2-hexynyl-NECA (10 micrograms/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 111In-labeled platelets in pulmonary microcirculation upon challenge with ADP 100 micrograms/kg. NECA (10 micrograms/kg) and 2-hexynyl-NECA (10 micrograms/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 micrograms/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 A2 receptor agonists, whereas the adenosine A1 receptor agonist was inactive, in consonance with the in vitro data.