In vivo and ex vivo effects of adenosine A 1 and A 2 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 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 μg/kg) adn 2-Hexynyl-NECA (10 μg/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 μg/kg. NECA (10 μg/kg) and 2-hexynyl-NECA (10 μg/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 μg/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.