Background: Brief preconditioning (PC) ischemia, in addition to its well-described cardioprotective effects, has been shown in some studies to act on circulating platelets and attenuate platelet adhesion and aggregation in models of unstable angina and acute myocardial infarction. This 'anti-platelet' effect of PC may be triggered by release of adenosine from ischemic/reperfused myocardium and activation of adenosine A2 receptors on the platelets' surface. However: (1) all current data on the platelet inhibitory effects of PC ischemia and A2 receptor stimulation have been obtained in adult populations; and (2) there is evidence of age-associated alterations in myocardial adenosine release, receptor responsiveness and post-receptor signaling. Objective: Our aim was to evaluate, using an established in vitro model of platelet aggregation and exogenous administration of an adenosine A2 agonist, whether the favorable effects of adenosine A2 receptor stimulation on platelet responsiveness are compromised in aging populations. Methods: Arterial blood samples were obtained from young adult versus old rabbits (6 months versus 4 years of age) and young adult versus senescent rats (4 months versus 2 years of age). Matched aliquots from each animal were randomly assigned to receive exogenous treatment with either the A2 agonist CGS 21680 or vehicle. Maximum platelet aggregation was quantified by whole blood impedance aggregometry, using collagen as the aggregatory stimulus. Results: In young adult rabbits, maximum platelet aggregation was, as expected, reduced by 30± 4% in CGS-treated aliquots versus vehicle-controls. In contrast, blood samples from 4 year old rabbits were refractory to A2 receptor stimulation: in the old cohort, treatment with CGS evoked no change in platelet aggregation (decrease of 2 ± 3% versus age-matched vehicle controls; p < .01 versus the decrease of 30% seen in young adults). Data obtained in the rat model were analogous to those seen in the rabbit: maximum platelet aggregation decreased by 18 ± 5% versus 1 ± 7% with CGS treatment in young adult versus senescent animals. Conclusion: Our results provide novel in vitro evidence of an age-associated loss in platelet responsiveness to adenosine-mediated 'preconditioning'.