We sought to determine whether the administration of a very low, nonvasodilating dose of a highly selective adenosine A_2A receptor agonist (ATL-193 or ATL-146e) would be cardioprotective in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Twenty-four anesthetized open-chest dogs underwent either 4 (n=12) or 10 cycles (n=12) of 5-minute left anterior descending coronary artery (LAD) occlusions interspersed by 5 or 10 minutes of reperfusion. LV thickening was measured beginning at baseline and continuing for 180 minutes after the last occlusion/reperfusion cycle. Regional flow was measured with microspheres. In 12 of 24 dogs, the A_2A receptor agonist was infused intravenously beginning 2 min prior to occlusion #1 and continuing throughout reperfusion at a dose below that which produces vasodilatation (0.01 µg/kg/min). Myocardial flow was similar between control and A_2A receptor agonist-treated animals confirming the absence of A₂ receptor agonist-induced vasodilatation. During occlusion, there was severe dyskinesis with marked LAD zone thinning in all animals. After 180 min of reperfusion following the last cycle, significantly greater recovery of LAD zone thickening was observed in A_2A receptor agonist-treated vs control animals in both the 4 cycles (91±7% vs. 56±12%, respectively, p<0.05) and the 10 cycles (65±9% vs. 8±16%, respectively, p<0.05) occlusion groups. The striking amount of functional recovery observed with the administration of low, nonvasodilating doses of the adenosine A_2A agonists ATL-193 or ATL-146e supports their further evaluation for the attenuation of post-ischemic stunning in the clinical setting.