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The adenosine A1/A2 receptor agonist AMP 579 has been reported to protect the heart against infarction even when administered after the onset of ischemia. The present study explored both the timing and the duration of treatment required to limit infarct size in in situ rabbit hearts subjected to 30 min of regional ischemia and 3 hours of reperfusion. In groups 1 and 2, AMP 579 was infused from10 min before reperfusion and continued for either 30 or 40 min. In group 3, AMP 579 was begun at the onset of reperfusion and continued for 70 min. In group 4, AMP 579 was also infused for 70 min but begun 10 min after reperfusion. In untreated hearts 36.4 ± 3.1% of the risk zone infarcted. Protection was observed only in hearts having a 70-minute infusion of AMP 579 starting at reperfusion (13.0 ± 1.9%, P < 0.05). Therefore, AMP 579 must be present at the moment of reperfusion and have a continued presence of more than 30 min thereafter to protect. Importantly, because AMP 579 can protect when administered up to the time of reperfusion, it likely prevents a reperfusion injury, and, therefore, has impressive clinical potential.