This study tested whether an irreversible agonist of the A1 adenosine receptor, m-DITC ADAC, can mimic the protective effect of ischemic preconditioning in the rabbit heart. Isolated Krebs buffer-perfused rabbit hearts experienced 30 mins of regional ischemia and 120 mins of reperfusion. Infarct size was measured with tetrazolium staining. In untreated hearts 32 +/- 2% of the risk zone infarcted while only 9 +/- 2% infarction was seen in hearts that were preconditioned with 5 mins of global ischemia followed by 10 mins of reperfusion (P < 0.05 versus control). Exposure to 200 nM of the A1-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA) for 5 mins followed by 10 mins of washout protected the hearts as well as preconditioning with 13 +/- 7% infarction (P < 0.05 versus control). Protection from CCPA was completely blocked by 200 nM DPCPX (8-cyclopentyl-1,3-dipropylxanthine) with 34 +/- 7% infarction (P < 0.05 versus CCPA) confirming that protection was via the A1 adenosine receptor. m-DITC ADAC, which irreversibly stimulates the A1 adenosine receptor, also protected the hearts with only 15 +/- 4% infarction (P < 0.05 versus control). It was concluded that m-DITC ADAC does mimic ischemic preconditioning and that an irreversible agonist might be a novel way to provide an extended window of protection to the heart from a single intracoronary injection.