Relative Importance of Adenosine A1and A3Receptors in Mediating Physiological or Pharmacological Protection from Ischemic Myocardial Injury in the Rabbit Heart

Although ischemic preconditioning (IP) in several species can be pharmacologically mimicked by selective adenosine A1or A3receptor agonists, it is currently unclear which receptor subtype (A1and/or A3) is physiologically involved in mediating IP. To investigate this question, we determined (a) the affinity of adenosine for rabbit adenosine A1and A3receptors, and (b) the effects of selective rabbit A1receptor blockade on IP and adenosine-mediated cardioprotection in a rabbit Langendorff model of myocardial ischemia-reperfusion injury. Adenosine was 19-fold selective for inhibition of N6-(4-amino-3-[125I]iodobenzyl)adenosine (125I-ABA) binding to recombinant rabbit A1vrabbit A3receptors (A1Ki: 28 nm; A3Ki532 nm). Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion, and infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR). Ischemic preconditioning (5 min global ischemia and 10 min reperfusion) or adenosine (20μm, 5 min) perfusion reduced infarct size (IA/AAR) to 17±3 and 14±2%, respectively (controls: 59±2%). Ischemic preconditioning and adenosine-mediated cardioprotection were completely blocked (57±2 and 61±4% IA/AAR, respectively) in the presence of a rabbit A1-selective concentration (50 nm) of the antagonist BWA1433 (rabbit A1Ki: 3 nm; A3Ki; 746 nm). Thus, whereas recent studies have demonstrated that selective A1or A3receptor agonists can both pharmacologically mimic IP, the results of the present study suggest that the adenosine-mediated component of IP in the isolated rabbit heart is preferentially mediated by adenosine A1receptors, potentially due to adenosine's selectivity for this receptor subtype.