RELATIVE IMPORTANCE OF ADENOSINE A(1) AND A(3) RECEPTORS IN MEDIATINGPHYSIOLOGICAL OR PHARMACOLOGICAL PROTECTION FROM ISCHEMIC MYOCARDIAL INJURY IN THE RABBIT HEART

Although ischemic preconditioning (IP) in several species can be pharm acologically mimicked by selective adenosine A(1) or A(3) receptor ago nists, it is currently unclear which receptor subtype (A(1) and/or A(3 )) is physiologically involved in mediating TP. To investigate this qu estion, we determined (a) the affinity of adenosine for rabbit adenosi ne A(1) and A(3) receptors, and (b) the effects of selective rabbit A( 1) receptor blockade on LP and adenosine-mediated cardioprotection in a rabbit Langendorff model of myocardial ischemia-reperfusion injury. Adenosine was 19-fold selective for inhibition of N-6-(4-amino-3-[I-12 5]iodobenzyl)adenosine (I-125-ABA) binding to recombinant rabbit A(1) v rabbit A(3) receptors (A(1) K-i: 28 nM; A(3) K-i 532 nM). Buffer-per fused rabbit hearts were exposed to 30 min regional ischemia and 120 m in of reperfusion, and infarct size was measured by tetrazolium staini ng and normalized for area-at-risk (IA/AAR). Ischemic preconditioning (5 min global ischemia and 10 min reperfusion) or adenosine (20 mu M, 5 min) perfusion reduced infarct size (IA/AAR) to 17 +/- 3 and 14 +/- 2%, respectively (controls: 59 +/- 2%). Ischemic preconditioning and a denosine-mediated cardioprotection were completely blocked (57 +/- 2 a nd 61 +/- 4% IA/AAR, respectively) in the presence of a rabbit A(1)-se lective concentration (50 nM) of the antagonist BWA1433 (rabbit A(1) K -i: 3 nM; A(3) K-i; 746 nM). Thus, whereas recent studies have demonst rated that selective A(1) or A(3) receptor agonists can both pharmacol ogically mimic IP, the results of the present study suggest that the a denosine-mediated component of IP in the isolated rabbit heart is pref erentially mediated by adenosine A(1) receptors. potentially due to ad enosine's selectivity for this receptor subtype. (C) 1998 Academic Pre ss Limited.