Adenosine A3 agonist cardioprotection in isolated rat and rabbit hearts is blocked by the A1 antagonist DPCPX

Adenosine A3 agonists have been shown to protect ischemic rat and rabbit myocardium. However, these agonists have been reported to exert A3 independent effects, and no cardiac A3 receptor has yet been identified. We thus tested whether A3 agonist protection is due to A1 receptor activation. Isolated rat and rabbit hearts were subjected to 25 and 45 min of global ischemia, respectively. Rat hearts pretreated with adenosine (100 microM), the A3 agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA, 50 nM), and vehicle recovered 73 +/- 2%, 75 +/- 4%, and 46 +/- 4%, respectively, of preischemic left ventricular developed pressure (LVDP) after 30 min of reperfusion. The A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM) blocked the beneficial effects of Cl-IB-MECA (51 +/- 5%) and adenosine (47 +/- 6%). In rabbit hearts, the beneficial effects of the A3 agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (50 nM) and the A1 agonist 2-chloro-N6-cyclopentyladenosine (100 nM) on postischemic LVDP (75 +/- 4 and 74 +/- 5%, respectively) were blocked by DPCPX (34 +/- 4 and 36 +/- 3%, respectively). The reduction in infarct size with both agonists was also completely blocked by DPCPX. These results suggest that these A3 agonists protect ischemic myocardium via A1 receptor activation.