Although the adenosine A 3 receptor agonist N 6 -(3-iodobenzyl)-adenosine-5Ј-N-methylcarboxamide (IB-MECA) has been reported to be cardioprotective at reperfusion, little is known about the mechanisms underlying the protection. We hypothesized that IB-MECA may protect the heart at reperfusion by preventing the opening of mitochondrial permeability transition pore (mPTP) through inactivation of glycogen synthase kinase (GSK) 3␤. IB-MECA (1 M) applied during reperfusion reduced infarct size in isolated rat hearts, an effect that was abrogated by the selective ) upon reperfusion, and the GSK-3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) (3 M) mimicked the protective effect of IB-MECA by attenuating both infarction and the loss of ⌬⌿ m . In addition, the effect of IB-MECA on GSK-3␤ was reversed by wortmannin (100 nM), and IB-MECA was shown to enhance Akt phosphorylation upon reperfusion. In contrast, rapamycin (2 nM) failed to affect GSK-3␤ phosphorylation by IB-MECA, and IB-MECA did not alter phosphorylation of either mTOR (Ser 2448 ) or 70s6K (Thr 389 ). Taken together, these data suggest that IB-MECA prevents myocardial reperfusion injury by inhibiting the mPTP opening through the inactivation of GSK-3␤ at reperfusion. IB-MECA-induced GSK-3␤ inhibition is mediated by the PI3-kinase/Akt signal pathway but not by the mTOR/p70s6K pathway.

The adenosine A 3 receptor plays an important role in ischemic preconditioning. Activation of the adenosine A 3 receptor with its agonists induces both early and late pharmacological preconditioning through various mechanisms. As the first potent and selective adenosine A 3 receptor agonist, IB-MECA (N 6 -(3-iodobenzyl)-adenosine-5¢-N-methylcarboxamide) has been demonstrated to induce cardioprotection against myocardial ischemia/reperfusion injury when given before onset of ischemia by triggering pharmacological preconditioning. More importantly, IB-MECA can also protect the heart even when administered at the onset of reperfusion after ischemia, indicating a strong likelihood that the drug may be useful for the treatment of patients with acute myocardial infarction. However, since IB-MECA has been reported to have lethal effects at higher concentrations, and may cause systemic hypertension in some species, further studies are needed to find the best treatment strategy to increase its therapeutic potential.

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