Adenosine A 3 receptor activation protects the myocardium from reperfusion/reoxygenation injury

Ischemia-reperfusion induces both necrotic and apoptotic cell death. The ability of adenosine to attenuate reperfusion-induced injury (RI) and the role played by adenosine receptors are unclear. We therefore studied the role of the A 3 receptor (A 3 R) in ameliorating RI using the specific A 3 R agonist 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9 H-purin-9-yl]-1-deoxi- N-methyl-b-d-ribofuranuronamide (2-Cl-IB-MECA). Isolated rat hearts and cardiomyocytes were subjected to ischemia or simulated ischemia, followed by reperfusion/reoxygenation. The end points were percent infarction/risk zone and annexin-V (apoptosis) and/or propidium iodide positivity (necrosis), respectively. In isolated hearts, 2-Cl-IB-MECA significantly limited infarct size (44.2 ± 2.7% in control vs. 21.9 ± 2.4% at 1 nM and 35.8 ± 3.3% at 0.1 nM, P < 0.05). In isolated myocytes, apoptosis and necrosis were significantly reduced compared with controls (5.7 ± 2.6% vs. 17.1 ± 1.3% and 13.7 ± 2.0% vs. 23.1 ± 1.5%, respectively, P < 0.0001). In both models, the beneficial effects were abrogated using the A 3 R antagonist MRS-1191. The involvement of A 2a receptor activation was also examined. This is the first study to demonstrate that A 3 R activation at reperfusion limits myocardial injury in the isolated rat heart and improves survival in isolated myocytes, possibly by antiapoptotic and antinecrotic mechanisms.