Targeted deletion of A(3) adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium

As adenosine receptors (A(3)ARs) have been implicated in regulating mast ce ll function and in cardioprotection during ischemia-reperfusion injury. The physiological role of A(3)ARs is unclear due to the lack of widely availab le selective antagonists. Therefore, we examined mice with targeted gene de letion of the A(3)AR together with pharmacological studies to determine the role of A(3)ARs in myocardial ischemia-reperfusion injury. We evaluated th e functional response to 15-min global ischemia and 30-min reperfusion in i sovolumic Langendorff hearts from A(3)AR(-/-) and wild-type (A(3)AR(+/+)) m ice. Loss of contractile function during ischemia was unchanged, but recove ry of developed pressure in hearts after reperfusion was improved in A(3)AR (-/-) compared with wildtype hearts (80 +/- 3 vs. 51 +/- 3% at 30 min), Tis sue viability assessed by efflux of lactate dehydrogenase was also improved in A(3)AR(-/-) hearts (4.5 +/- 1 vs. 7.5 +/- 1 U/g). The adenosine recepto r antagonist BW-A1433 (50 muM) decreased functional recovery following isch emia in A(3)AR(-/-) but not in wild-type hearts. We also examined myocardia l infarct size using an intact model with 30-min left anterior descending c oronary artery occlusion and 24-h reperfusion. Infarct size, was reduced by over 60% in A(3)AR(-/-) hearts. In summary, targeted deletion of the A(3)A R improved functional recovery and tissue viability during reperfusion foll owing ischemia. These data suggest that activation of A(3)ARs contributes t o myocardial injury in this setting in the rodent. Since AsARs are thought to be present on resident mast cells in the rodent myocardium, we speculate that A(3)ARs may have proinflammatory actions that mediate the deleterious effects of A(3)AR activation during ischemia-reperfusion injury.