Genetic Deletion of the A 1 Adenosine Receptor Limits Myocardial Ischemic Tolerance

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Abstract
Adenosine receptors may be important determinants of intrinsic ischemic tolerance. Genetically modified mice were used to examine effects of global A 1 adenosine receptor (A 1 AR) knockout (KO) on function and ischemic tolerance in perfused mouse hearts. Baseline contractile function and heart rate were unaltered by A 1 AR KO, which was shown to abolish the negative chronotropic effects of 2-chloroadenosine (A 1 AR-mediated) without altering A 2 adenosine receptor–mediated coronary dilation. Tolerance to 25 minutes global normothermic ischemia (followed by 45 minutes reperfusion) was significantly limited by A 1 AR KO, with impaired contractile recovery (reduced by ≈25%) and enhanced lactate dehydrogenase (LDH) efflux (increased by ≈100%). Functional effects of A 1 AR KO involved worsened systolic pressure development with little to no change in diastolic dysfunction. In contrast, cardiac specific A 1 AR overexpression enhanced ischemic tolerance with a primary action on diastolic dysfunction. Nonselective receptor agonism (10 μmol/L 2-chloroadenosine) protected wild-type and also A 1 AR KO hearts (albeit to a lesser extent), implicating protection via subtypes additional to A 1 ARs. However, A 1 AR KO abrogated effects of 2-chloroadenosine on ischemic contracture and diastolic dysfunction. These data are the first demonstrating global deletion of the A 1 AR limits intrinsic myocardial resistance to ischemia. Data indicate the function of intrinsically activated A 1 ARs appears primarily to be enhancement of postischemic contractility and limitation of cell death.

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