Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance

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 approximate to25%) and enhanced lactate dehydrogenase (LDH) efflux (increased by approximate to100%). 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 mumol/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.