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Adenosine receptors may be important determinants of intrinsic ischemic tolerance. Genetically modified mice were used to examine effects of global A₁ adenosine receptor (A₁AR) knockout (KO) on function and ischemic tolerance in perfused mouse hearts. Baseline contractile function and heart rate were unaltered by A₁AR KO, which was shown to abolish the negative chronotropic effects of 2-chloroadenosine (A₁AR-mediated) without altering A₂ adenosine receptor–mediated coronary dilation. Tolerance to 25 minutes global normothermic ischemia (followed by 45 minutes reperfusion) was significantly limited by A₁AR KO, with impaired contractile recovery (reduced by ≈25%) and enhanced lactate dehydrogenase (LDH) efflux (increased by ≈100%). Functional effects of A₁AR KO involved worsened systolic pressure development with little to no change in diastolic dysfunction. In contrast, cardiac specific A₁ …