In mice lacking ecto-5'-nucleotidase (CD73) reduced extracellular AMP degradation to adenosine was reported to result in loss of ischemic preconditioning (IPC) (Eckle et al., Circ. 115: 1581, 2007). This was surprising, since myocardial ischemia induces ATP and nucleotide degradation as well as a rapid rise in intracellular adenosine. Adenosine is then released into the extracellular space where it is known to be a major trigger of IPC. It remained thus an open question how CD73-mediated extracellular adenosine formation could contribute to IPC.

To better define the role of CD73 in IPC, hearts from female WT (C57BL/6) and CD73-deficient mice (CD73^-/-) were compared. Isolated saline perfused hearts were subjected to global ischemia (20 min), followed by 90 minutes of reperfusion. In controls without IPC, post-ischemic myocardial infarct size was 46 6,3% of area at risk in WT and 56,1 7,6% in CD73^-/- hearts and did not differ between these groups. IPC was induced by 3 cycles of ischemia and reperfusion (5 min each) and reduced infarct size substantially both in WT (26,8 4,7%, p < 0,05 vs. control, n = 7 each) and in the CD73^-/- group (25,6 4,7%, p < 0,05 vs. control, n = 7 each). In spite of this impressive effect, IPC resulted only in a trend towards improved post-ischemic recovery of contractile function.

Each cycle of ischemia in IPC enhanced coronary venous adenosine release in reperfusion, which reached up to 1,6 0,7 respectively 2,2 0,6 mM (WT vs. CD73^-/-) and was not different between these groups. In separate experiments in WT hearts, 3 times 2,5 mM coronary arterial adenosine for 5 min each, resulting in 1,2 0,5 mM coronary venous adenosine, induced pharmacological preconditioning (34 5,5% infarct size) which was as effective as IPC (37,6 9,7%) and compared to 58 12% in controls (n=6 each).

In summary, IPC was as effective in WT as in CD73^-/- saline perfused mouse hearts; both groups released a comparable concentration of adenosine which was sufficient to elicit preconditioning. Thus, in this model, extracellular adenosine generation via CD73 does not play an essential role in IPC. It is however well conceivable that in the blood perfused heart in vivo, adenosine formed by CD73 exerts protective anti-inflammatory effects and impedes cellular interactions at the endothelial surface, thereby contributing to IPC.