Targeted deletion of [A.sub.2A] adenosine receptors attenuates the protective effects of myocardial postconditioning

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (POC), yet it is unclear which adenosine receptor subtype is primarily responsible. To evaluate the role of [A.sub.2A] adenosine receptors in POC-induced protection, global ischemia-reperfusion was performed with and without POC in isolated wild-type (WT) and [A.sub.2A] adenosine receptor knockout ([A.sub.2A]KO) mouse hearts. Injury was measured in terms of postischemic functional recovery and release of cardiac troponin I (cTnI). Activation of protective signaling with POC was assessed by Akt and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. In WT hearts, POC improved recovery of postischemic developed pressure in early (81.6 [+ or -] 6.4% of preischemic baseline vs. 37.5 [+ or -] 5.6% for non-POC WT at 1 min) and late (62.2 [+ or -] 4.2% of baseline vs. 45.5 [+ or -] 5.3% for non-POC WT at 30 min) reperfusion, reduced cTnI release by 37%, and doubled the phosphorylation of both Akt and ERK1/2. These beneficial effects of POC were blocked by treatment with the selective [A2.sub.A] adenosine receptor antagonist ZM-241385 during reperfusion. Postischemic functional recovery, cTnI release, and phosphorylation of Akt and ERK1/2 were not different between non-POC WT and [A.sub.2A]KO hearts. In [A.sub.2A]KO hearts, POC did not improve functional recovery, reduce cTnI release, nor increase phosphorylation of Akt or ERK1/2. Thus the protective effects of POC are attenuated by both selective [A.sub.2A] receptor antagonism and targeted deletion of the gene encoding [A.sub.2A] adenosine receptors. These observations support the conclusion that endogenous activation of [A.sub.2A] adenosine receptors is an essential trigger leading to the protective effects of POC in isolated murine hearts. ischemia-reperfusion; cardiac troponin I; phosphorylated Akt; phosphorylated extracellular signal-regulated kinase 1/2