Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine

Objective: This study tested the hypothesis that brief cycles of iterative ischemia-reperfusion at onset of reperfusion (termed 'postconditioning, post-con) delays washout of intravascular adenosine and thereby increases endogenous adenosine receptor (AR) activation during the early moments of reperfusion (R). Methods: Isolated mouse hearts were subjected to 20 min global ischernia (I) and 30 min R with or without post-con (3 or 6 cycles of 10 s R&I). Intravascular purines in coronary effluent were analyzed by HPLC. To assess the functional role of endogenous AR activation in post-con, an open-chest rat model of myocardial infarction was employed. Rats were randomly divided into 11 groups: control, no intervention at R; post-con, three cycles of 10 s R followed by 10 s LCA re-occlusion immediately upon R. In the following interventions, drugs (or vehicle) were administered 5 min before R in the absence or presence (+/-) of post-con. Vehicle (DMSO < 300 mu l/kg); 8-SPT (non-selective AR antagonist, 10 mg/kg) +/- post-con; DPCPX (A(1A)R antagonist, 0.1 mg/kg) +/- post-con; ZM241385 (A(2A)AR antagonist, 0.2 mg/kg) +/- postcon; MRS1523 (A(3)AR antagonist, 2 mg/kg) post-con. Results: In isolated mouse hearts, post-con reduced diastolic pressure during both early (26 +/- 3* vs. 37 +/- 3 mmHg at 5 min) and late (22 3* vs. 34 3 mmHg at 30 min) R. Post-con also hastened the early recovery of contractile function (developed pressure 39 +/- 6* vs. 16 2 mmHg at 5 min R), although differences did not persist at 30 min R. Importantly, post-con was associated with reduced adenosine washout (58 +/- 5* vs. 155 +/- 16 nM/min/g) at 2 min R suggesting greater retention time of intravascular adenosine. In rats, post-con significantly attenuated infarct size compared to control (40 +/- 3% vs. 53 +/- 2%* in control), an effect that was unaltered by DPCPX (42 +/- 2%) but was abrogated by 8-SPT (50 2%), ZM241385 (49 +/- 3%) or MRS1523 (52 +/- 1%) (P < 0.02). Conclusion: These data suggest that post-con involves endogenous activation of A(2A) and A(3) but not AIAR subtypes. This activation maybe linked to the delay in the washout of intravascular adenosine during the early minutes of R during which post-con is applied. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.