Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A(1) and A(3) receptors.

OBJECTIVES There is currently general agreement that adenosine is not involved in ischemic preconditioning (IP) in rat hearts. We hypothesized that the failure to show a role for adenosine is due to the use of brief preconditioning stimuli, and therefore investigated whether adenosine is involved when longer stimuli are employed and which receptor subtypes are involved. METHODS AND RESULTS Infarct size (IS) was determined in anesthetized rats after 180 min of reperfusion (REP) following a 60-min coronary artery occlusion (CAO). IS was 69+/-2% (n=15) of the risk area in control rats and 45+/-2% (n=19; P<0.05) following IP by a single 15-min CAO. The non-selective adenosine receptor antagonist SPT, which itself had no effect on IS (74+/-1%), blunted the protection by IP (IS=57+/-2%, P<0.05) in a dose of 2 x 5 mg/kg i.v., and abolished the protection (IS=70+/-1%) at 2 x 25 mg/kg i.v. Following IP by three cycles of 3-min CAO and 3-min REP, IS was 24+/-6% (P<0.05), which was not affected by SPT in doses of 2 x 10 and 2 x 25 mg/kg i.v. The A(3) antagonist MRS-1191 (3.3 mg/kg, i.p.), which itself did not affect IS (70+/-2%), blunted the protection by IP with a 15-min CAO (IS=54+/-2%, P<0.05). When 2 x 5 mg/kg SPT (a dose selective for A(1)-receptors, as it did not affect the protection by the A(3) selective agonist IB-MECA, 51+/-3%) and MRS 1191 were combined the protection by IP was abolished (IS=67+/-2%). CONCLUSIONS Involvement of adenosine in IP in rats depends critically on the duration of the stimulus. Thus, whereas adenosine was not involved when stimuli of 3-min duration were employed, activation of both A(1) and A(3) receptors contributed when a stimulus of 15 min was used.