We investigated whether activation of A1 or A3 adenosine receptors (ARs) induces late preconditioning (PC) against infarction in conscious rabbits using the selective AR agonists 2-chloro-N6-cyclopentyladenosine (CCPA) and N6-3-iodobenzyladenosine-5′-N-methylcarboxamide (IB-MECA). In vitro radioligand binding and cAMP assays demonstrated CCPA to be ≈200- to 400-fold selective for the rabbit A1AR and IB-MECA to be ≈20-fold selective for the rabbit A3AR. We observed that (1) pretreatment of rabbits 24 hours earlier with CCPA (100 μg/kg IV bolus) or IB-MECA (100 or 300 μg/kg) resulted in an ≈35% to 40% reduction in the size of the infarct induced by 30 minutes of coronary artery occlusion and 72 hours of reperfusion compared with vehicle-treated rabbits, whereas pretreatment with the selective A2AAR agonist CGS 21680 (100 μg/kg) had no effect; (2) the delayed cardioprotective effect of CCPA, but not that of IB-MECA, was completely blocked by coadministration of the highly selective A1AR antagonist N-0861; (3) inhibition of nitric oxide synthase (NOS) with Nω-nitro-L-arginine during the 30-minute occlusion abrogated the infarct-sparing action of CCPA but not that of IB-MECA; and (4) inhibition of ATP-sensitive potassium (KATP) channels with sodium 5-hydroxydecanoate during the 30-minute occlusion blocked the cardioprotective effects of both CCPA and IB-MECA. Taken together, these results indicate that activation of either A1ARs or A3ARs (but not A2AARs) elicits delayed protection against infarction in conscious rabbits and that both A1AR- and A3AR-induced cardioprotection involves opening of KATP channels. However, A1AR-induced late PC uses an NOS-dependent pathway whereas A3AR-induced late PC is mediated by an NOS-independent pathway.
- ATP-dependent potassium channels
- Adenosine receptors
- Ischemia/reperfusion injury
- Myocardial infarction
- Nitric oxide synthase
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine