A(1) or A(3) adenosine receptors induce late preconditioning against infarction in conscious rabbits by different mechanisms

We investigated whether activation of A(1) or A(3) adenosine receptors (ARs ) induces late preconditioning (PC) against infarction in conscious rabbits using the selective AR agonists 2-chloro-N-6-cyclopentyladenosine (CCPA) a nd N6-3-iodobenzyladenosine-5'-N-methylcarboxamide (IB-MECA), In vitro radi oligand binding and cAMP assays demonstrated CCPA to be similar to 200- to 400-fold selective for the rabbit A,AR and IB-MECA to be similar to 20-fold selective for the rabbit A,AR. We observed that (1) pretreatment of rabbit s 24 hours earlier with CCPA (100 mug/kg IV bolus) or IB-MECA (100 or 300 m ug/kg) resulted in an approximate to 35% to 40% reduction in the size of th e infarct induced by 30 minutes of coronary artery occlusion and 72 hours o f reperfusion compared with vehicle-treated rabbits, whereas pretreatment w ith the selective A(2A)AR agonist CGS 21680 (100 mug/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 A,AR antagon ist N-0861; (3) inhibition of nitric oxide synthase (NOS) with N-omega-nitr o-L-arginine during the 30-minute occlusion abrogated the infarct-sparing a ction of CCPA but not that of IB-MECA; and (4) inhibition of ATP-sensitive potassium (K-ATP) channels with sodium 5-hydroxydecanoate during the 30-min ute occlusion blocked the cardioprotective effects of both CCPA and IB-MECA . Taken together, these results indicate that activation of either A(1)ARs or A(3)ARs (but not A(2A)ARs) elicits delayed protection against infarction in conscious rabbits and that both A(1)AR- and A(3)AR-induced cardioprotec tion involves opening of K-ATP channels. However, A,AR-induced late PC uses an NOS-dependent pathway whereas A(3)AR-induced late PC is mediated by an NOS-independent pathway.