Adenosine-Mediated Cardioprotection in Ischemic-Reperfused Mouse Heart

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Summary:We investigated the roles of A 1 , A 2A , or A 3 receptors and purine salvage in cardioprotection with exogenous adenosine, and tested whether A 2A -mediated reductions in perfusion pressure modify post-ischemic recovery. Treatment with 10 −5 or 5 × 10 −5 M adenosine improved contractile recovery from 20 min ischemia 45 min reperfusion in isolated mouse hearts. Protection was attenuated by adenosine kinase inhibition (10 −5 M iodotubercidin) and receptor antagonism (5 × 10 −5 M 8-ρ-sulfophenyltheophylline, 8-SPT). Enzyme efflux mirrored contractile recoveries. A 3 agonism with 10 −7 M 2-chloro-N6 -(3-iodobenzyl)-adenosine-5´-N-methyluronamide (Cl-IB-MECA) improved ischemic tolerance whereas A 1 agonism with 5 × 10 −8 M N6 -cyclopentyladenosine (CPA) and A 2A agonism with 10 −9 M 2-[p-(2-carboxyethyl) phenethylamino]-5´-N-ethylcarboxamidoadenosine (CGS21680) or 2 × 10 −8 M methyl-4-(3-{9-[4S,5S,2R,3R)-5-(N-ethylcarbamoyl)-3,4-dihydroxyoxolan-2-yl]-6-aminopurin-2-yl)}prop-2-ynyl) cyclohexane-carboxylate (ATL-146e) were ineffective. Protection via A 1 receptor overexpression was enhanced by adenosine, but unaltered by A 1 or A 2A agonists. Finally, post-ischemic dysfunction in hearts perfused at constant flow was dependent on coronary pressure, with A 2A AR-mediated reductions in pressure reducing diastolic contracture, and elevated perfusion pressure worsening contracture. Data indicate that cardioprotection with exogenous adenosine in asanguinous hearts involves purine salvage and activation of A 3 but not A 1 or A 2A receptors.

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