Abstract 217: Selective Adenosine A2b Receptor Activation Mimics Postconditioning in a Rabbit Infarct Model
Pre-ischemic treatment for cardioprotection against ischemia/reperfusion injury is seldom possible in the clinical setting of acute myocardial infarction. Herein we present evidence that a specific adenosine A2b receptor agonist limits infarction when administered to ischemic rabbit hearts just prior to reperfusion. Bayer was the first to synthesize specific non-adenosine-like A2b receptor agonists. One of these, BAY 60 – 6583, was characterized with CHO cells expressing recombinant human A1, A2a or A2b receptors. EC50 values for receptor activation by BAY 60 – 6583 were >10,000 nM for both A1 and A2a and 3 nM for A2b receptors. Furthermore BAY 60 – 6583 dilated precontracted isolated rabbit coronary arteries with an EC50 value of 200 nM. BAY 60 – 6583 was then tested in open-chest rabbits anesthetized with sodium pentobarbital and subjected to 30 min of regional ischemia and 3 h of reperfusion. In untreated rabbits 40.2±3.4% of the risk zone infarcted. In rabbits postconditioned with four cycles of 30-sec reperfusion/30-sec occlusion following the index ischemia, infarction was reduced to 15.5±2.5% (p<0.001 vs control). Protection from postconditioning was blocked by either 9.5 μg/kg of the specific A2b receptor antagonist MRS 1754 (38.2±4.3% infarction) or 7.5 mg/kg of the non-selective adenosine receptor antagonist 8-p-sulfophenyl theophylline (43.8±5.9% infarction) indicating A2b involvement. 100 μg/kg of BAY 60 – 6583 infused iv 5 min before the onset of reperfusion and repeated 15 min after reperfusion was equipotent with postconditioning (9.9±3.9% infarction). No adverse hemodynamic effects were seen with the agent. We conclude that protection from postconditioning involves activation of A2b receptors and this protection can be mimicked by iv administration of the specific A2b receptor agonist BAY 60 – 6583 at reperfusion.