Selective Activation of A3Adenosine Receptors WithN6-(3-Iodobenzyl)Adenosine-5′-N-Methyluronamide Protects Against Myocardial Stunning and Infarction Without Hemodynamic Changes in Conscious Rabbits

Abstract

AbstractTo examine the cardioprotective role of A3adenosine receptors during myocardial ischemia/reperfusion injury, we tested the effect ofN6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA), a potent and selective A3adenosine receptor agonist, in models of myocardial stunning and infarction in chronically instrumented conscious rabbits. In phase I (studies of myocardial stunning), rabbits were subjected to six 4-minute coronary occlusions, each separated by 4-minute reperfusion periods, after which the recovery of systolic wall thickening was measured (ultrasonic crystals). In phase II (studies of myocardial infarction), rabbits were subjected to a 30-minute coronary occlusion followed by 3 days of reperfusion. In both phases, IB-MECA was administered as an intravenous bolus (100 μg/kg) 10 minutes before the first coronary occlusion. This dose of IB-MECA was determined in pilot studies to have no effect on heart rate, arterial blood pressure, or plasma histamine concentration in rabbits. In phase I, IB-MECA markedly improved the recovery of wall thickening after the six occlusion/reperfusion cycles, and this effect was sustained throughout the 5-hour observation period; the total deficit of wall thickening (a measure of the overall severity of myocardial stunning) was reduced by 68% (control, 129±16 arbitrary units, n=7; IB-MECA, 41±6 arbitrary units, n=6;P<.01). The protective effects of IB-MECA against stunning were completely blocked by pretreatment with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or the specific protein kinase C inhibitor chelerythrine. In phase II, IB-MECA reduced myocardial infarct size by 61%; infarct size (tetrazolium staining) was 41±4% of the risk region in control animals (n=8) and 16±6% in IB-MECA–treated animals (n=8,P<.01). These results demonstrate that in conscious rabbits the A3adenosine receptor agonist IB-MECA confers a powerful protection against both reversible (stunning) and irreversible (infarction) injury during acute myocardial ischemia and reperfusion by a protein kinase C–mediated pathway, suggesting that selective activation of A3receptors is an effective means of protecting the ischemic myocardium without hemodynamic changes.