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© 1997 American Heart Association, Inc.
Articles |
Selective Activation of A3 Adenosine Receptors With N6-(3-Iodobenzyl)Adenosine-5'-N-Methyluronamide Protects Against Myocardial Stunning and Infarction Without Hemodynamic Changes in Conscious Rabbits
From the Division of Cardiology, University of Louisville (Ky).
Correspondence to Roberto Bolli, MD, Division of Cardiology, 550 S Jackson St, ACB 3rd Floor, University of Louisville, Louisville, KY 40292. E-mail r0boll01{at}ulkyvm.louisville.edu
Abstract To examine the cardioprotective role of A3 adenosine receptors during myocardial ischemia/reperfusion injury, we tested the effect of N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a potent and selective A3 adenosine 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 A3 adenosine 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 A3 receptors is an effective means of protecting the ischemic myocardium without hemodynamic changes.
Key Words: ischemia/reperfusion injury • myocardial stunning • myocardial infarction • adenosine receptor • protein kinase C
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