SELECTIVE ACTIVATION OF A(3) ADENOSINE RECEPTORS WITH N-6-(3-IODOBENZYL)ADENOSINE-5'-N-METHYLURONAMIDE PROTECTS AGAINST MYOCARDIAL STUNNINGAND INFARCTION WITHOUT HEMODYNAMIC-CHANGES IN CONSCIOUS RABBITS

To examine the cardioprotective role of A, adenosine receptors during myocardial ischemia/reperfusion injury, we tested the effect of N-b-(3 -iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a potent and sel ective A(3) adenosine receptor agonist, in models of myocardial stunni ng and infarction in chronically instrumented conscious rabbits. In ph ase I (studies of myocardial stunning), rabbits were subjected to sh 4 -minute coronary occlusions, each separated by 4-minute reperfusion pe riods, after which the recovery of systolic wall thickening was measur ed (ultrasonic crystals). In phase II (studies of myocardial infarctio n), 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 mu g/kg) 10 minutes before the first coronar y occlusion. This dose of IB-MECA was determined in pilot studies to h ave no effect on heart rate, arterial blood pressure, or plasma histam ine concentration in rabbits. In phase I, IB-MECA markedly improved th e recovery of wall thickening after the six occlusion/reperfusion cycl es, and this effect was sustained throughout the 5-hour observation pe riod; the total deficit of wall thickening (a measure of the overall s everity of myocardial stunning) was reduced by 68% (control, 129+/-16 arbitrary units, n=7; IB-MECA, 41+/-6 arbitrary units, n=6; P<.01). Th e protective effects of IB-MECA against stunning were completely block ed by pretreatment with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or the specific protein kinase C inhibit or chelerythrine. In phase III IB-MECA reduced myocardial infarct size by 61%; infarct size (tetrazolium staining) was 41+/-4% of the risk r egion 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 Az adenosine receptor agonist IB-MECA confers a powerful protection ag ainst 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 A(3) recept ors is an effective means of protecting the ischemic myocardium withou t hemodynamic changes.