Cardiovascular Pharmacology of the Adenosine A1/A2-Receptor Agonist AMP 579: Coronary Hemodynamic and Cardioprotective Effects in the Canine Myocardium

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Abstract
The hemodynamic and cardioprotective properties of the novel adenosine A1/A2 receptor agonist AMP 579 (1S-[1a,2b,3b,4a(S*)]-4-[7-[[1-[(3-chloro-2-thienyl)methyl]propylamino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxy cyclopentanecarboxamide) were studied in two canine models designed to simulate (a) mild single-vessel coronary artery disease, and (b) myocardial ischemia/reperfusion injury. In the first model, a moderate stenosis was placed on the left circumflex coronary artery (LCCA), and the effects of AMP 579 on regional myocardial blood flow were assessed. AMP 579, 10 μg/kg/min, i.v., for 10 min, induced coronary dilation without causing endocardial steal. In the model of ischemia/reperfusion injury (60 min LCCA occlusion/5 h reperfusion), AMP 579, 10 μg/kg/min, i.v., administered for 15 min before ischemia significantly decreased myocardial infarct size. Control infarct size to area at risk (IS/AAR) equaled 34 ± 3% (n = 9); IS/AAR for AMP 579-treated dogs equaled 16 ± 4% (n = 9). Preconditioning (5 min LCCA occlusion + 10 min reperfusion) immediately before the 60-min LCCA occlusion also resulted in a marked decrease in IS/AAR: 9 ± 3% (n = 6). The selective A1 agonist CPA reduced infarct size when administered at 3 μg/kg/min, i.v., for 15 min before LCCA occlusion: IS/AAR = 11 ± 3% (n = 5). Pretreatment of animals with the adenosine-receptor antagonist 8-SPT, 10 mg/kg, i.v., attenuated the myocardial protective effects associated with preconditioning, CPA, and AMP 579, resulting in IS/AAR values of 28 ± 7% (n = 7), 28 ± 4% (n = 8), and 26 ± 3% (n = 8), respectively. The ability of 8-SPT to block the cardioprotective effects suggests that these effects were mediated through an interaction with adenosine receptors. These experimental results indicate that AMP 579 is an effective coronary vasodilator, which also can protect the heart from ischemic injury. Thus AMP 579 has the potential to be useful in cardiovascular therapeutics.