Cardioprotection by adenosine A_2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia

Abstract

GA. Cardioprotection by adenosine A2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Am J Physiol Heart Circ Physiol 292: H3164 -H3171, 2007. First published February 16, 2007; doi:10.1152/ajpheart.00743.2005.-We sought to determine whether administration of a very low, nonvasodilating dose of a highly selective adenosine A2A receptor agonist or ATL-146e) would be cardioprotective in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Twenty-four anesthetized open-chest dogs underwent either 4 (n ϭ 12) or 10 cycles (n ϭ 12) of 5-min left anterior descending coronary artery (LAD) occlusions interspersed by 5 or 10 min of reperfusion. Left ventricular thickening was measured from baseline through 180 min after the last occlusion-reperfusion cycle. Regional flow was measured with microspheres. In 12 of 24 dogs, A2A receptor agonist was infused intravenously beginning 2 min prior to the first occlusion and continuing throughout reperfusion at a dose below that which produces vasodilatation (0.01 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Myocardial flow was similar between control and A2A receptor agonist-treated animals, confirming the absence of A2 receptor agonist-induced vasodilatation. During occlusion, there was severe dyskinesis with marked LAD zone thinning in all animals. After 180 min of reperfusion following the last cycle, significantly greater recovery of LAD zone thickening was observed in A2A receptor agonist-treated vs. control animals in both the 4-cycle (91 Ϯ 7 vs. 56 Ϯ 12%, respectively; P Ͻ 0.05) and the 10-cycle (65 Ϯ 9 vs. 8 Ϯ 16%, respectively; P Ͻ 0.05) occlusion groups. The striking amount of functional recovery observed with administration of low, nonvasodilating doses of adenosine A2A agonist ATL-193 or ATL-146e supports their further evaluation for the attenuation of postischemic stunning in the clinical setting. left ventricular dysfunction; demand ischemia; reperfusion injury MYOCARDIAL STUNNING IS A FORM of reversible reperfusion injury characterized by prolonged depression of left ventricular (LV) contractile function in viable myocardium despite restoration of normal or near-normal resting blood flow (7,28). Clinical studies have demonstrated that many patients with coronary artery disease experience repetitive episodes of myocardial ischemia in the same vascular territory while going about their daily activities (14). Echocardiographic and radionuclide studies have demonstrated that severe postischemic contractile dysfunction, or myocardial stunning, occurs following periods of exercise or pharmacological stress-induced ischemia (15,30,34). Importantly, animal studies have shown that frequent episodes of myocardial ischemia that occur in close temporal proximity have a cumulative effect on the deterioration of myocardial contractility, and some (29, 33, 52) have proposed that repetitive myocardial stunning following demand ischemia is the mechanism for myocardial hibernation. In addition, this phenomenon has ...

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