ATL 313, A Selective A(2A) Adenosine Receptor Agonist, Reduces Myocardial Infarct Size in a Rat Ischemia/Reperfusion Model

Objective: The cardioprotective effects of activation of the A(2A) adenosine receptor (A(2A)AR) on ischemia/reperfusion injury in the heart remain controversial. We investigated whether ATL 313, a new selective A2AAR agonist, could reduce myocardial infarct size in a rat ischemia/reperfusion model. Methods: Sprague-Dawley rats were subjected to a 40 minute occlusion of the left coronary artery followed by 3 hours reperfusion. Hemodynamics were monitored during the procedure. The rats were divided into 3 groups: Group 1 received continuous intravenous infusion of saline given 10 min prior to ischemia and throughout reperfusion (n=8); Group 2 received continuous intravenous infusion of 10 ng/kg/min of ATL 313 given 10 min prior to ischemia, and throughout reperfusion (n=8); and group 3 received an intravenous bolus of ATL 313 (900 ng/Kg body weight) given 10 min prior to ischemia, and continuous intravenous infusion of 10 ng/kg/min of ATL 313 started at 20 min after ischemia and throughout reperfusion (n=8). After euthanasia of the rats, the hearts were harvested for the assessment of risk zone and zone of necrosis of the left ventricle. Results: The percentage of risk zone in the left ventricle was similar among group 1 (47 +/- 3.7 %), group 2 (41.5 +/- 4.2 %) and group 3 (42.4 +/- 3.8 %). However, the infarct size, expressed as a percentage of the risk zone, was significantly decreased in group 3 (30.6 +/- 5 %, P=0.01) compared with group 1 (53.8 +/- 6.2 %) and group 2 (52.1 +/- 4.8 %). In group 3, the bolus injection of ATL 313 caused a reduction in blood pressure during the procedure, and decreased heart rate and LV +/- dp/dt before coronary artery occlusion; but increased LV +dp/dt at the end of reperfusion compared to the other 2 groups. Conclusion: A2AAR agonist ATL313 significantly reduced infarct size and improved LV contractility at the end of reperfusion assessed by LV dp/dt at a dose of 900 ng/Kg. The mechanisms for the observed cardioprotection effect of ATL313 remain to be determined.