Submitted on January 30, 2008
Revised on September 24, 2008
Accepted on October 8, 2008
Timing of Adenosine 2A Receptor Stimulation Relative to Reperfusion has Differential Effects on Infarct Size and Cardiac Function as Assessed in Mice by MRI
Zequan Yang1, Joel M. Linden1, Stuart S Berr, Irving L Kron1, George A Beller2, and Brent A. French2*
1 University of Virginia Health System
2 University of Virginia
* To whom correspondence should be addressed. E-mail: bf4g{at}virginia.edu.
Background: Activation of adenosine 2A receptors (A2AR) prior to reperfusion following coronary artery occlusion reduces infarct size and improves ejection fraction (EF). In this study, we examined the effects of delaying treatment with the A2AR agonist ATL146e (ATL) until 1 hour post-reperfusion. Methods: Infarct size and EF were serially assessed by Gd-DTPA-enhanced MRI in C57BL/6 mice at 1 & 24 hours post-reperfusion. Infarct size was also assessed by TTC staining at 24 hours. Mice were treated with ATL (10 µg/kg, IP) either 2 min before reperfusion (Early-ATL) or 1 hour post-reperfusion (Late-ATL) following the 45 min coronary occlusion. Results: The two methods used to assess infarct size at 24 hours post-reperfusion (MRI & TTC) showed excellent correlation (R=0.96). Risk region, determined at 24 hours post-reperfusion, was comparable between control and ATL-treated groups. Infarct size by MRI at 1 vs. 24 hours post-reperfusion was 25±1 vs. 26±1% of LV mass (mean±SEM) in control mice, 16±2 vs. 17±2% in Early-ATL mice and 24±2 vs. 25±2% in Late-ATL mice (intra-group: p=NS; inter-group: Early-ATL vs. control or Late-ATL, p<0.05). EF was reduced in control mice, but was largely preserved between 1 and 24 hours in both Early-ATL and Late-ATL mice (p<0.05). Conclusions: After coronary occlusion in mice, the extent of myocellular death due to ischemia/reperfusion injury is 95% complete within one hour of reperfusion. Infarct size was significantly reduced by ATL146e when given just prior to reperfusion, but not 1 hour post-reperfusion. Either treatment window helped preserve EF between 1 and 24 hours post-reperfusion.
