Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI.
The activation of adenosine 2A receptors before 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 adenosine 2A receptor agonist ATL146e (ATL) until 1 h postreperfusion. The infarct size and EF were serially assessed by gadolinium-diethylenetriaminepentaacetic acid-enhanced MRI in C57BL/6 mice at 1 and 24 h postreperfusion. The infarct size was also assessed by 2,3,5-triphenyltetrazolium chloride staining at 24 h. Mice were treated with ATL (10 microg/kg ip) either 2 min before reperfusion (early ATL) or 1 h postreperfusion (late ATL) following the 45-min coronary occlusion. The two methods used to assess infarct size at 24 h postreperfusion (MRI and 2,3,5-triphenyltetrazolium chloride) showed an excellent correlation (R=0.96). The risk region, determined at 24 h postreperfusion, was comparable between the control and ATL-treated groups. The infarct size by MRI at 1 versus 24 h postreperfusion was 25+/-1 vs. 26+/-1% of left ventricular mass (means+/-SE) in control mice, 16+/-2 versus 17+/-2% in early-ATL mice, and 24+/-2 versus 25+/-2% in late-ATL mice (intragroup, P=not significant; and intergroup, early ATL vs. control or late ATL, P<0.05). EF was reduced in control mice but was largely preserved between 1 and 24 h in both early-ATL and late-ATL mice (P<0.05). In conclusion, after coronary occlusion in mice, the extent of myocellular death due to ischemia-reperfusion injury is 95% complete within 1 h of reperfusion. The infarct size was significantly reduced by ATL when given just before reperfusion, but not 1 h postreperfusion. Either treatment window helped preserve the EF between 1 and 24 h postreperfusion.
Department of Surgery, University of Virginia, MR5 Bldg. Rm. 1219, Box 800759, 415 Lane Rd., Charlottesville, VA 22903, USA.
Zequan
Z
Yang
Joel
J
Linden
Stuart S
SS
Berr
Irving L
IL
Kron
George A
GA
Beller
Brent A
BA
French
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D004396:Coloring Agents; D003287:Contrast Media; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D019786:Gadolinium DTPA; D006339:Heart Rate / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011687:Purines / Q000008:administration & dosage*; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D013778:Tetrazolium Salts; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D002316:Cardiotonic Agents; D004396:Coloring Agents; D003287:Contrast Media; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D043683:Receptors, Adenosine A2; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D019786:Gadolinium DTPA