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Am J Physiol Heart Circ Physiol (December 9, 2004). doi:10.1152/ajpheart.00362.2004
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Submitted on April 14, 2004
Accepted on December 1, 2004

Reduction of infarct size and post-ischemic inflammation from a highly selective adenosine A2A receptor agonist, ATL-146e, in reperfused canine myocardium

David K Glover1*, Laurent M Riou1, Mirta Ruiz1, Gail W Sullivan1, Joel Linden1, Jayson M Rieger2, Timothy L Macdonald2, Denny D Watson1, and George A Beller1

1 Internal Medicine/Cardiology, University of Virginia, Charlottesville, VA, USA
2 Chemistry, University of Virginia, Charlottesville, VA, USA

* To whom correspondence should be addressed. E-mail: dglover{at}virginia.edu.

Adenosine and adenosine A2A receptor agonists have been shown to limit myocardial infarct size when given at vasodilatory doses during reperfusion. This beneficial effect is thought to be due, in part, to stimulation of adenosine A2A receptors on inflammatory cells. The specific aims of this study were to determine whether the anti-inflammatory and cardioprotective properties of a novel adenosine A2A receptor agonist, ATL-146e (ATL) alone, or in combination with the PDE-IV inhibitor rolipram, would occur using very low, nonvasodilating doses. In a canine model of reperfused myocardial infarction, low dose ATL given alone reduced infarct size by 45% (p<0.05 vs control). When ATL was combined with a very low dose of rolipram (0.001 µg/kg/min), a marked reduction in P-selectin expression and neutrophil infiltration ({downarrow}51%, p<0.001 vs control) was seen and the infarct size reduction ({downarrow}58%, p<0.01 vs control) was greater than observed with ATL (({downarrow}45%; p<0.05) or rolipram (({downarrow}33%; p<0.05) alone. In conclusion, a low, nonvasodilating dose of ATL, a highly selective adenosine A2A receptor agonist, reduced infarct size after reperfusion. Furthermore, combining ATL and the PDE IV inhibitor rolipram reduced infarct size even more than either agent alone. Such combination therapy may be beneficial clinically by potentiating cardioprotection following coronary reperfusion at doses far below those producing vasodilatation or side effects.




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