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Am J Physiol Heart Circ Physiol 290: H441-H449, 2006. First published September 9, 2005; doi:10.1152/ajpheart.00589.2005
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Endogenous adenosine protects preconditioned heart during early minutes of reperfusion by activating Akt

Nataliya V. Solenkova,1 Viktoriya Solodushko,1 Michael V. Cohen,1,2 and James M. Downey1

Departments of 1Physiology and 2Medicine, University of South Alabama, Mobile, Alabama

Submitted 3 June 2005 ; accepted in final form 26 August 2005

Ischemic preconditioning (IPC) is thought to protect by activating survival kinases during reperfusion. We tested whether binding of adenosine receptors is also required during reperfusion and, if so, how long these receptors must be populated. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. IPC reduced infarct size from 32.1 ± 4.6% of the risk zone in control hearts to 7.3 ± 3.6%. IPC protection was blocked by a 20-min pulse of the nonselective adenosine receptor blocker 8-(p-sulfophenyl)-theophylline when started either 5 min before or 10 min after the onset of reperfusion but not when started after 30 min of reperfusion. Protection was also blocked by either 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1-selective receptor antagonist, or MRS1754, an A2B-selective antagonist, but not by 8-(3-chlorostyryl)caffeine, an A2A-selective antagonist. Blockade of phosphatidylinositol 3-OH kinase (PI3K) with a 20-min pulse of wortmannin also aborted protection when started either 5 min before or 10 or 30 min after the onset of reperfusion but failed when started after 60 min of reflow. U-0126, an antagonist of MEK1/2 and therefore of ERK1/2, blocked protection when started 5 min before reperfusion but not when started after only 10 min of reperfusion. These studies reveal that A1 and/or A2B receptors initiate the protective signal transduction cascade during reperfusion. Although PI3K activity must continue long into the reperfusion phase, adenosine receptor occupancy is no longer needed by 30 min of reperfusion, and ERK activity is only required in the first few minutes of reperfusion.

adenosine receptors; extracellular signal-regulated kinases 1 and 2; ischemia-reperfusion; ischemic preconditioning; phosphatidylinositol 3-OH kinase



Address for reprint requests and other correspondence: J. M. Downey, Dept. of Physiology, MSB 3074, Univ. of South Alabama, College of Medicine, Mobile, AL 36688 (E-mail: jdowney{at}usouthal.edu)




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