Authors: Yanping Liu Xiulan Yang XiMing Yang Sheree Walker Karina Förster Michael V Cohen Thomas Krieg James M Downey
Publish Date: 2009/08/29
Volume: 105, Issue: 1, Pages: 129-
Abstract
The mixed A1/A2aadenosine agonist AMP579 given at reperfusion is protective in animal models of myocardial infarction Receptorblocking studies have indicated that the protection came from an adenosine receptor AR but neither A1 nor A2aselective agonists could duplicate its protection We recently found that A2bselective agonists given at reperfusion are protective and therefore tested whether AMP579 might also be an A2b agonist We used human embryonic kidney cells overexpressing human A2b receptors as an assay system In these cells A2b receptor occupancy causes phosphorylation of ERK AMP579 induced ERK phosphorylation with an EC50 of 250 nM and this phosphorylation could be blocked by MRS1754 or PSB1115 two highly selective blockers of human A2b receptors We attempted to confirm our A2b hypothesis in a rabbit heart model of ischemia–reperfusion AMP579 500 nM for 1 h starting at reperfusion reduced infarct size in isolated rabbit hearts exposed to 30 min of regional ischemia and 2 h of reperfusion 129 ± 22 infarction of risk zone vs 320 ± 19 in untreated hearts PSB1115 500 nM given for the first 15 min of reperfusion blocked AMP579’s protection 322 ± 31 infarction which is consistent with an A2b mechanism We conclude that AMP579 is a nonselective but potent A2bAR agonist and that its protection against infarction is through that receptor
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