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Am J Physiol Heart Circ Physiol 284: H519-H527, 2003. First published September 19, 2002; doi:10.1152/ajpheart.00717.2002
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Vol. 284, Issue 2, H519-H527, February 2003

Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine

Jason Peart, Laura Willems, and John P. Headrick

Heart Foundation Research Centre, School of Health Science, Griffith University Gold Coast Campus, Southport, Queensland 4217, Australia

The relative roles of mitochondrial (mito) ATP-sensitive K+ (mitoKATP) channels, protein kinase C (PKC), and adenosine kinase (AK) in adenosine-mediated protection were assessed in Langendorff-perfused mouse hearts subjected to 20-min ischemia and 45-min reperfusion. Control hearts recovered 72 ± 3 mmHg of ventricular pressure (50% preischemia) and released 23 ± 2 IU/g lactate dehydrogenase (LDH). Adenosine (50 µM) during ischemia-reperfusion improved recovery (149 ± 8 mmHg) and reduced LDH efflux (5 ± 1 IU/g). Treatment during ischemia alone was less effective. Treatment with 50 µM diazoxide (mitoKATP opener) during ischemia and reperfusion enhanced recovery and was equally effective during ischemia alone. A3 agonism [100 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide], A1 agonism (N6-cyclohexyladenosine), and AK inhibition (10 µM iodotubercidin) all reduced necrosis to the same extent as adenosine, but less effectively reduced contractile dysfunction. These responses were abolished by 100 µM 5-hydroxydecanoate (5-HD, mitoKATP channel blocker) or 3 µM chelerythrine (PKC inhibitor). However, the protective effects of adenosine during ischemia-reperfusion were resistant to 5-HD and chelerythrine and only abolished when inhibitors were coinfused with iodotubercidin. Data indicate adenosine-mediated protection via A1/A3 adenosine receptors is mitoKATP channel and PKC dependent, with evidence for a downstream location of PKC. Adenosine provides additional and substantial protection via phosphorylation to 5'-AMP, primarily during reperfusion.

ischemia-reperfusion; mitochondrial adenosine 5'-triphosphate-sensitive K+ channel; mouse; protein kinase C


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