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Cardiovascular Research 2002 53(1):147-155; doi:10.1016/S0008-6363(01)00424-2
© 2002 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Effects of A3 adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart

Glenn J Harrisona, Rachael J Cerniwayb, Jason Pearta, Stuart S Berrc, Kevin Ashtona, Sara Reganb, G Paul Matherneb and John P Headricka,*

aHeart Foundation Research Centre, Griffith University Gold Coast Campus, Southport, QLD Australia
bDepartment of Pediatrics and the Cardiovascular Research Center, University of Virginia Health Sciences Center, Charlottesville, VA, USA
cDepartment of Radiology, University of Virginia Health Sciences Center, Charlottesville, VA, USA

* Corresponding author. Tel.: +61-7-5552-8292; fax: +61-7-5552-8802 j.headrick{at}mailbox.gu.edu.au

Objectives: To characterize effects of A3 adenosine receptor (A3AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Methods: Perfused hearts from wild-type and A3AR gene knock-out (A3AR KO) mice were subjected to 20 min ischemia and 30 min reperfusion. Functional responses were assessed and changes in energy metabolism and cytosolic pH monitored via 31P-NMR spectroscopy. Results: Selective A3AR agonism with 100 nM 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (chloro-IB-MECA) enhanced post-ischemic contractile recovery without altering contracture development in wild-type hearts, an effect unrelated to non-selective activation of A1 or A2 adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A1ARs. Paradoxically, post-ischemic recovery was enhanced by A3AR KO. Developed pressure, +dP/dt, and –dP/dt all recovered to higher levels in A3AR KO (70–80% of pre-ischemia) vs. wild-type hearts (45–50% of pre-ischemia) (P<0.05). Enhanced recovery was unrelated to recoveries of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), energy state ([ATP]/[ADP]. [Pi], {Delta}GATP) or cytosolic pH. Conclusions: Selective A3AR activation is cardioprotective in wild-type hearts and hearts overexpressing A1ARs, yet A3AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to compensatory changes or undefined genotypic differences in A3AR KO vs. wild-type hearts.

KEYWORDS Adenosine; Gene expression; Ischemia; NMR; Receptors; Reperfusion; Stunning


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