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

Objectives: To characterize effects of A, adenosine receptor (A(3)AR) activation and gene knock-out on responses to ischemia-reperfusion in mouse heart. Methods: Perfused hearts from wild-type and AA(3)R gene knock-out (A(3)AR 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 P-31-NMR spectroscopy. Results: Selective A(3)AR agonism with 100 nM 2-chloro-N-6-(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-sciective activation of A, or A, adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A(3)ARs. Paradoxically, post-ischemic recovery was enhanced by A(3)AR KO. Developed pressure, +dP/dt, and -dP/dt all recovered to higher levels in A(3)AR 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 (P-i), energy state ([ATP]/[ADP]. [P-i], DeltaG(ATP)) or cytosolic pH. Conclusions: Selective A(3)AR activation is cardioprotective in wild-type hearts and hearts overexpressing A(1)ARs, yet A3AR gene deletion generates an ischemia-tolerant phenotype without altering energy metabolism or pH. This may be due to to compensatory changes or undefined genotypic differences in A(3)AR KO vs. wild-type hearts. (C) 2002 Elsevier Science B.V. All rights reserved.