Key result
A3AR gene knock-out enhanced post-ischemic recovery of developed pressure and dP/dt to 70-80% of pre-ischemia compared to 45-50% in wild-type hearts (P<0.05).
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Both selective A(3)AR activation and A(3)AR gene deletion paradoxically enhance post-ischemic contractile recovery in mouse hearts, suggesting complex or compensatory mechanisms in ischemia tolerance.
OBJECTIVES: To characterize effects of A(3) 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 A(3)AR 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 31P-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-selective activation of A(1) or A(2) adenosine receptors. Chloro-IB-MECA also improved recovery in hearts overexpressing A(1)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] x [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 A(3)AR 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 A(3)AR KO vs. wild-type hearts.
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Glenn Harrison (2002) studied Ischemia-reperfusion. A3 adenosine receptor activation and gene knock-out vs. Wild-type hearts was evaluated on Post-ischemic contractile recovery (Developed pressure, +dP/dt, and -dP/dt) (p=<0.05). A3AR gene knock-out enhanced post-ischemic recovery of developed pressure and dP/dt to 70-80% of pre-ischemia compared to 45-50% in wild-type hearts (P<0.05).
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