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Limitation of Myocardial Reperfusion Injury by AMP579, an Adenosine A1/A2A Receptor Agonist: Role of A2A Receptor and Erk1/2

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Abstract

AMP579, an adenosine A1/A2A receptor agonist, protects against myocardial infarction when given at the onset of reperfusion. However, it is unclear which receptor subtype mediates its protective actions. Anaesthetised rabbits were subjected to 30 min regional ischaemia/180 min reperfusion in vivo. AMP579 (30 μg kg−1 bolus + 3 μg kg−1 min−1 for 70 min) reduced heart rate and mean arterial blood pressure with the latter being abolished with ZM241385 (a selective A2A receptor antagonist). AMP579 reduced infarct size from 46.0 ± 3.4% in vehicle control hearts to 29.6 ± 3.5% (P < 0.05), an effect that was attenuated in the presence of ZM241385, in a dose-dependent manner (38.2 ± 4.9% at 1 mg kg−1; 45.1 ± 4.2% at 2.5 mg kg−1). CGS21680 (a selective A2A agonist, 30 μg kg−1 bolus + 3 μg kg−1 min−1 for 70 min), or CCPA (a selective A1 agonist, 50 μg kg−1), alone or in combination showed no protection (44.7 ± 5.8%; 39.8 ± 2.8%; 39.1 ± 5.1%, respectively) when given at the commencement of reperfusion. Furthermore, we hypothesized that the prosurvival MEK1/2-Erk1/2 pathway was involved in the downstream mechanism of cardioprotection afforded by AMP579. PD098059, an inhibitor of MEK1/2 showed a dose dependent attenuation on infarct size (39.9 ± 5.3% at 2 mg kg−1; 48.3 ± 5.7% at 4 mg kg−1, iv, respectively). PD098059 alone had no effect on infarct size (44.7 ± 5.8%, 2 mg kg−1, iv). We conclude that AMP579 limits myocardial infarction by activating A2A adenosine receptors that might be linked to further downstream kinases such as Erk1/2.

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Authors and Affiliations

  1. The Hatter Institute, UCL Hospitals and Medical School, London, UK

    Adrienn Kis

  2. The Royal Veterinary College, London, UK

    Gary F. Baxter

  3. The Hatter Institute, UCL Hospitals and Medical School, London, UK

    Derek M. Yellon

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Kis, A., Baxter, G.F. & Yellon, D.M. Limitation of Myocardial Reperfusion Injury by AMP579, an Adenosine A1/A2A Receptor Agonist: Role of A2A Receptor and Erk1/2. Cardiovasc Drugs Ther 17, 415–425 (2003). https://doi.org/10.1023/B:CARD.0000015856.02691.fa

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