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AICAR inhibits the Na+/H+ exchanger in rat hearts—possible contribution to cardioprotection

  • Cardiovascular System
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Abstract

AICAR (5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide) is an adenosine analog which improves the recovery of the heart after ischemia. In some tissues AICAR enters cells and stimulates AMP-activated protein kinase (AMPK). We explored the mechanism of cardioprotection in isolated rat hearts. We confirmed that AICAR (0.5 mM) applied 10 min prior to a 30-min period of ischemia and present throughout ischemia and reperfusion caused a substantial improvement in the recovery of developed pressure on reperfusion. However, adenosine (100 μM) produced no improvement, suggesting that the mechanism of action of AICAR was not increased endogenous adenosine production. Measurements of intracellular sodium concentration ([Na+]i) showed that AICAR prevented the rapid rise of [Na+]i, which normally occurs on reperfusion. Inhibitors of the cardiac sodium–hydrogen exchanger (NHE1) also protect the heart from ischemic damage and also prevent the rapid rise of [Na+]i on reperfusion, suggesting that AICAR might cause the inhibition of NHE1. We tested this possibility on isolated rat ventricular myocytes in which the recovery of pHi after NH4Cl exposure provides a measure of NHE1 activity. AICAR (0.5 μmM) inhibited NHE1 activity in response to an acid load by about 80%. To test whether the AICAR-induced inhibition of NHE1 arose through adenosine, we used the adenosine receptor blocker 8-sulfophenyltheophylline (8-SPT) and found that it had no measureable effect. To test whether the AICAR-induced inhibition of NHE1 might occur through the activation of AMPK, we measured the activity of two isoforms of AMPK. Surprisingly, activity was reduced, whereas in many other tissues AICAR increases AMPK activity. Furthermore, this effect of AMPK was blocked by 8-SPT, suggesting that the inhibition of AMPK arose through an adenosine-receptor-related pathway. We conclude that AICAR inhibits NHE1 through an unidentified pathway. This inhibition may make a contribution to the cardioprotective effects of AICAR.

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Acknowledgement

This study was supported by the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Physiology and Institute for Biomedical Research, University of Sydney, Sydney, NSW, 2006, Australia

    Terence R. Moopanar, Xiao-Hui Xiao, Lele Jiang & David G. Allen

  2. St Vincent’s Institute for Medical Research, Fitzroy, Victoria, 3065, Australia

    Zhi-Ping Chen & Bruce E. Kemp

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  1. Terence R. Moopanar
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  2. Xiao-Hui Xiao
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Correspondence to David G. Allen.

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Moopanar, T.R., Xiao, XH., Jiang, L. et al. AICAR inhibits the Na+/H+ exchanger in rat hearts—possible contribution to cardioprotection. Pflugers Arch - Eur J Physiol 453, 147–156 (2006). https://doi.org/10.1007/s00424-006-0124-z

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