Insights into adenosine A₁ and A₃ receptors function: Cardiotoxicity and cardioprotection

Adenosine (ADO) is a well-known regulator of a variety of physiological functions in the heart. It exerts protective effects in the heart by activation of the adenosine receptors (AR). In stress conditions like hypoxia or ischemia, the concentration of ADO in the extracellular space rises dramatically. This elevated amount of adenosine might protect the heart from the hypoxic damage. It has been also shown that adenosine can significantly decrease doxorubicin (DOX)-induced heart toxicity. An highly selective A₁ receptor (A₁R) agonist CCPA (2-chloro-N⁶-cyclopentyladenosine) and A₃R agonists IB-MECA or CI-IB-MECA (2-chloro-N⁶-(3-iodobenzyl)adenosine-5'-N-methyluronamide) have been shown to protect against hypoxia or DOX. Blocking adenosine receptors with selective A₁ and A₃ receptor antagonists DPCPX (8-cyclopentyl-1-3-dipropylxanthine) for A₁R and MRS1523 [5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carbo xylate] for A₃R abolished the protective effects of adenosine. In addition the mean survival time of cardiomyocytes cultures treated with ADO together with DOX was significantly increased. However, at high concentrations A₃R agonists IB-MECA, CI-IB-MECA (≥10 μM), or ADO (200 μM) induced apoptosis. Under these conditions, A₁R, A(2A)R, and A(2B)R agonists did not have any detectable effect on cardiac cells. The selective antagonist MRS1523 protected the cardiocytes if briefly exposed to CI-IB-MECA and only partially protected from prolonged (48 h) agonist exposure. Apoptosis induced by CI-IB-MECA was not redox-dependent, since the mitochondrial membrane potential remained constant until the terminal stages of cell death. (C) 2000 Wiley-Liss, Inc.