Insights into adenosine A(1) and A(3) receptors function: Cardiotoxicity and cardioprotection

Adenosine (ADO) is a well-known regulator of a variety of physiological fun ctions in the heart. It exerts protective effects in the heart by activatio n of the adenosine receptors (AR). In stress conditions like hypoxia or isc hemia, the concentration of ADO in the extracellular space rises dramatical ly. This elevated amount of adenosine might protect the heart from the hypo xic damage. It has be en also shown that adenosine can significantly decrea se doxorubicin (DOX)-induced heart toxicity. An highly selective Al recepto r (A(1)R) agonist CCPA (2-chloro-N-6-cyclopentyladenosine) and A(3)R agonis ts IB-MECA or CI-IB-MECA (2-chloro-N-6- (3-iodobenzyl)adenosine-5'-N-methyl uronamide) have been shown to protect against hypoxia or DOX. Blocking aden osine receptors with selective A(1) and A(3) receptor antagonists DPCPX (8- cyclopentyl-1-3-dipropylxanthine) for A(1)R and MRS1523 [5-propyl-2-ethyl-4 -propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] for A(3)R abolished the protective effects of adenosine. In addition the mean surviv al time of cardiomyocytes cultures treated with ADO together with DOX was s ignificantly increased. However, at high concentrations A(3)R agonists IB-M ECA, CI-IB-MECA (less than or equal to 10 mu M), or ADO (200 mu M) induced apoptosis. Under these conditions, A(1)R, A(2A)R, and A(2B)R agonists did n ot have any detectable effect on cardiac cells. The selective antagonist MR S1523 protected the cardiocytes if briefly exposed to CI-IB-MECA and only p artially protected from prolonged (48 h) agonist exposure. Apoptosis induce d by CI-IB-MECA was not redox-dependent, since the mitochondrial membrane p otential remained constant until the terminal stages of cell death. Drug De v. Res. 50:324-337, 2000. (C) 2000 Wiley-Liss, Inc.