Activation of A(3) adenosine receptor protects against doxorubicin-inducedcardiotoxicity

Adenosine exerts a marked protective effect on the heart during cardiac isc hemia. This protection is mediated by binding to the A(1) and A(3) subtypes of adenosine receptor (A(1)R and A(3)R, respectively). The objective of th e present study was to investigate whether activation of A(1) and A(3) aden osine receptors may reduce doxorubicin-induced damage to cardiomyocytes in culture, Cultured cardiomyocytes from newborn rats were treated with 0.5-5 muM doxorubicin (DOX) for 18 h and then incubated in drug-free medium for a n additional 24 h. This treatment resulted in cell damage and lactate dehyd rogenase release, even after low (0.5 muM) doses of the drug, and increased in a concentration-dependent manner, Activation of A(3)-subtype but not A( 1)-subtype receptors attenuated doxorubicin-cardiotoxicity after drug treat ment for 18 h followed by 24 h incubation in drug-free medium. Modulation o f intracellular calcium mediated by activation of A(3)R. but not by A(2)R, in cultured myocytes suggested an important pathophysiological significance of this subtype of adenosine receptors. Protection by A(3)R agonist Cl-IB- MECA (2-chloro-N-6-(3-iodobenzyl)adenosine-5'-N-methyluronamide) following DOX treatment is evident in: (1) decreases in intracellular calcium overloa ding and abnormalities in Ca2+ transients; (2) reduction of free-radical ge neration and lipid peroxidation: (3) attenuation of mitochondrial damage by protection of the terminal link (COX-complex) of respiratory chain: (4) at tenuation of the decrease in ATP production and irreversible cardiomyocyte damage. Cardioprotection caused by Cl-IB-MECA was antagonized considerably by the selective A(3) adenosine receptor antagonist MRS1523. (C) 2001 Acade mic Press.