Activation of A3Adenosine Receptor Protects Against Doxorubicin-induced Cardiotoxicity

Adenosine exerts a marked protective effect on the heart during cardiac ischemia. This protection is mediated by binding to the A1and A3subtypes of adenosine receptor (A1R and A3R, respectively). The objective of the present study was to investigate whether activation of A1and A3adenosine receptors may reduce doxorubicin-induced damage to cardiomyocytes in culture. Cultured cardiomyocytes from newborn rats were treated with 0.5–5 μ m doxorubicin (DOX) for 18 h and then incubated in drug-free medium for an additional 24 h. This treatment resulted in cell damage and lactate dehydrogenase release, even after low (0.5 μ m) doses of the drug, and increased in a concentration-dependent manner. Activation of A3-subtype but not A1-subtype receptors attenuated doxorubicin-cardiotoxicity after drug treatment for 18 h followed by 24 h incubation in drug-free medium. Modulation of intracellular calcium mediated by activation of A3R, but not by A1R, in cultured myocytes suggested an important pathophysiological significance of this subtype of adenosine receptors. Protection by A3R agonist Cl-IB-MECA (2-chloro-N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide) following DOX treatment is evident in: (1) decreases in intracellular calcium overloading and abnormalities in Ca2+transients; (2) reduction of free-radical generation and lipid peroxidation; (3) attenuation of mitochondrial damage by protection of the terminal link (COX-complex) of respiratory chain; (4) attenuation of the decrease in ATP production and irreversible cardiomyocyte damage. Cardioprotection caused by Cl-IB-MECA was antagonized considerably by the selective A3adenosine receptor antagonist MRS1523.