Activation of A₃ adenosine 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 A₁ and A₃ subtypes of adenosine receptor (A₁R and A₃R, respectively). The objective of the present study was to investigate whether activation of A₁ and A₃ adenosine receptors may reduce doxorubicin-induced damage to cardiomyocytes in culture. Cultured cardiomyocytes from newborn rats were treated with 0.5-5 μM 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 μM) 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 A₃ adenosine receptor antagonist MRS1523.