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.