Activation of A(3)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 A(1)and A(3)subtypes of adenosine receptor (A(1)R and A(3)R, respectively). The objective of the present study was to investigate whether activation of A(1)and A(3)adenosine receptors may reduce doxorubicin-induced damage to cardiomyocytes in culture. Cultured cardiomyocytes from newborn rats were treated with 0.5--5 microm 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 microm) 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 treatment for 18 h followed by 24 h incubation in drug-free medium. Modulation of intracellular calcium mediated by activation of A(3)R, but not by A(1)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 overloading and abnormalities in Ca(2+)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 A(3)adenosine receptor antagonist MRS1523.
Shneyvays
V
V
Gonda (Goldschmied) Medical Diagnostic Research Center, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Mamedova
L
L
Zinman
T
T
Jacobson
K
K
Shainberg
A
A
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism*
C419146:2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; D000903:Antibiotics, Antineoplastic; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; C058394:2-chloro-N(6)cyclopentyladenosine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D003576:Electron Transport Complex IV; D000241:Adenosine; D002118:Calcium; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide