EFFECTS OF DOXORUBICIN, 4'-EPIRUBICIN, AND ANTIOXIDANT ENZYMES ON THECONTRACTILITY OF ISOLATED CARDIOMYOCYTES

The purpose of this study was to determine the acute effects of doxoru bicin and its less cardiotoxic epimer, 4'-epirubicin, on the contracti le response of isolated myocytes, and to assess similarities or differ ences with respect to active oxygen-derived mechanisms. Calcium-tolera nt myocytes from rat ventricle were field stimulated at 1.0 Hz, and th e maximum extent of cell shortening, peak shortening velocity, and pea k relaxation velocity of single twitches were measured by video edge d etection. The contractile responses of the myocytes to the two anthrac yclines were approximately equal. Exposure of the cells to 10 mu M of either anthracycline for 20 min decreased all indices of contractility by 28% (p < 0.05). The active oxygen scavengers, superoxide dismutase and catalase, distinguished the extent to which active oxygen was inv olved in modifying cellular contractility. Paradoxically, superoxide d ismutase done (10 U/mL) decreased contractility by 21%. Nevertheless, superoxide dismutase (10 U/mL) prevented the decreases in contractilit y produced by doxorubicin. In contrast, superoxide dismutase only mild ly (32%) protected against 4'-epirubicin. Catalase (10 U/mL), however, provided substantial (82-93%) protection against both anthracyclines. Hydrogen peroxide therefore, and presumably hydroxyl radicals, were i nvolved in mediating the decreases in contractility from both doxorubi cin and 4'-epirubicin. These results show that an acute exposure to cl inically relevant concentrations of these anthracyclines significantly depresses myocyte contractility and that, in this respect, 4'-epirubi cin is as potentially cardiotoxic as doxorubicin. The results with ant ioxidant enzymes also strongly support a free radical mechanism for th e toxicity of doxorubicin and 4'-epirubicin to cardiomyocytes.