Abstract
Daunorubicin (DNR) is an anti-cancer drug limited by fatal cardiac complications in which rhythm disturbances precede ventricular failure. We have used isolated working rat hearts to study the mechanism of myocardial DNR-induced work failure. DNR perfused at 19 to 38 μmol/l severely disturbed the aortic pressure profile and produced complete contractile failure within 90 min. It rapidly accumulates in isolated rat hearts to 2 μmol/g dry weight. Cardiac mechanical activity is not restored after removal of DNR from the perfusate. Nor is bound DNR eluted by DNR-free perfusion. DNR produces irreversible cardiac arrest with paradoxical conservation of ATP and creatine phosphate. Thus, DNR-induced work failure is associated with an inability to use ATP. Routes of ATP production appear functional. Normal production of lactate during perfusion indicates conservation of oxidative metabolism. At the end of the experimental period DNR-inhibited cells contain more lactate than controls. Myocardial fluid distribution is disturbed only at high perfusion concentrations of DNR. Total protection against DNR-induced myocardial work failure is provided by prior digitalization of the donor rats.
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