Acute doxorubicin cardiotoxicity: Functional, metabolic, and morphologic alterations in the isolated, perfused rat heart

The acute effects of doxorubicin on coronary perfusion and left ventricular pressures and intracellular phosphate metabolite levels, the latter obtained by ³¹P nuclear magnetic resonance, were measured simultaneously in isolated, isovolumic rat hearts (Langendorf preparation) perfused at constant flow. Nineteen experimental hearts were perfused for 70 min with oxygenated HEPES-buffered solution containing 6 mg/L doxorubicin. These were compared with 18 control hearts (C), perfused under identical conditions but without doxorubicin, by repeated measures analysis of variance. In the experimental group, coronary perfusion pressure steadily increased to 226.3 ± 13.8% (mean ± SEM) of initial levels (p < 0.0001 vs. C). Because flow was constant, the increase in coronary perfusion pressure in experimental hearts indicates a greater than twofold increase in coronary resistance. Intracellular phosphocreatine and ATP decreased to 80.3 ± 3.9% (p < 0.005 vs. C) and 82.1 ± 6.4% (p < 0.05 vs. C), whereas inorganic phosphate increased to 149.7 ± 19.1% (p < 0.05 vs. C) of initial levels, respectively. Accompanying these changes, diastolic pressure steadily increased to 521.7 ± 91.4% of initial levels (p < 0.0001 vs. C). Developed pressure initially increased to 107.1 ± 4.5% at 30 min, and thereafter decreased to 76.2 ± 6.3% at 70 min (p < 0.05 vs. C). Typical structural alterations in myocyte nuclei were noted. Cellular calcium was not increased in doxorubicin-exposed hearts. Thus, acute doxorubicin cardiotoxicity is characterized by an increase in coronary resistance and is closely correlated with alterations in ventricular function and a decrease in intracellular high-energy phosphate content. These findings suggest that chronic doxorubicin cardiomyopathy may result, in part, from acute hemodynamic and metabolic effects accompanying each drug exposure.