Doxorubicin: Mechanism of cardiodepressant actions in guinea pigs

The clinical use of doxorubicin is frequently limited by its depressant effects on cardiac muscle, presumably resulting from alterations of Ca²⁺ movements. Therefore, the modification of various Ca²⁺ pools that contribute to cardiac contraction was assessed from developed tension observed in isolated atrial muscle preparations incubated at 31°C and stimulated at 0.5 Hz. Doxorubicin (100 or 200 μM) caused a transient positive inotropic effect followed by a sustained and marked negative effect, prolonged the time to peak twitch tension and decreased the rate of relaxation. Potentiated postrest contraction was depressed to a greater extent compared with contractions observed at 0.5 Hz stimulation. After a 3-hr exposure to doxorubicin, effects of ryanodine to depress developed tension observed in preparations stimulated at 0.5 Hz were markedly smaller, indicating a reduced contribution of the ryanodine-sensitive Ca²⁺ pool to contractile activation. In atrial muscle preparations obtained from guinea pigs treated for 10 days with doxorubicin (total dose 5 mg/kg iv), similar results as above were observed. Moreover, a longer quiescent period was required to attain the maximal postrest contraction. These results indicate that an acute or subacute exposure to doxorubicin impairs the function of the cardiac sarcoplasmic reticulum.