CELLULAR CA2+ LOADING AND INOTROPIC EFFECTS OF DOXORUBICIN IN ATRIAL MUSCLE PREPARATIONS ISOLATED FROM RAT OR GUINEA-PIG HEARTS

The inotropic effects of doxorubicin were examined under conditions that alter the Ca2+ loading of myocardial cells. Atrial muscle preparations isolated from rat or guinea-pig hearts were used. Cellular Ca2+ loading was altered by changing the temperature, extracellular Ca2+ concentrations or the frequency of electrical stimulation. In guinea-pig heart muscle preparations stimulated at 2 Hz at 30 degrees C in the presence of 1.2 mM CaCl2, 30 mu M doxorubicin caused biphasic (early and late phase) positive inotropic effects. A higher concentration (200 mu M) of doxorubicin caused a transient positive inotropic effect followed by a gradual decrease in developed tension. An increase in CaCl2 concentration from 1.2 to 2.4 mM decreased the positive inotropic effect of 30 mu M doxorubicin and changed the inotropic effect of 200 mu M doxorubicin from positive to negative after a transient increase in developed tension. At 0.5-Hz stimulation or 36 degrees C incubation, 30 or 200 mu M doxorubicin produced remarkable late phase positive inotropic effects. In rat heart muscle preparations, the patterns of the inotropic effects of doxorubicin were similar to those observed with guinea-pig hearts; however, the negative inotropic effect observed at 200 mu M doxorubicin was greater. These results indicate that the early and the late phase positive inotropic effects of doxorubicin have different mechanisms. The pattern of inotropic effects of doxorubicin is affected by conditions that alter cellular Ca2+ loading or the concentration of doxorubicin.