Effects of Doxorubicin on Excitation-Contraction Coupling in Guinea Pig Ventricular Myocardium

Abstract

Abstract Doxorubicin, an anticancer drug, was recently shown to release Ca 2+ from cardiac sarcoplasmic reticulum (SR) by increasing the open probability of Ca 2+ release channels. In the present study, we investigated the effects of doxorubicin on excitation-contraction coupling of guinea pig heart preparations. In papillary muscles contracting at 0.5 Hz, 100 μmol/L doxorubicin produced within 3 hours the following effects: it increased the force of contraction by 269.3±19.8% (n=6) and prolonged the time to peak force by 75.1±8.7% (n=6), relaxation time by 54.7±8.7% (n=6), and action potential duration (APD) at 90% repolarization (APD 90 ) by 38.6±2.9% (n=3). Despite its positive inotropic effect, doxorubicin depressed the early contraction component by increasing the latency between stimulus and the onset of force development. In single myocytes, 100 μmol/L doxorubicin prolonged APD 90 by 62.1% (n=18) and blocked time-dependent delayed rectifier K + current (I K ) by 44% (n=9). Ca 2+ inward current and inward rectifier K + current were not affected by doxorubicin. Ca 2+ transients elicited in myocytes loaded with the fluorescent Ca 2+ indicator fura 2 were strongly suppressed by doxorubicin in their initial rising phase. Thereafter, doxorubicin produced a delayed rise in intracellular Ca 2+ , which reached a late peak exceeding that of the control peak by 52±8% (n=5). The results suggest that doxorubicin decreases Ca 2+ -induced Ca 2+ release from cardiac SR, probably by increasing the SR Ca 2+ leak. On the other hand, prolongation of APD due to inhibition of I K allows more Ca 2+ to enter the cell. After being only temporarily buffered by the SR, Ca 2+ may accumulate in the cytosol as long as depolarization is maintained and lead to a more complete activation of contractile proteins.