Doxorubicin alters Ca(2+) transients but fails to change Ca(2+) sensitivity of contractile proteins

Doxorubicin produced a transient increase and a subsequent decrease in the amplitude of twitch contraction in myocytes isolated from guinea-pig heart and loaded with fura-2. These changes were associated with an increase and a subsequent decrease, respectively, in the amplitude of Ca(2+) transients (peak minus diastolic Ca(2+) concentrations). Doxorubicin increased the diastolic Ca(2+) concentration with a concomitant shortening of the diastolic myocyte length. The time to peak Ca(2+) transients and the time to peak twitch contraction increased in parallel. Doxorubicin failed to affect the Ca(2+) concentration-contraction curve in skinned fibers obtained from atrial muscle. We conclude that biphasic inotropic effects of doxorubicin result from biphasic changes in Ca(2+) transients, and that doxorubicin fails to alter Ca(2+) sensitivity of contractile proteins. These findings are consistent with the hypothesis that doxorubicin enhances Ca(2+) release and impairs Ca(2+) uptake by the sarcoplasmic reticulum.