Doxorubicin alters Ca2+ transients but fails to change Ca2+ 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 Ca2+ transients (peak minus diastolic Ca2+ concentrations). Doxorubicin increased the diastolic Ca2+ concentration with a concomitant shortening of the diastolic myocyte length. The time to peak Ca2+ transients and the time to peak twitch contraction increased in parallel, Doxorubicin failed to affect the Ca2+ concentration-contraction curve in skinned fibers obtained from atrial muscle. We conclude that biphasic inotropic effects of doxorubicin result from biphasic changes in Ca2+ transients, and that doxorubicin fails to alter Ca2+ sensitivity of contractile proteins. These findings are consistent with the hypothesis that doxorubicin enhances Ca2+ release and impairs Ca2+ uptake by the sarcoplasmic reticulum.