Calcium Overload or Underload? The Effects of Doxorubicin on the Calcium Dynamics in Guinea Pig Hearts

The severe doxorubicin (DOXO) side effect of cardiomyopathy limits it clinical application as an effective anticancer drug. Although Ca²⁺ overload was postulated as one of the mechanisms for this toxicity, its role was, however, disputable in terms of the contractile dysfunction. In this work, the dynamics of the intracellular Ca²⁺ signal were optically mapped in a Langendorff guinea pig heart. We found that DOXO treatment: (1) Delayed the activation of the Ca²⁺ signal. With the reference time set at the peak of the action potential (AP), the time lag between the peak of the Ca²⁺ signal and AP (Ca-AP-Lag) was significantly prolonged. (2) Slowed down the intracellular Ca²⁺ releasing and sequestering process. Both the maximum rising (MRV) and falling (MFV) velocity of the Ca²⁺ signal were decreased. (3) Shortened the duration of the Ca²⁺ signal in one cycle of Ca²⁺ oscillation. The duration of the Ca²⁺ signal at 50% amplitude (CaD50) was significantly shortened. These results suggested a reduced level of intracellular Ca²⁺ after DOXO treatment. Furthermore, we found that the effect of tachypacing was similar to that of DOXO, and, interestingly, DOXO exerted contradictory effects on the tachypaced hearts: it shortened the Ca-AP-Lag, accelerated the MRV and MFV, and prolonged the CaD50. We, therefore, concluded that DOXO had a different effect on intracellular Ca²⁺. It caused Ca²⁺ underload in hearts with sinus rhythm; this might relate to the contractile dysfunction in DOXO cardiomyopathy. It led to Ca²⁺ overload in the tachypaced hearts, which might contribute to the Ca²⁺-overload-related toxicity.