Effects of In Vitro and In Vivo Exposure to Doxorubicin (Adriamycin) on Caffeine-Induced Ca²⁺ Release from Sarcoplasmic Reticulum and Contractile Protein Function in ‘Chemically-Skinned’ Rabbit Ventricular Trabeculae

Abstract

Doxorubicin is an anthracycline antibiotic that is used widely as a chemotherapeutic agent. However, the usefulness of this agent is limited due to its cardiotoxic effects. The mechanisms associated with this cardiotoxicity remain essentially unknown, despite numerous studies describing a range of structural and functional abnormalities. The purpose of the present study was to determine the in vivo and in vitro effects of doxorubicin exposure on sarcoplasmic reticulum (SR) Ca²⁺-content and contractile protein function. The Ca²⁺-content of SR is shown to have a biphasic response to in vivo and in vitro doxorubicin exposure that is time- and dose-dependent. In vitro doxorubicin exposure initially reduces the SR Ca²⁺-content, but the predominant action to block the SR Ca²⁺-release channel increases SR Ca²⁺-content within 60 min. Similar results are observed with in vivo doxorubicin exposure: it leads to Ca²⁺-overload. These data are consistent with the view that doxorubicin acts in a similar manner to ryanodine and results in cardiomyopathy due to Ca²⁺-overload.