EFFECTS OF IN-VITRO AND IN-VIVO EXPOSURE TO DOXORUBICIN (ADRIAMYCIN) ON CAFFEINE-INDUCED CA2-RETICULUM AND CONTRACTILE PROTEIN FUNCTION IN CHEMICALLY-SKINNED RABBIT VENTRICULAR TRABECULAE( RELEASE FROM SARCOPLASMIC)

Doxorubicin is an anthracycline antibiotic that is used widely as a ch emotherapeutic agent. However, the usefulness of this agent is limited due to its cardiotoxic effects. The mechanisms associated with this c ardiotoxicity remain essentially unknown, despite numerous studies des cribing a range of structural and functional abnormalities. The purpos e of the present study was to determine the in vivo and in vitro effec ts 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 initial ly reduces the SR Ca2+-content, but the predominant action to block th e SR Ca2+-release channel increases SR Ca2+-content within 60 min. Sim ilar results are observed with in vivo doxorubicin exposure: it leads to Ca2+-overload. These data are consistent with the view that doxorub icin acts in a similar manner to ryanodine and results in cardiomyopat hy due to Ca2+-overload.