ANTHRACYCLINES ENHANCE TENSION DEVELOPMENT IN CARDIAC MUSCLE BY DIRECT INTERACTION WITH THE CONTRACTILE SYSTEM

Abstract Anthracyclines are highly effective anticancer agents which induce a well described but incompletely understood cardiac toxicity. In this study, a direct action of several anthracyclines on the force generating mechanism of heart muscle preparations is described. To allow discrimination between membrane related effects and a direct action of anthracyclines on the actin–myosin contractile system, both inner and outer membranes of cardiac fibres were permeabilized. All anthracyclines tested in this study [doxorubicin (Dox), epirubicin, daunorubicin and idarubicin] showed positive inotropic actions. Dox and epirubicin, which are considered the most cardiotoxic drugs of the anthracycline family, significantly increased the maximal calcium activated tension by 33% ( n =8, P n =8, P P =n.s.). Other chemotherapeutic drugs (Taxol and 5-FU) had no effect on maximal tension. To elucidate the mechanism behind this Dox-induced increase in maximal tension, calcium sensitivity curves were measured and rigor experiments were performed. A small but significant increase in pCa 50 value (+0.14±0.03, P μ m Dox. Dox acted during the transition to force generating cross-bridges as reflected by the significant increase in rigor tension (12%, P