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

Anthracyclines are highly effective anticancer agents which induce a w ell described but incompletely understood cardiac toxicity. In this st udy, a direct action of several anthracyclines on the force generating mechanism of heart muscle preparations is described. To allow discrim ination between membrane related effects and a direct action of anthra cyclines on the actin-myosin contractile system, both inner and outer membranes of cardiac fibres were permeabilized. All anthracyclines tes ted in this study [doxorubicin (Dox), epirubicin, daunorubicin and ida rubicin] 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 < 0.01) and by 26% (n = 8, P < 0.01) respectively. Daunorubi cin and idarubicin increased the maximal tension by 12% and 9% respect ively (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 < 0.05) was observed onl y after incubation with 20 mu M Dox. Dox acted during the transition t o force generating cross-bridges as reflected by the significant incre ase in rigor tension (12%, P < 0.05) after preincubation of cardiac fi bres with Dox. Cycling of cross-bridges is a prerequisite for Dox to i ncrease tension because no effect on tension was seen after Dox was ad ded to fibres in an established rigor. In summary, anthracyclines incr eased the maximal tension in cardiac muscle fibres by direct interacti on with the actin-myosin cross-bridges. Changes in calcium sensitivity are unlikely to contribute to the observed increase in maximal tensio n. The rise in tension as is seen in this experimental set-up may cont ribute to destruction of the contractile machinery of cardiac muscle. In agreement with this hypothesis is the observation that the more car diotoxic anthracyclines induced the largest increase in maximal tensio n of the cardiac fibres. (C) 1997 Academic Press Limited.