IMPAIRMENT OF THE ACTIN-MYOSIN INTERACTION IN PERMEABILIZED CARDIAC TRABECULAE AFTER CHRONIC DOXORUBICIN TREATMENT

The development of chronic cardiotoxicity in cancer patients treated w ith doxorubicin (DOX) and other anthracycline antineoplastic agents is a major dose-limiting factor, Zn a previous study, we demonstrated an acute effect of anthracyclines on the actin-myosin contractile system , Here, we report chronic effects of DOX both on the contractile syste m and on the function of the sarcoplasmic reticulum (SR), Male Wistar rats were treated with DOX (2 mg/kg, i,v,, once a week for 4 weeks), w hereas control rats received equal volumes of saline, Right ventricula r trabeculae were isolated and skinned by exposure to Triton X-100 or saponin at 1, 2, 4, and 6 weeks after the final DOX administration, Th e maximal tension of trabeculae was similar between DOX-treated and co ntrol animals at 1 week posttreatment, At 2, 4, and 6 weeks posttreatm ent, the maximal tension of trabeculae of DOX-treated animals was sign ificantly decreased by 27, 32, and 37%, respectively (P < 0.01), The r igor tension in trabeculae of DOX-treated animals was similar at 1 wee k posttreatment but significantly decreased at 2, 4, and 6 weeks postt reatment (by 25, 25, and 37%, respectively; P < 0.01), The ratio betwe en rigor tension and maximal tension was significantly higher in DOX-t reated groups as compared to controls (0.39 +/- 0.01 and 0.36 +/- 0.01 ; P < 0.05), Calcium sensitivity of DOX-treated preparations was signi ficantly decreased as compared to controls (5.59 +/- 0.02 and 5.65 +/- 0.01; P < 0.05), whereas no effects were found on the cooperativity o f the regulatory proteins, as measured by the Hill coefficient, The ca lcium release function of the SR, measured by caffeine (25 mM) stimula tion in saponin-skinned trabeculae, was the same in DOX-treated and co ntrol groups at all posttreatment periods, The results of the present study show that long-term DOX treatment causes substantial impairment of the cross-bridge interaction in skinned trabeculae, which is reflec ted by a progressive attenuation of the contractile performance, The f unction of the SR, however, remains unaffected by DOX treatment in our preparations, The direct effect of chronic DOX treatment on the actin -myosin system provides an additional mechanism through which anthracy clines exert their cardiotoxic effects and mag facilitate the developm ent of cardioprotective strategies.