Doxorubicin impairs crossbridge turnover kinetics in skinned cardiac trabeculae after acute and chronic treatment

Evert L. De Beer*, Antonio E. Bottone, Jolanda Van Der Velden, Emile E. Voest

*Corresponding author for this work

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Crossbridge dynamics underlying the acute and chronic inotropic effects of doxorubicin (Dox) were studied by application of releasing length steps (amplitude, 0.5-10%) to skinned cardiac trabeculae. Acute incubation of trabeculae with 20 μM Dox for 30 min resulted in a decrease of the velocity of unloaded shortening (V(o), from 9.3 ± 1.1 to 7.7 ± 0.7 μm/s, P < .05) and in an increase of the rate of force redevelopment (τ(r) from 56 ± 4 to 65 ± 3 ms, P < .05) in response to step amplitudes ranging from 5 to 10%. In contrast, chronic Dox treatment in rats (2 mg/kg/week for 4 weeks) significantly impaired trabecular crossbridge dynamics after step releases of 0.5%. This was reflected by an increase of all time constants describing tension recovery: τ1, from 10 ± 1 to 14 ± 1 ms; τ2 from 65 ± 6 to 82 ± 6 ms; τ3, from 92 ± 7 to 293 ± 67 ms; P < .05. In addition, V(o) was decreased (from 8.6 ± 0.6 to 6.8 ± 0.3 μm/s, P < .05) and τ(r) was increased (from 67 ± 4 to 89 ± 3 ms; P < .05) in the slack-test. We found that chronic Dox treatment resulted in a shift from the 'high ATPase' α- myosin heavy chain (MHC) isoform toward the 'low-ATPase' β-MHC isoform in the ventricles (control: α-MHC 79 ± 2% and β-MHC 21 ± 2%; Dox, treated: α-MHC 53 ± 2% and β-MHC 47 ± 2%; P < .05). The present results show that acute Dox incubation affects the detachment rate of crossbridges, which leads to a delayed relaxation and an arrest of crossbridges in strongly bound states. In contrast, chronic Dox treatment leads to an impairment of both the attachment and detachment rates in the crossbridge cycle, which may be explained by an altered MHC isoform composition in ventricular myocardium. Interfering with Dox-induced alterations of crossbridge kinetics may provide a new strategy to prevent Dox-associated cardiotoxicity.

Original languageEnglish
Pages (from-to)1152-1157
Number of pages6
JournalMolecular Pharmacology
Issue number6
Publication statusPublished - 26 Jun 2000

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