Dexrazoxane pre-treatment protects skinned rat cardiac trabeculae against delayed doxorubicin-induced impairment of crossbridge kinetics

Evert L de Beer, Antonio E Bottone, Maartje C van Rijk, Jolanda van der Velden, Emile E Voest
British Journal of Pharmacology 2002, 135 (7): 1707-14
1. Dexrazoxane (DXR, ICRF-187) has been shown both in animal studies and clinical trials to provide a substantial cardioprotection when co-administered with anthracycline drugs like Doxorubicin (DOX). In a previous study, we showed that chronic DOX treatment in rats is associated with a clear impairment of the crossbridge kinetics and shift in myosin iso-enzymes. 2. The present study was adopted to investigate whether the cardioprotective action of DXR involves preservation of the normal actin-myosin interaction. Rats were treated for 4 weeks with either DOX at a weekly dose of 2 mg kg(-1) (i.v.), or were pre-injected with DXR (40 mg kg(-1), i.v.) at a 20 : 1 dose ratio 30 min prior to the DOX infusion. Rats receiving saline or DXR alone were included in the experiments. Cardiac trabeculae were isolated 4 weeks after the last infusion and were skinned with detergent. 3. Crossbridge turnover kinetics were studied after application of rapid length perturbations of varying amplitudes in Ca(2+)-activated preparations. DXR treatment offered a significant protection against the DOX-induced impairment of the crossbridge kinetics in isolated cardiac trabeculae. Time constants describing transitions between different crossbridge states were restored to normal in both the quick release protocol and the slack-test. DXR prevented the shift from the 'high ATPase' alpha-myosin heavy chain (MHC) isoform towards the 'low-ATPase' beta-MHC isoform in the ventricles. 4. We conclude that pre-administration of DXR in rats greatly reduces the deleterious effects of chronic DOX treatment on the trabecular actin - myosin crossbridge cycle. Preventing direct deleterious effects on the actin - myosin crossbridge system may provide a new target for preventing or reducing DOX-related cardiotoxicity and may enable patients to continue the treatment beyond currently imposed limits.

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