Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibres

Objective: This work was designed to determine whether the doxorubicin-induced changes in heart electrical activity are due to increased free radical production and membrane oxidative damage. Methods: Four groups of rats (60 days old) were used. One group was untreated and the others were treated with doxorubicin (DXR), DXR and vitamin E, and DXR and N-acetylcysteine (NAC), respectively. DXR was administered by single i.p. injection (20 mg/kg b.wt.). Vitamin E was administered by ten daily i.m. injections (100 mg/kg), while NAG (100 mg/kg) was injected i.p. 1 h before and 7 h after DXR. The effectiveness of the drug in inducing oxidative stress in different tissues and of the antioxidants in offering protection was established by determining antioxidant capacity, susceptibility to oxidative stress, and Lipid peroxidation in heart, Liver, and blood. The drug effect on heart electrical activity was determined by measuring the heart rate in vivo and action potential configuration in papillary muscle fibres in vitro. Heart Lipid peroxidation and electrical activity were also examined in both vitamin E and NAC-treated rats. Results: DXR treatment decreased antioxidant capacity and increased lipid peroxidation and susceptibility to oxidative stress in heart and blood, but not in Liver. DXR administration to rats treated with antioxidants did not produce significant changes in antioxidant capacity and susceptibility to oxidative stress even in heart and blood. Furthermore, lipid peroxidation in heart and liver from DXR- and vitamin E-treated rats, and in liver from DXR- and NAG-treated rats was lower than in untreated controls. DXR treatment also increased the duration of ventricular action potentials in untreated rats, but not in antioxidant-treated rats. The treatment of control animals with the antioxidants affected lipid peroxidation, but not cardiac electrical activity. Conclusions: The protection offered by antioxidants against electrophysiological alterations indicates a free radical involvement in such alterations. In contrast, although electrical modifications are associated with increased peroxidative processes and both are prevented by the antioxidants, it is not yet clear whether a causative relationship exists between them. (C) 1998 Elsevier Science B.V. All rights reserved.