title: Electrocardiographic and transmembrane potential effects of 5-iminodaunorubicin in the rat.
abstract: 5-Iminodaunorubicin (5-ID) is a quinone-modified anthracycline that retains antitumor activity but lacks the usual redox-cycling effects of quinoid agents. As a test for decreased cardiotoxicity, we have compared the dose- and time-dependent effects of multiple doses of 5-ID and doxorubicin (DXR) on the rat electrocardiogram (ECG) using a signal-averaging process and have related the ECG changes induced by 5-ID to transmembrane potential alterations in myocardial preparations isolated from treated rats. 5-ID was studied at dose levels of 16, 4, and 1 mg/kg, while DXR was given at 4, 2, and 1 mg/kg. At the high- and medium-dose levels, both agents produced widening of the QRS complex, increased R- and S-wave voltage, and prolonged the Q alpha T interval. The QRS widening reversed in all surviving rats, whereas Q alpha T prolongation was reversible with 5-ID but irreversible with DXR. At the lowest dose, 5-ID had no effect on the ECG until the end of treatment. Microelectrode studies on single cells showed that QRS widening occurring with 5-ID treatment was related to a decrease in the maximum rate of depolarization (Vmax) and that Q alpha T prolongation resulted from an increase in the duration of the action potential. Electron microscopic examination showed that although these toxic changes could not be related to specific morphological alterations, in general, the more severe the electrophysiological change, the greater the ultrastructural change. The most consistent ECG change was Q alpha T prolongation. Using this parameter as a marker for cardiotoxicity, 5-ID was about 4 to 5 times less cardiotoxic than was DXR at high- and medium-dose levels and was noncardiotoxic (i.e., below a threshold for cardiotoxicity) compared with DXR at 1 mg/kg over 20 (DXR) to 35 (5-ID) treatments. The decrease in cardiotoxicity relative to DXR is consistent with previous findings that quinone redox cycling is suppressed in 5-ID. However, the ECG and transmembrane potential effects that we identified at elevated doses of 5-ID can be associated with toxic changes in cardiac cell membranes. Therefore, membrane changes other than those due to quinone redox cycling and, presumably, lipid peroxidation must underlie the electrophysiological changes and structural modifications observed with 5-ID in this study. We believe that 5-ID is a useful mechanistic probe in anthracycline cardiotoxicity studies as well as being of obvious interest for clinical trials.
mesh_terms: D000818:Animals; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000633:toxicity; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D008854:Microscopy, Electron; D009206:Myocardium / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: C018979:5-iminodaunorubicin; D003630:Daunorubicin