Cardiac Electrophysiologic Effects of 9-Deoxydoxorubicin

Abstract

Electrophysiology of 9-Deoxydoxorubicin.Introduction: The purpose of this investigation was to use standard microelectrode techniques to study the actions of the anthracycline antibiotic, 9-deoxydoxorubicin (9-DOD), on cellular electrophysiologic properties of canine Purkinje fibers and on ouabain-induced ventricular tachycardia (VT) in intact dogs. Methods and Results: 9-DOD, 1-5 μM, suppressed delayed afterdepolarizations and prolonged repolarization and the effective refractory period in Purkinje fibers. It had no effect on maximum diastolic potential, Vmax of phase 0, or action potential overshoot through a 10 μM concentration. Although 9-DOD did augment early afterdepolarizations (EAD) induced by cesium, it did not induce EAD. In six of eight intact dogs with ouabain-induced VT, 9-DOD, 0.32-1.28 mg/m2 IV, brought conversion to sinus or junctional rhythm. In its cellular and intact animal antiarrhythmic actions, 9-DOD is about 50 times more potent than the parent compound, doxorubicin. Like doxorubicin, it is highly selective for delayed afterdepolarization-induced rhythms, suppressing these at concentrations lower than those required to reduce the rate of automatic rhythms. Moreover, it has a greater Class III action than doxorubicin and prolongs the duration of normal and calcium-induced (slow response) action potentials. Hence, this subtle variation on the doxorubicin molecule adds greatly to the antiarrhythmic action of the drug. Conclusions: Although useful as an investigative tool, clinical development of 9-DOD as an antiarrhythmic is not possible because the antitumor activity of the parent compound, which results in lipid peroxidation and cardiotoxicity, persists.