Thioridazine-5-sulfoxide cardiotoxicity in the isolated, perfused rat heart

The potential cardiotoxicity of a racemic mixture of thioridazine-5-sulfoxide, an oxidative metabolite of thioridazine, was studied in the isolated, perfused rat heart. Thioridazine-5-sulfoxide (ring sulfoxide) was prepared by a new method in which a racemic mixture of the two diastereoisomeric forms of the compound was formed. Hearts from male Sprague-Dawley rats were perfused using a modified Langendorff preparation. Quinidine (31 microM) served as a positive control for the measurements of the electrocardiogram (ECG) and the heart rate. Thioridazine (13 microM) perfusion resulted in a variable heart rate and elevated S-T segment. Perfusate concentrations of the ring sulfoxide as low as 12 microM increased P-R and Q-T intervals, produced delays in A-V and ventricular conduction, premature ventricular contractions and ultimately A-V block. These findings suggest that thioridazine cardiotoxicity may be due in part to the actions of thioridazine ring sulfoxide.