Effect of perphenazine on electrogram of rat isolated heart

Abstract

The aim of this study was to clarify whether administration of antipsychotic perphenazine contributes to the electrophysiological changes of the isolated heart. Fourteen adult male Wistar rats were divided into two groups. Langendorff hearts were perfused with Krebs-Henseleit solution at constant pressure (85 mmHg) and 37 °C (CaCl 2 , 1.2 mM). The electrogram was recorded by touch-free method. The hearts of the first group were exposed to 3.10 -5 M perphenazine, the hearts of the second group to 3.10 -8 M perphenazine. The incidence of arrhythmias and the heart rate and QT interval changes were studied on electrogram during 30 min periods of control, the first perphenazine administration, washout, and the second drug administration.Perphenazine administration significantly prolonged QT (p < 0.001) and QTc (p < 0.05) in group 1. In group 2, QT and QTc prolongation was less pronounced (p < 0.05). A number of arrhythmias appeared, from single premature ventricular complexes to more severe ones in both groups. The heart rate changes were non-significant.We conclude that although phenothiazines are still medicaments of choice in certain psychoses, their cardiovascular side effects should be always taken in consideration. Phenothiazines, Langendorff heart, QT-interval, arrhythmiaCardiovascular system disorders are among the most common causes of morbidity and mortality in developed countries. Many of them are caused by side effects of noncardiovascular drugs whose nature and mode of action vary greatly. A typical example is psychotropic drugs, substances with reported high incidence of cardiovascular side effects, often expressed as various electrophysiological changes. Their representative perphenazine has been used as a psychotropic drug for several decades in therapy of certain psychiatric disorders. It has been reported to induce asymptomatic ECG changes, tachyarrhythmias, self-terminating arrhythmias, or even ventricular fibrillation resulting in the cardiac arrest, especially when overdosed. There are no reports that perphenazine affects electrophysiological properties of the cardiac tissue at therapeutic doses, but, certain ECG changes were observed during its administration in the presence of other potentially arrhythmogenic factors (Magorien et al. 1979).In isolated cardiomyocytes, the effects of perphenazine is functionally related to a variety of ion membrane currents. It reversibly blocks fast sodium current I Na and transient outward potassium current I to . Sensitivity of I Na and I to to perphenazine lies in the micromolar range, whereas the therapeutic plasma concentrations are in the nanomolar range (Bébarová et al. 2009). In isolated rat hearts, perphenazine at concentrations highly above the clinically relevant range caused numerous ECG changes (Langslet 1970).Perphenazine-triggered cardiovascular side effects may be of various severities. Prolonged QT interval is supposed to be a marker for the drug arrhythmogenic capacity. Therefore, L-QT is of major concern; however, there is growing evid...