Effect of antipsychotic drug perphenazine on fast sodium current and transient outward potassium current in rat ventricular myocytes

摘要

Antipsychotic drug perphenazine belongs to the phenothiazine group commonly reported to induce ECG changes and tachyarrhythmias. Data about its effect on ionic membrane currents in cardiomyocytes are missing. We analyzed the effect of perphenazine (0.1–100 µM) on fast sodium current I _Na and transient outward potassium current I _to in enzymatically isolated rat right ventricular myocytes by the whole-cell patch-clamp technique at room temperature. Perphenazine reversibly blocked I _Na (reducing its amplitude; IC₅₀ = 1.24 ± 0.10 µM) and I _to (accelerating its apparent inactivation with a slight decrease of its amplitude; IC₅₀ = 38.2 ± 3.5 µM, evaluated from changes of the time integral). The fast time constant of I _to inactivation was significantly decreased in a concentration-dependent manner (IC₅₀ = 30.0 ± 6.6 µM). Both blocks were use and frequency dependent at 3.3 Hz. We conclude that perphenazine causes concentration-, use-, and frequency-dependent block of I _Na and I _to . Computer simulations suggest that perphenazine interacts preferentially with I _Na channels in inactivated states and with I _to channels in both open and open-inactivated states. Keywords Perphenazine - Phenothiazine - Sodium current - Transient outward potassium current - Rat ventricular myocytes - Mathematical simulations