Trifluoperazine blocks the human cardiac sodium channel, Nav1.5, independent of calmodulin

Trifluoperazine is a phenothiazine derivative which is mainly used in the management of schizophrenia and also acts as a calmodulin inhibitor. We used the whole-cell patch-clamp technique to study the effects of trifluoperazine on human Na(v)1.5 (hNa(v)1.5) currents expressed in HEK293 cells. The 50% inhibitory concentration of trifluoperazine was 15.5 +/- 0.3 mu M and the Hill coefficient was 2.7 +/- 0.1. The effects of trifluoperazine on hNa(v)1.5 were completely and repeatedly reversible after washout. Trifluoperazine caused depolarizing shifts in the activation and hyperpolarizing shifts in the steady-state inactivation of hNa(v)1.5. Trifluoperazine also showed strong use-dependent inhibition of hNa(v)1.5. The blockade of hNa(v)1.5 currents by trifluoperazine was not affected by the whole cell dialysis of the calmodulin inhibitory peptide. Our results indicated that trifluoperazine blocks hNa(v)1.5 current in concentration-, state- and use-dependent manners rather than via calmodulin inhibition. (C) 2016 Elsevier Inc. All rights reserved.