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

ABSTRACT

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 Nav1.5 (hNav1.5) currents expressed in HEK293 cells. The 50% inhibitory concentration of trifluoperazine was 15.5 ± 0.3 µM and the Hill coefficient was 2.7 ± 0.1. The effects of trifluoperazine on hNav1.5 were completely and repeatedly reversible after washout. Trifluoperazine caused depolarizing shifts in the activation and hyperpolarizing shifts in the steady-state inactivation of hNav1.5. Trifluoperazine also showed strong use-dependent inhibition of hNav1.5. The blockade of hNav1.5 currents by trifluoperazine was not affected by the whole cell dialysis of the calmodulin inhibitory peptide. Our results indicated that trifluoperazine blocks hNav1.5 current in concentration-, state- and use-dependent manners rather than via calmodulin inhibition.