Norquetiapine blocks the human cardiac sodium channel Na_v1.5 in a state-dependent manner

Quetiapine, an atypical antipsychotic drug, is used for the treatment of schizophrenia and acute mania. Although a previous report showed that quetiapine blocked hERG potassium current, quetiapine has been considered relatively safe in terms of cardiovascular side effects. In the present study, we used the whole-cell patch-clamp technique to investigate the effect that quetiapine and its major metabolite norquetiapine can exert on human cardiac sodium channels (hNa_v1.5). The half-maximal inhibitory concentrations of quetiapine and norquetiapine at a holding potential of -90 mV near the resting potential of cardiomyocytes were 30 and 6 μM, respectively. Norquetiapine as well as quetiapine was preferentially bound in the inactivated state of the hNa_v1.5 channel. Norquetiapine slowed the recovery from inactivation of hNa_v1.5 and consequently induced strong use-dependent inhibition. Our results indicate that norquetiapine blocks hNa_v1.5 current in concentration-, state- and use-dependent manners, suggesting that the blockade of hNa_v1.5 current by norquetiapine may shorten the cardiac action potential duration and reduce the risk of QT interval prolongation induced by the inhibition of hERG potassium currents.