Norquetiapine blocks the human cardiac sodium channel Na<inf>v</inf>1.5 in a state-dependent manner

Abstract

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(v)1.5). 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 mu M, respectively. Norquetiapine as well as quetiapine was preferentially bound in the inactivated state of the hNa(v)1.5 channel. Norquetiapine slowed the recovery from inactivation of hNa(v)1.5 and consequently induced strong use-dependent inhibition. Our results indicate that norquetiapine blocks hNa(v)1.5 current in concentration-, state- and usedependent manners, suggesting that the blockade of hNa(v)1.5 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.