The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes

1 The antipsychotic drug haloperidol can induce a marked QT prolongation and polymorphic ventricular arrhythmias. In this study, we expressed several cloned cardiac K+ channels, including the human ether-a-go-go related gene (HERG) channels, in Xenopus oocytes and tested them for their haloperidol sensitivity. 2 Haloperidol had only little effects on the delayed rectifier channels Kv1.1, Kv1.2, Kv1.5 and L(sK), the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition < 6% at 3 mu M haloperidol). 3 In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 mu M. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 mu M. 4 Haloperidol block was use- and voltage-dependent, suggesting that it binds preferentially to either open or inactivated HERG channels. As haloperidol increased the degree and rate of HERG inactivation, binding to inactivated HERG channels is suggested. 5 The channel mutant HERG S631A has been shown to exhibit greatly reduced C-type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weaker than for HERG wild-type channels. Haloperidol affinity for HERG S631A was increased four fold at +40 mV compared to 0 mV. 6 In summary, the data suggest that HERG channel blockade is involved in the arrhythmogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.