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 prolongati on and polymorphic ventricular arrhythmias. In this study, we expresse d several cloned cardiac K+ channels, including the human ether-a-go-g o 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 (inhibitio n < 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 volta ge-dependent, suggesting that it binds preferentially to either open o r inactivated HERG channels. As haloperidol increased the degree and r ate of HERG inactivation, binding to inactivated HERG channels is sugg ested. 5 The channel mutant HERG S631A has been shown to exhibit great ly reduced C-type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weak er than for HERG wild-type channels. Haloperidol affinity for HERG S63 1A was increased four fold at +40 mV compared to 0 mV. 6 In summary, t he data suggest that HERG channel blockade is involved in the arrhythm ogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.