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The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.
Br J Pharmacol. 1997 Mar; 120(5):968-74.BJ

Abstract

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 IsK, the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition < 6% at 3 microM haloperidol). 3. In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 microM. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 microM. 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.

Authors+Show Affiliations

Institute of Physiology I, Eberhard-Karls-University Tübinger, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9138706

Citation

Suessbrich, H, et al. "The Inhibitory Effect of the Antipsychotic Drug Haloperidol On HERG Potassium Channels Expressed in Xenopus Oocytes." British Journal of Pharmacology, vol. 120, no. 5, 1997, pp. 968-74.
Suessbrich H, Schönherr R, Heinemann SH, et al. The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br J Pharmacol. 1997;120(5):968-74.
Suessbrich, H., Schönherr, R., Heinemann, S. H., Attali, B., Lang, F., & Busch, A. E. (1997). The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. British Journal of Pharmacology, 120(5), 968-74.
Suessbrich H, et al. The Inhibitory Effect of the Antipsychotic Drug Haloperidol On HERG Potassium Channels Expressed in Xenopus Oocytes. Br J Pharmacol. 1997;120(5):968-74. PubMed PMID: 9138706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. AU - Suessbrich,H, AU - Schönherr,R, AU - Heinemann,S H, AU - Attali,B, AU - Lang,F, AU - Busch,A E, PY - 1997/3/1/pubmed PY - 1997/3/1/medline PY - 1997/3/1/entrez SP - 968 EP - 74 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 120 IS - 5 N2 - 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 IsK, the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition < 6% at 3 microM haloperidol). 3. In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 microM. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 microM. 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/9138706/The_inhibitory_effect_of_the_antipsychotic_drug_haloperidol_on_HERG_potassium_channels_expressed_in_Xenopus_oocytes_ L2 - https://doi.org/10.1038/sj.bjp.0700989 DB - PRIME DP - Unbound Medicine ER -