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[Testosterone modulation of HERG potassium channel blockade induced by neuroleptics].
Fiziol Zh. 2001; 47(3):11-8.FZ

Abstract

The repolarisation phase of cardiac action potential is characterized by sexual dimorphism suggesting the role of sex steroid hormones in the regulation of K+ channels. Here we report on the effect of testosterone on blockade of HERG-encoded K+ channels induced by neuroleptics. These compounds are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac delayed rectifier K+ current, IKr. HERG was expressed in Xenopus oocytes, HERG-expressing oocytes were preincubated in 1 microM of testosterone from 3 to 8 hours before experiments. The extent of the blockade by neuroleptics in control oocytes increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism. The IC50 and A (maximal block) values for the haloperidol-, pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36 microM and 73%, 1.74 microM and 76%, 2.34 microM and 65% respectively. Testosterone decreased extent of maximal block and significantly diminished block voltage-dependance of IKr inhibition, it also decreased the efficiency of block, with IC50 and A values of 2.73 microM and 65%, 2.08 microM and 59%, 5.04 microM and 64% for haloperidol, pimozide and fluspirilen respectively. Testosterone treatment increased IC50 and decreased A for all three agents. The largest decrease in A was with pimozide and the largest increase in IC50 was with fluspirilen. Our results suggest protective role of testosterone (androgens) against proarrhythmic side effects of some compounds.

Authors+Show Affiliations

A. A. Bogomoletz Institute of Physiology, and International Center of Molecular Physiology, National Academy of Sciences of Ukraine, Kiev, Ukraine.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

English Abstract
Journal Article

Language

ukr

PubMed ID

11519244

Citation

Osypenko, V M., et al. "[Testosterone Modulation of HERG Potassium Channel Blockade Induced By Neuroleptics]." Fiziolohichnyi Zhurnal (Kiev, Ukraine : 1994), vol. 47, no. 3, 2001, pp. 11-8.
Osypenko VM, Dehtiar VIe, Shuba IaM, et al. [Testosterone modulation of HERG potassium channel blockade induced by neuroleptics]. Fiziol Zh. 2001;47(3):11-8.
Osypenko, V. M., Dehtiar, V. I. e., Shuba, I. a. M., & Naĭd'onov, V. H. (2001). [Testosterone modulation of HERG potassium channel blockade induced by neuroleptics]. Fiziolohichnyi Zhurnal (Kiev, Ukraine : 1994), 47(3), 11-8.
Osypenko VM, et al. [Testosterone Modulation of HERG Potassium Channel Blockade Induced By Neuroleptics]. Fiziol Zh. 2001;47(3):11-8. PubMed PMID: 11519244.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [Testosterone modulation of HERG potassium channel blockade induced by neuroleptics]. AU - Osypenko,V M, AU - Dehtiar,V Ie, AU - Shuba,Ia M, AU - Naĭd'onov,V H, PY - 2001/8/25/pubmed PY - 2002/8/16/medline PY - 2001/8/25/entrez SP - 11 EP - 8 JF - Fiziolohichnyi zhurnal (Kiev, Ukraine : 1994) JO - Fiziol Zh VL - 47 IS - 3 N2 - The repolarisation phase of cardiac action potential is characterized by sexual dimorphism suggesting the role of sex steroid hormones in the regulation of K+ channels. Here we report on the effect of testosterone on blockade of HERG-encoded K+ channels induced by neuroleptics. These compounds are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac delayed rectifier K+ current, IKr. HERG was expressed in Xenopus oocytes, HERG-expressing oocytes were preincubated in 1 microM of testosterone from 3 to 8 hours before experiments. The extent of the blockade by neuroleptics in control oocytes increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism. The IC50 and A (maximal block) values for the haloperidol-, pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36 microM and 73%, 1.74 microM and 76%, 2.34 microM and 65% respectively. Testosterone decreased extent of maximal block and significantly diminished block voltage-dependance of IKr inhibition, it also decreased the efficiency of block, with IC50 and A values of 2.73 microM and 65%, 2.08 microM and 59%, 5.04 microM and 64% for haloperidol, pimozide and fluspirilen respectively. Testosterone treatment increased IC50 and decreased A for all three agents. The largest decrease in A was with pimozide and the largest increase in IC50 was with fluspirilen. Our results suggest protective role of testosterone (androgens) against proarrhythmic side effects of some compounds. SN - 2522-9028 UR - https://www.unboundmedicine.com/medline/citation/11519244/[Testosterone_modulation_of_HERG_potassium_channel_blockade_induced_by_neuroleptics]_ L2 - http://www.xenbase.org/literature/article.do?method=display&articleId=8513 DB - PRIME DP - Unbound Medicine ER -