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Testosterone-mediated modulation of HERG blockade by proarrhythmic agents.
Biochem Pharmacol. 2001 Jul 01; 62(1):41-9.BP

Abstract

Diverse drugs from many therapeutic classes exert cardiotoxic side effects by inducing torsades de pointes (TdP), a life threatening cardiac arrhythmia, which often results from drug interaction with HERG (human ether-a-go-go related gene) encoded K(+) channels, that generate an I(Kr) component of the delayed rectifier cardiac K(+) current. Men are known to be at a lower risk for drug-induced TdP than women suggesting a role of sex steroid hormones, androgens and estrogens, in modulation of drug sensitivity of cardiac K(+) channels, particularly those encoded by HERG. Here by using neuroleptic agents haloperidol, pimozide, and fluspirilene, all of which can induce TdP, and a steroid hormone-sensitive system Xenopus oocytes for HERG channels expression we show that testosterone is able to reduce HERG-blocking potency of neuroleptics. Haloperidol, pimozide, and fluspirilene inhibited HERG current with IC(50) of 1.36, 1.74, and 2.34 microM, and maximal block of 73%, 76% and 65%, respectively. The action of these neuroleptics was voltage-dependent, most consistent with an open-channel blocking mechanism. Pretreatment of HERG-expressing oocytes with 1 microM testosterone increased the IC(50) values to 2.73, 2.08, and 5.04 microM, reduced the maximal block to 65%, 59%, and 64%, and strongly diminished voltage-dependence of the blockade. Testosterone treatment per se produced about a 35% reduction of HERG current compared with untreated oocytes. Our data suggest that androgens may protect against the arrhythmogenic actions of some cardiotoxic drugs.

Authors+Show Affiliations

Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Bogomoletz St., 4, Kyiv-24, Ukraine. yshuba@serv.biph.kiev.uaNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11377395

Citation

Shuba, Y M., et al. "Testosterone-mediated Modulation of HERG Blockade By Proarrhythmic Agents." Biochemical Pharmacology, vol. 62, no. 1, 2001, pp. 41-9.
Shuba YM, Degtiar VE, Osipenko VN, et al. Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem Pharmacol. 2001;62(1):41-9.
Shuba, Y. M., Degtiar, V. E., Osipenko, V. N., Naidenov, V. G., & Woosley, R. L. (2001). Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochemical Pharmacology, 62(1), 41-9.
Shuba YM, et al. Testosterone-mediated Modulation of HERG Blockade By Proarrhythmic Agents. Biochem Pharmacol. 2001 Jul 1;62(1):41-9. PubMed PMID: 11377395.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. AU - Shuba,Y M, AU - Degtiar,V E, AU - Osipenko,V N, AU - Naidenov,V G, AU - Woosley,R L, PY - 2001/5/30/pubmed PY - 2001/6/15/medline PY - 2001/5/30/entrez SP - 41 EP - 9 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 62 IS - 1 N2 - Diverse drugs from many therapeutic classes exert cardiotoxic side effects by inducing torsades de pointes (TdP), a life threatening cardiac arrhythmia, which often results from drug interaction with HERG (human ether-a-go-go related gene) encoded K(+) channels, that generate an I(Kr) component of the delayed rectifier cardiac K(+) current. Men are known to be at a lower risk for drug-induced TdP than women suggesting a role of sex steroid hormones, androgens and estrogens, in modulation of drug sensitivity of cardiac K(+) channels, particularly those encoded by HERG. Here by using neuroleptic agents haloperidol, pimozide, and fluspirilene, all of which can induce TdP, and a steroid hormone-sensitive system Xenopus oocytes for HERG channels expression we show that testosterone is able to reduce HERG-blocking potency of neuroleptics. Haloperidol, pimozide, and fluspirilene inhibited HERG current with IC(50) of 1.36, 1.74, and 2.34 microM, and maximal block of 73%, 76% and 65%, respectively. The action of these neuroleptics was voltage-dependent, most consistent with an open-channel blocking mechanism. Pretreatment of HERG-expressing oocytes with 1 microM testosterone increased the IC(50) values to 2.73, 2.08, and 5.04 microM, reduced the maximal block to 65%, 59%, and 64%, and strongly diminished voltage-dependence of the blockade. Testosterone treatment per se produced about a 35% reduction of HERG current compared with untreated oocytes. Our data suggest that androgens may protect against the arrhythmogenic actions of some cardiotoxic drugs. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/11377395/Testosterone_mediated_modulation_of_HERG_blockade_by_proarrhythmic_agents_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(01)00611-6 DB - PRIME DP - Unbound Medicine ER -