title: Testosterone-mediated modulation of HERG blockade by proarrhythmic agents.
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.affiliation: Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Bogomoletz St., 4, Kyiv-24, Ukraine. yshuba@serv.biph.kiev.ua
authors.forename: Y M
authors.initials: YM
authors.lastname: Shuba
authors.forename: V E
authors.initials: VE
authors.lastname: Degtiar
authors.forename: V N
authors.initials: VN
authors.lastname: Osipenko
authors.forename: V G
authors.initials: VG
authors.lastname: Naidenov
authors.forename: R L
authors.initials: RL
authors.lastname: Woosley
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D004347:Drug Interactions; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005484:Fluspirilene / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010868:Pimozide / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013739:Testosterone / Q000494:pharmacology*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000728:Androgens; D014150:Antipsychotic Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D010868:Pimozide; D013739:Testosterone; D005484:Fluspirilene; D006220:Haloperidol