Testosterone-mediated modulation of HERG blockade by proarrhythmic agents

• Published in: Biochemical pharmacology 2001-07, Vol.62 (1), p.41-49
• Main Authors: Shuba, Yaroslav M, Degtiar, Vadim E, Osipenko, Vadim N, Naidenov, Valeri G, Woosley, Raymond L
• Format: Article
• Language: English
• Subjects: Androgens - pharmacology; Animals; Antipsychotic Agents - pharmacology; Arrhythmia; Biological and medical sciences; Cation Transport Proteins; DNA-Binding Proteins; Drug Interactions; Drug toxicity and drugs side effects treatment; Electrophysiology; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Fluspirilene - pharmacology; Haloperidol - pharmacology; HERG-encoded K + channel; Humans; Medical sciences; Neuroleptic agents; Oocytes - drug effects; Oocytes - metabolism; Pharmacology. Drug treatments; Pimozide - pharmacology; Potassium Channel Blockers; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels - physiology; Potassium Channels, Voltage-Gated; Testosterone; Testosterone - pharmacology; Toxicity: cardiovascular system; Trans-Activators; Transcriptional Regulator ERG; Transfection; Xenopus laevis; Xenopus oocytes
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(01)00611-6

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 μM, 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 μM testosterone increased the ic 50 values to 2.73, 2.08, and 5.04 μM, 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.