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Testosterone-mediated modulation of HERG blockade by proarrhythmic agents
Y M Shuba1, V E Degtiar, V N Osipenko
1Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Bogomoletz St., 4, Kyiv-24, Ukraine. yshuba@serv.biph.kiev.ua
Insights
Androgens like testosterone may protect against drug-induced torsades de pointes (TdP) by reducing the blocking potency of neuroleptics on human ether-a-go-go related gene (HERG) potassium channels, lowering arrhythmia risk.
Area of Science:
- Pharmacology
- Cardiology
- Molecular Biology
Background:
- Drug-induced torsades de pointes (TdP) is a life-threatening arrhythmia often caused by blockade of HERG potassium channels.
- Men exhibit lower TdP risk than women, suggesting sex steroid hormone involvement in cardiac channel sensitivity.
Purpose of the Study:
- To investigate the effect of testosterone on the cardiotoxicity of neuroleptic agents that block HERG channels.
- To explore the potential protective role of androgens against drug-induced arrhythmias.
Main Methods:
- Utilized a Xenopus oocyte expression system to study HERG channels.
- Administered neuroleptic agents (haloperidol, pimozide, fluspirilene) and testosterone to oocytes expressing HERG channels.
- Measured HERG current inhibition and analyzed drug-channel interactions.
Main Results:
- Testosterone pretreatment significantly reduced the HERG channel-blocking potency of haloperidol, pimozide, and fluspirilene.
- Testosterone diminished the voltage-dependence of neuroleptic-induced HERG channel blockade.
- Testosterone alone caused a moderate reduction in HERG current.
Conclusions:
- Androgens, specifically testosterone, may offer protection against the arrhythmogenic effects of certain cardiotoxic drugs.
- This finding provides a molecular basis for the observed sex differences in drug-induced TdP risk.
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.