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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
Biochemical Pharmacology
|May 30, 2001
Summary
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.