Abstract
Fluoxetine is a commonly prescribed antidepressant compound. Its action is primarily attributed to selective inhibition of the reuptake of serotonin (5-hydroxytryptamine) in the central nervous system. Although this group of antidepressant drugs is generally believed to cause fewer proarrhythmic side effects compared with tricyclic antidepressants, serious concerns have been raised by case reports of tachycardia and syncopes associated with fluoxetine treatment. To determine the electrophysiological basis for the arrhythmogenic potential of fluoxetine, we investigated the effects of this drug on cloned human ether-a-go-go-related gene (HERG) potassium channels heterologously expressed in Xenopus oocytes using the two-microelectrode voltage-clamp technique. We found that fluoxetine blocked HERG channels with an IC50 value of 3.1 μM. Inhibition occurred fast to open channels with very slow unbinding kinetics. Analysis of the voltage dependence of block revealed loss of inhibition at membrane potentials greater than 40 mV, indicating that channel inactivation prevented block by fluoxetine. No pronounced changes in electrophysiological parameters such as voltage dependence of activation or inactivation, or inactivation time constant could be observed, and block was not frequency-dependent. This is the first study demonstrating that HERG potassium channels are blocked by the selective serotonin reuptake inhibitor fluoxetine. We conclude that HERG current inhibition might be an explanation for the arrhythmogenic side effects of this drug.
Footnotes
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This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Project Ki 663/1-1 to J.K.). D.T. was supported by the German National Merit Scholarship Foundation. Data presented here are part of the doctoral thesis of B.G.
- Abbreviations:
- HERG
- human ether-a-go-go-related gene
- ICa
- L-type calcium current
- IK
- delayed rectifier potassium current
- IKr
- rapidly activating component of IK
- IKs
- slowly activating component of IK
- LQT-2
- inherited long QT syndrome
- Received July 20, 2001.
- Accepted October 15, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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