Selective serotonin re-uptake inhibitors (SSRIs) are generally considered to compare favourably with tricyclic antidepressants in terms of their cardiac safety profile. Fluvoxamine is a SSRI that can be associated at excessively high concentrations with QT interval prolongation (Rodriguez et al. 1999) and arrhythmia (Manet et al. 1993). Excessive ventricular action potential prolongation can lead to the acquired long QT syndrome and to the polymorphic ventricular tachyarrhythmia torsade de pointes (Viskin, 1999). I_Kr and the current carried by its cloned equivalent HERG mediate an important repolarizing current, which when blocked by a wide variety of clinically used drugs leads to ventricular action potential prolongation and its associated risks. The objectives of this study were first to determine whether or not fluvoxamine can inhibit K⁺ channels encoded by HERG and, second, to characterize the nature of any observed effect.

Heterologous HERG K⁺ current (I_HERG) was measured at 37 °C in a mammalian cell line (HEK 293) stably expressing HERG channels, using the whole-cell patch-clamp technique. Cells were superfused with a physiological (Na⁺-based) Tyrode solution, and the pipette solution was a K⁺-based intracellular salt solution. I_HERG was sensitive to blockade by fluvoxamine. A total of six different concentrations of fluvoxamine between 10 nM and 30 mM were tested using a minimum of six replicates for each concentration. When the holding potential was -80 mV I_HERG ‘tails’ at -40 mV following an activating pulse to +20 mV were blocked with a half-maximal inhibitory concentration (IC₅₀) of 3.63 mM (95 % CI: 2.92-4.5 mM) and a Hill coefficient of 0.75 (95 % CI: 0.62-0.89). The inhibition of I_HERG during applied test pulses and of I_HERG ‘tails’ by fluvoxamine was observed to be voltage dependent. Fluvoxamine exerted a dual effect, with current at more negative test pulses being increased in the presence of drug, whilst at -10 mV and more positive to this blockade became evident. These observations corresponded with a significant ~-10 mV (P < 0.001, paired t test, n = 7) shift in the voltage-dependent activation curve for I_HERG.

The results demonstrate that fluvoxamine can inhibit I_HERG within a clinically relevant concentration range. Thus observed alterations to the electrocardiogram and arrhythmia at excessively high fluvoxamine concentrations may in part be due to the drug’s ability to block HERG K⁺ channels.

This work was supported by the British Heart Foundation.

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