Korean J Physiol Pharmacol.  2012 Oct;16(5):327-332. 10.4196/kjpp.2012.16.5.327.

Wide Spectrum of Inhibitory Effects of Sertraline on Cardiac Ion Channels

• Lee HA
• Kim KS
• Hyun SA
• Park SG
• Kim SJ

• KMID: 1493965
• DOI: http://doi.org/10.4196/kjpp.2012.16.5.327

Abstract

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In these experiments, we have used the whole cell patch clamp technique to examine the effects of sertraline on the major cardiac ion channels expressed in HEK293 cells and the native voltage-gated Ca2+ channels in rat ventricular myocytes. According to the results, sertraline is a potent blocker of cardiac K+ channels, such as hERG, IKs and IK1. The rank order of inhibitory potency was hERG >IK1> IKs with IC50 values of 0.7, 10.5, and 15.2 microM, respectively. In addition to K+ channels, sertraline also inhibited INa and ICa, and the IC50 values are 6.1 and 2.6 microM, respectively. Modification of these ion channels by sertraline could induce changes of the cardiac action potential duration and QT interval, and might result in cardiac arrhythmia.

Keyword

Antidepressant; Cardiac; Ion channel; Selective serotonin reuptake inhibitor; Sertraline

MeSH Terms

Action Potentials
Animals
Arrhythmias, Cardiac
HEK293 Cells
Inhibitory Concentration 50
Ion Channels
Muscle Cells
Rats
Serotonin Uptake Inhibitors
Sertraline
Ion Channels
Serotonin Uptake Inhibitors
Sertraline

Figure

• 

  Fig. 1 Structure of sertraline.

• 

  Fig. 2 The effect of sertraline on human ether-a-go-go-related gene (hERG) currents expressed in HEK293 cells. (A) Current responses to step voltage pulses of -80 to +50 mV in 10 mV steps from a holding potential of -80 mV (upper panel). Center: absence of sertraline, control condition; lower: in the presence of 1 µM sertraline. (B) Voltage-relationship of the hERG current measured at the end of depolarizing pulses against the pulse potential in the control and 1 µM sertraline. (C) Voltage-relationship of the tail current measured at its peak just after repolarization in control and after application of 1 µM sertraline. Data were fitted using Boltzmann equation. (D) Dose-response relationship for inhibition of hERG currents by serial application of 0.1, 0.3, 1, and 3 µM sertraline (n=4). The relationship was fitted to a Hill equation. The IC50 and Hill coefficient were 0.7 µM and 1.3, respectively.

• 

  Fig. 3 The effect of sertraline on IKs expressed in HEK293 cells. (A) The cells were depolarized to +60 mV from a holding potential of -80 mV, followed by a 3-s repolarization back to -40 mV (upper). Representative current traces under control condition and after application of 1, 3, 10, and 30 µM sertraline (lower). (B) Concentration response curve for inhibition of IKs by serial application of 1, 3, 10, and 30 µM sertraline. The relationship was fitted to a Hill equation. The IC50 and Hill coefficient were 12.3 µM and 2.5, respectively (n=4). (C) Voltage-relationship of the peak IKs measured at the end of depolarizing pulses against the pulse potential in the control and 10 µM sertraline (n=4).

• 

  Fig. 4 The effect of sertraline on IK1 expressed in HEK293 cells. (A) The IK1 was elicited by the voltage of a one-step pulse (lasting 1 s) from -80 mV to -120 mV (upper). Representative current traces under control condition and after application of 1, 3, 10, and 30 µM sertraline (lower). (B) Concentration response curve for inhibition of IK1 by serial application of 1, 3, 10, and 30 µM sertraline. The relationship was fitted to a Hill equation. The IC50 and Hill coefficient were 10.5 µM and 2.1, respectively (n=4). (C) Voltage-relationship of the IK1 measured at the end of hyperpolarizing pulses against the pulse potential in the control and 10 µM sertraline (n=4).

• 

  Fig. 5 The effect of sertraline on INa expressed in HEK293 cells. (A) The peak inward INa was generated by pulses of 20 ms duration to -40 mV from a holding potential of -100 mV delivered at a frequency of 10 Hz (upper). Representative current traces under control condition and after application of 0.1, 1, 3, and 10 µM sertraline (lower). (B) Concentration response curve for inhibition of INa by serial application of 0.1, 1, 3, and 10 µM sertraline. The relationship was fitted to a Hill equation. The IC50 and Hill coefficient were 6.1 µM and 0.7, respectively (n=4). (C) Voltage-relationship of the INa measured at its peak just after depolarization pulse against the pulse potential in the control and 3 µM sertraline.

• 

  Fig. 6 The effect of sertraline on ICa in rat ventricular myocytes. (A) The peak of the ICa was induced by a single 500 ms voltage pulse to 0 mV from the holding potential of -80 mV (upper). Representative current traces under control condition and after application of 0.1, 1, 3, and 10 µM sertraline (lower). (B) Concentration response curve for inhibition of ICa by serial application of 0.1, 1, 3, and 10 µM sertraline. The relationship was fitted to a Hill equation. The IC50 and Hill coefficient were 2.6 µM and 1.9, respectively (n=4).

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