Contributions of S- and R-citalopram to the citalopram-induced modulation of the function of Nav1.5 voltage-gated sodium channels.

Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been reported to have adverse effects such as cardiotoxicity, including prolongation of the QTc interval. Although citalopram is well known to be a racemic compound comprised of S-citalopram (escitalopram) and R-citalopram, it is still unclear which enantiomer is responsible for cardiotoxicity induced by citalopram. It is also unclear which biomolecule is the target that produces the adverse effect of citalopram. In this study, we investigated whether citalopram, escitalopram and R-citalopram had an electrophysiological effect on Nav1.5 voltage-gated sodium channel (VGSC) current and how their electrophysiological properties affected Nav1.5 VGSC. To examine the effects of the electrophysiological properties of them, whole-cell patch clamp recording was performed using HEK293 cells expressing human Nav1.5 VGSCs. Nav1.5 VGSC current decreased by 60.0 ± 6.3% and 55.1 ± 12.5% under treatment with 100 μM citalopram and escitalopram, respectively. However, 100 μM R-citalopram decreased Nav1.5 VGSC current by only 36.2 ± 8.7%. In addition, treatment with 100 μM citalopram and escitalopram changed the voltage-dependence of activation and induced a negative shift of the voltage of half-maximal activation compared to 100 μM R-citalopram. In contrast, treatment with 100 μM citalopram and escitalopram, but not R-citalopram, changed the voltage-dependence of inactivation, and the voltage at half-maximal inactivation slightly shifted toward negative potential. These results suggest that the adverse cardiac effect produced by citalopram might result from modification of the electrophysiological properties of Nav1.5 VGSCs, and escitalopram might contribute more to this adverse effect than R-citalopram.