330 HA Lee, et al 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 depolari- zation pulse against the pulse potential in the control and 3 μM sertraline. Effect of sertraline on INa Fig. 5 shows the inhibitory effect of sertraline on INa in SCN5A-transfected HEK293 cells. Sertraline at concentra- tions of 0.1, 1, 3, and 10 μM reduced the INa amplitude by 12.8±1.8%, 19.5±3.6%, 33.9±5.0%, and 62.0±7.6%, respec- tively (n=4). The IC50 value calculated from the concen- tration-response curve was 6.1±1.7 μM, and the Hill co- efficient was 0.7±0.2 (Fig. 5B). Fig. 5C demonstrated the current-voltage relationship (I-V curve) of INa in the contro1 and presence of 3 μM sertraline. Sertraline exerted a con- centration-dependent inhibition of INa. The peak ampliti- dude was observed similary observed at around －50 mV. Effect of sertraline on ICa Fig. 6 shows the effects of sertraline on the ICa in freshly isolated rat ventricular myocytes. Sertraline at concen- trations of 1, 3, 10, and 30 μM reduced the ICa amplitude by 6.7±3.5%, 18.6±3.6%, 53.5±4.1%, and 99.4±5.2%, respec- tively (n=4). The IC50 value calculated from the concen- tration-response curve was 2.6±0.4 μM, and the Hill co- efficient was 1.9±0.5 (Fig. 6B). DISCUSSION The use of SSRIs has increased dramatically [17], be- cause of their superior safety profile compared to TCAs [18]. Several studies have shown that the SSRIs affected various 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) Concen- tration 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). ion channels including volume-regulated anion channels (VRAC) in endothelial cells [19], rat Nav1.4 (encoded by SCN4A both in GH3 cells and heterologously expressed in HEK293) [20], and G protein-activated inwardly rectifying K＋ (GIRK) channels expressed in Xenopus oocyte [21]. In the present study, we investigated the effect of sertra- line on hERG (for IKr), KCNQ1/KCNE1 (for IKs), KCNJ2 (for IK1), and SCN5A cDNA-transfected HEK293 cells and native rat ventricular myocyte for L-type calcium currents (ICa). All potassium channel currents tested in this study were inhibited by sertraline in concentration-dependent manner. Sertraline is a potent blocker of hERG current with an IC50 of 0.7 μM (Fig. 2), and of IKs (Fig. 3) and IK1 (Fig. 4) as well. The rank order of potency was hERG＞ IK1＞IKs with IC50 values of 0.7, 10.5, and 15.2 μM, respec- tively. It is well known that K＋ channels play an important role in the repolarization of mammalian cardiac action potential in different species, including human. Specially, hERG channel current, mediating the rapidly activating delayed rectifier K＋ current (IKr) in the heart [22], has a key role in repolarization of the cardiac action potential and in con- trolling action potential duration. Following multiple oral once-daily doses of 200 mg, the mean peak plasma concen- tration (Cmax) of sertraline is 0.19 μg/ml, approximately 0.6 μM [23]. This value is similar with the IC50 value of the hERG on our study. A 30-fold margin between the effec- tive therapeutic plasma concentration and the IC50 value for IKr block has been suggested as margin of safety relative to the risk of TdP for all drugs with IKr-blocking properties [24]. In this respect, potentially harmful effect of sertraline on cardiac action potential should be considered afterwards. It is well known that the congenital dysfunction of IKs caused by genetic mutations in the KCNQ1 or KCNE1 gene is linked to congenital long QT syndrome subtype LQT1 or LQT5 [25]. Electrical remodeling in the diseased hearts, like as myocardial infarction [26], chronic heart failure [27], and cardiac hypertrophy [28], is often linked with a reduc- tion of IKs. In case of IK1, the IK1-related heart rhythm dis- turbances also known [29] but it’s less prevalent than those associated with IKr or IKs. In addition to K＋ channels, sertraline also inhibited INa and ICa, and the IC50 value is 6.1 and 2.6 μM, respectively. Because the voltage-gated sodium channel is important to the upstroke phase of the action potential in most excitable