Korean J Physiol Pharmacol Vol 16: 327－332, October, 2012 http://dx.doi.org/10.4196/kjpp.2012.16.5.327 W ide Spectrum of Inhibitory Effects of Sertraline on Cardiac Ion Channels Hyang-Ae Lee1,2, Ki-Suk Kim1, Sung-Ae Hyun1, Sung-Gurl Park1, and Sung Joon Kim2 1Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon 305-600, 2Department of Physiology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea 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 μ M, respectively. In addition to K＋ channels, sertraline also inhibited INa and ICa, and the IC50 values are 6.1 and 2.6 μ M, 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. Key Words: Antidepressant, Cardiac, Ion channel, Selective serotonin reuptake inhibitor, Sertraline INTRODUCTION The most considerable concern about the new drugs is cardiovascular toxicity including tachycardia, QT prolonga- tion, and hypertension. Specially, QT prolongation is asso- ciated with potentially fatal, cardiac arrhythmia termed Torsade de Pointes (TdP) [1,2]. It is well known that some psychotropic drugs, including neuroleptics, antipsychotics, antidepressants, stimulants, and antianxiety agents, can be associated with risks of car- diac arrhythmia and sudden death [3]. The common tricy- clic antidepressants (TCAs) such as imipramine and ami- triptyline exert a significant increase in QT variability that is associated with ventricular arrhythmia [4-6]. Newer com- pounds, such as selective serotonin reuptake inhibitors (SSRIs) have been reported to have a more benign car- diovascular profile, otherwise fluvoxamine have been re- ported to prolong QT, even at therapeutic doses [7]. In the perfused rat hearts, SSRIs presented undesired effects on the contractility [8] that may be induced by the inhibition of L-type Ca2＋ and transient outward K＋ currents of ven- Received June 3, 2012, Revised September 11, 2012, Accepted September 11, 2012 Corresponding to: Sung Joon Kim, Department of Physiology and Department of Biomedical Sciences, Seoul National University College of Medicine, 103, Daehakro, Jongro-gu, Seoul 110-799, Korea. (Tel) 82-2-740-8230, (Fax) 82-2-763-9667, (E-mail) sjoonkim@ snu.ac.kr This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 327 tricular myocytes [9]. Sertraline is a commonly used antidepressant of the SSRI class (Fig. 1). It was investigated that sertraline had no significant effect on cardiac function like as RR, PR, QRS, and QT intervals in an adult outpatient population (n= 1,048) [10]. Whereas previous studies did not reveal any QT prolongation as a side-effect of sertraline, some reports released recently suggests it may have this potential [11]. The sudden cardiac death is also reported in patient taking clozapine and sertraline together [12]. Many antidepressants, especially TCAs can modulate the cardiac action potential (AP) by blocking different cardiac ion channels present in ventricular myocytes. There are various ion channels involved in both the depolarization and repolarization of AP: the inward sodium channel cur- rent (INa), the inward Ca2＋ channel current (ICa), and sev- eral types of outward potassium channels, such as the rapid and slow components of outward delayed rectifier potas- sium channel currents (IKr and IKs, respectively), the inward rectifying potassium channel current (IK1). Among these po- tassium channels, the human ether-a-go-go-related gene (hERG) channels conducting IKr is mainly responsible for cardiac repolarization [13,14]. To our knowledge, there is no report investigating the effect of sertraline on various cardiac ion channels. In the present study, we investigated the effect of sertraline on the major cardiac ion channels, such as hERG, IKs, IK1, INa and ICa to evaluate the potential effects of the drug on car- diac repolarization. ABBREVIATIONS: SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; hERG, human ether-a-go-go-related gene; AP, action potential.