title: Cellular mechanisms for trazodone-induced cardiotoxicity.
abstract: The second-generation selective 5-HT2 receptor antagonists and reuptake inhibitors (SARIs) class antidepressants are known to have fewer cardiovascular side effects than the older ones. However, several case reports showed that trazodone, one of the second-generation SARIs, induces QT prolongation, cardiac arrhythmia, and ventricular tachycardia. Although these clinical cases suggested trazodone-induced cardiotoxicity, the toxicological actions of trazodone on cardiac action potentials (APs) beyond the human ether-a-go-go related gene (hERG) remain unclear. To elucidate the cellular mechanism for the adverse cardiac effects of trazodone, we investigated its effects on cardiac APs and ion channels using whole-cell patch clamp techniques in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and transiently transfected human embryonic kidney cells (HEK293) with cardiac ion channel complementary DNA. Trazodone dose-dependently decreased the maximum upstroke velocity (Vmax) and prolonged the AP duration, inducing early after depolarizations at 3 and 10 μM that triggered ventricular arrhythmias in hiPSC-CMs. Trazodone also inhibited all of the major ion channels (IKr, IKs, INa, and ICa), with an especially high inhibitory potency on hERG. These data indicate that the prolonged AP duration and decreased Vmax due to trazodone are mainly the result of hERG and sodium ion inhibition, and its inhibitory effects on cardiac ion channels can be exhibited in hiPSC-CMs.
authors.affiliation: Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Korea Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H-A
authors.initials: HA
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea sjoonkim@snu.ac.kr.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Korea idkks00@gmail.com.
authors.forename: K-S
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D066126:Cardiotoxicity; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D014162:Transfection; D014196:Trazodone / Q000633:toxicity*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000072237:ERG1 Potassium Channel; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; C496909:KCNQ1 protein, human
keywords: Selective 5-HT2 receptor antagonists and reuptake inhibitors (SARIs); action potentials; cardiotoxicity; human ether-a-go-go related gene (hERG); ion channels; trazodone