TY - JOUR T1 - Blockade of the human ether a-go-go related gene (hERG) potassium channel by fentanyl JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.114751 SP - mol.118.114751 AU - Jared N Tschirhart AU - Wentao Li AU - Jun Guo AU - Shetuan Zhang Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/01/21/mol.118.114751.abstract N2 - The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). Drug- or medical condition-mediated disruption of hERG function is the primary cause of acquired long QT syndrome (LQTS), which predisposes affected individuals to ventricular arrhythmias and sudden death. Fentanyl abuse poses a serious health concern, with abuse and death rates rising over recent years. As fentanyl has a propensity to cause sudden death, we investigated its effects on the hERG channel. The effects of norfentanyl, the main metabolite, and naloxone, an antidote used in fentanyl overdose, were also examined. Currents of hERG channels stably expressed in HEK293 cells were recorded using whole-cell voltage-clamp method. When hERG tail currents upon −50 mV repolarization following a 50 mV depolarization were analyzed, fentanyl and naloxone blocked hERG current (IhERG) with an IC50 of 0.9 μM and 74.3 μM, respectively, while norfentanyl did not block. However, fentanyl-mediated block of IhERG was voltage-dependent. When a voltage protocol that mimics a human ventricular action potential (AP) was used, fentanyl blocked IhERG with an IC50 of 0.3 μM. Furthermore, fentanyl (0.5 μM) significantly prolonged AP duration and blocked IKr in ventricular myocytes isolated from neonatal rats. The concentrations of fentanyl used in this study were higher than seen with clinical use but overlap with post-mortem overdose concentrations. While mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to the death for individuals with high-concentration overdose or compromised cardiac repolarization. ER -