Blockade of the Human Ether A-Go-Go–Related Gene (hERG) Potassium Channel by Fentanyl

Abstract

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (I Kr ). Drug-mediated or medical conditionmediated disruption of hERG function is the primary cause of acquired long-QT syndrome, 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 the whole-cell voltage-clamp method. When hERG tail currents were analyzed upon -50 mV repolarization after a 50 mV depolarization, fentanyl and naloxone blocked hERG current (I hERG ) with IC 50 values of 0.9 and 74.3 mM, respectively, whereas norfentanyl did not block. However, fentanyl-mediated block of I hERG was voltage dependent. When a voltage protocol that mimics a human ventricular action potential (AP) was used, fentanyl blocked I hERG with an IC 50 of 0.3 mM. Furthermore, fentanyl (0.5 mM) prolonged AP duration and blocked I Kr 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 postmortem overdose concentrations. Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to the death of individuals with high-concentration overdose or compromised cardiac repolarization.

Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block

“…In the micromolar to sub-millimolar concentration range, naloxone has been shown to prolong ventricular APD [40][41][42][43][44] and decrease V max [41,42]-changes suggestive of drug effects on multiple cardiac ion channels. Indeed, in the tens of micromolar concentration range, naloxone has been found to decrease I Na , I to , I CaL , and I Kr , and increase I K1 (inward rectifier current that sets the resting membrane potential) in native myocytes [44], and inhibit I hERG in overexpression cells [45] (Table 1). The present data are consistent with the literature, showing that naloxone inhibits I hERG , I CaL , I NaL , and I NaP with IC 50 s ranging from tens to hundreds of micromolar ( Fig 6; Table 1).…”

Prolongation of QT interval after pulmonary vein isolation for paroxysmal atrial fibrillation

“…Some anesthetic agents have potential risk for QT prolongation. The effects of dexmedetomidine [24][25][26][27][28] and fentanyl 29,30 on QT interval is controversial.…”

The rising crisis of illicit fentanyl use, overdose, and potential therapeutic strategies

“…β-funaltrexamine was shown to inhibit both fentanyl-induced analgesia and lethality 71 . Overdose-related concentrations of fentanyl were shown to block human ether-a-go-go-related gene (hERG) potassium channels in ventricular myocytes that were isolated from neonatal rats, which may contribute to fentanyl-related overdose death or sudden death 72 .…”