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dc.contributor.authorTschirhart, Jared
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2019-06-28T19:29:28Z
dc.date.available2019-06-28T19:29:28Z
dc.identifier.urihttp://hdl.handle.net/1974/26348
dc.description.abstractFentanyl poses a serious health concern, with abuse and death rates rising over recent years. Despite the high number of overdose deaths attributed to fentanyl, the complete molecular mechanisms of such deaths have not been well-defined. Although activation of opioid receptors in the brainstem causes respiratory depression, in most cases of drug-induced sudden death cardiac arrhythmias are implicated. Therefore, we posited that disruption of cardiac electrophysiology may contribute to fentanyl-induced death. The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). Drug-mediated disruption of hERG function is the primary cause of acquired long QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. Therefore, we investigated the effects of fentanyl on hERG channels. 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. When hERG tail currents upon −50 mV repolarization after a 50 mV depolarization were analyzed, fentanyl and naloxone blocked hERG current (IhERG) with IC50 values of 0.9 and 74.3 μM, respectively, whereas norfentanyl did not block. The reduction of IhERG by fentanyl was not antagonized by naloxone, indicating that the reduction was not through activation of opioid receptors. An interesting finding is that fentanyl-mediated block of IhERG was voltage-dependent. Consequently, when a human ventricular action potential waveform voltage protocol was used, fentanyl blocked IhERG with an IC50 of 0.3 μM, which is within the range of blood concentrations after overdose deaths in humans. Furthermore, fentanyl (0.5 μM) blocked IKr and prolonged action potential duration in ventricular myocytes isolated from neonatal rats. The concentrations of fentanyl used in this project were higher than seen with clinical use but overlap with post-mortem overdose concentrations. Further, co-expressed long and short isoforms of hERG, proposed to mimic native channels, displayed an increased sensitivity to fentanyl. Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to death for individuals with high-concentration overdose or compromised cardiac repolarization.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjecthERGen_US
dc.subjectpotassium channelen_US
dc.subjectcardiac action potentialen_US
dc.subjectsudden deathen_US
dc.subjectvoltage clampen_US
dc.subjectfentanylen_US
dc.subjectelectrophysiologyen_US
dc.titleBlockade of the Human Ether A-Go-Go-Related Gene (hERG) Potassium Channel by Fentanylen_US
dc.typethesisen
dc.description.degreeMaster of Scienceen_US
dc.contributor.supervisorZhang, Shetuan
dc.contributor.departmentBiomedical and Molecular Sciencesen_US


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