Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Fentanyl-induced block of hERG channels is exacerbated by hypoxia, hypokalemia, alkalosis, and the presence of hERG1b

Jared N. Tschirhart and Shetuan Zhang
Molecular Pharmacology April 22, 2020, mol.119.119271; DOI: https://doi.org/10.1124/mol.119.119271
Jared N. Tschirhart
Queen's University
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shetuan Zhang
Queen's University
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr) important for repolarization of cardiac action potentials. Drug-induced disruption of hERG channel function is a main cause of acquired long QT syndrome (LQTS), which can lead to ventricular arrhythmias and sudden death. Illicit fentanyl use is associated with sudden death. We have demonstrated that fentanyl blocks hERG current (IhERG) at concentrations that overlap with the upper range of postmortem blood concentrations in fentanyl-related deaths. Since fentanyl can cause respiratory depression and electrolyte imbalances, in the present study, we investigated whether certain pathological circumstances exacerbate fentanyl-induced block of IhERG. Our results showed that chronic hypoxia or hypokalemia additively reduced IhERG with fentanyl. As well, high pH potentiated the fentanyl-mediated block of hERG channels, with an IC50 at pH 8.4 being 7-fold lower than that at pH 7.4. Furthermore, while the full-length hERG variant, hERG1a, has been widely used to study hERG channels, coexpression with the short variant, hERG1b (which does not produce current when expressed alone), produces functional hERG1a/1b channels, which gate more closely resembling native IKr. Our results showed that fentanyl blocked hERG1a/1b channels with a 3-fold greater potency than hERG1a channels. Thus, in addition to a greater susceptibility due to the presence of hERG1b in the human heart, hERG channel block by fentanyl can be exacerbated by certain conditions such as hypoxia, hypokalemia, or alkalosis, which may increase the risk of fentanyl-induced ventricular arrhythmias and sudden death.

SIGNIFICANCE STATEMENT This work demonstrates that heterologously expressed hERG1a/1b channels, which more closely resemble IKr in the human heart, are blocked by fentanyl with a 3-fold greater potency than the previously studied hERG1a expressed alone. Additionally, chronic hypoxia, hypokalemia, and alkalosis can increase the block of hERG current by fentanyl, potentially increasing the risk of cardiac arrhythmias and sudden death.

  • Arrythmia
  • Cardiac electrophysiology
  • Drug abuse
  • hERG
  • Hypoxia
  • Ion channels
  • Patch clamp recording
  • Potassium channels
  • QT interval
  • The American Society for Pharmacology and Experimental Therapeutics
Next
Back to top

In this issue

Molecular Pharmacology: 102 (5)
Molecular Pharmacology
Vol. 102, Issue 5
1 Nov 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Fentanyl-induced block of hERG channels is exacerbated by hypoxia, hypokalemia, alkalosis, and the presence of hERG1b
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Fentanyl-induced block of hERG channels is exacerbated by hypoxia, hypokalemia, alkalosis, and the presence of hERG1b

Jared N. Tschirhart and Shetuan Zhang
Molecular Pharmacology April 22, 2020, mol.119.119271; DOI: https://doi.org/10.1124/mol.119.119271

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Fentanyl-induced block of hERG channels is exacerbated by hypoxia, hypokalemia, alkalosis, and the presence of hERG1b

Jared N. Tschirhart and Shetuan Zhang
Molecular Pharmacology April 22, 2020, mol.119.119271; DOI: https://doi.org/10.1124/mol.119.119271
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Anti-aromatase Activity of Exemestane Phase II Metabolites
  • Effect of Nifekalant on D540K hERG Channels
  • Allosteric inhibition of HIF-2 by belzutifan
Show more Article

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics