ArticleBritish journal of pharmacology2014
The opioid methadone induces a local anaesthetic-like inhibition of the cardiac Na⁺ channel, Na(v)1.5.
Article in British journal of pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- In silico modeling of methadone-related ion current effects to predict QT interval prolongation.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- A structural atlas of druggable sites on NaChannels (Austin, Tex.) · 2024Review
- Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health.Cardiovascular toxicology · 2024Review
- The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Local Anesthetic Like Inhibition of the Cardiac NaJournal of experimental pharmacology · 2022Article
- Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner.Frontiers in pharmacology · 2021Article
- Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block.PloS one · 2020Article
- The opioid oxycodone use-dependently inhibits the cardiac sodium channel NaBritish journal of pharmacology · 2018Article
- Determination of the unbound fraction of R- and S-methadone in human brain.International journal of legal medicine · 2017Article
- Tetrodotoxin-sensitive α-subunits of voltage-gated sodium channels are relevant for inhibition of cardiac sodium currents by local anesthetics.Naunyn-Schmiedeberg's archives of pharmacology · 2016Article
- Inhibition of the cardiac Na⁺ channel α-subunit Nav1.5 by propofol and dexmedetomidine.Naunyn-Schmiedeberg's archives of pharmacology · 2016Article
- Activity-dependent depression of neuronal sodium channels by the general anaesthetic isoflurane.British journal of anaesthesia · 2015Article
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Authors and funding
10 authors.
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Abstract
background and purposeTreatment with methadone is associated with severe cardiac arrhythmias, a side effect that seems to result from an inhibition of cardiac hERG K⁺ channels. However, several other opioids are inhibitors of voltage-gated Na⁺ channels. Considering the common assumption that an inhibition of the cardiac Na⁺ channel Na(v)1.5, is the primary mechanism for local anaesthetic (LA)-induced cardiotoxicity, we hypothesized that methadone has LA-like properties leading to a modulation of Na(v)1.5 channels. EXPERIMENTAL APPROACH: The whole-cell patch clamp technique was applied to investigate the effects of methadone on wild-type and mutant human Na(v)1.5 channels expressed in HEK293 cells. A homology model of human Na(v)1.5 channels was used to perform automated ligand-docking studies. KEY
resultsMethadone inhibited Na(v)1.5 channels in a state-dependent manner, that is, tonic block was stronger with inactivated channels than with resting channels and a use-dependent block at 10 Hz. Methadone induced a concentration-dependent shift of the voltage dependency of both fast and slow inactivation towards more hyperpolarized potentials, and impaired recovery from fast and slow inactivation. The LA-insensitive mutants N406K and F1760A exhibited reduced tonic and use-dependent block by methadone, and docking predictions positioned methadone in a cavity that was delimited by the residue F1760. Dextromethadone and levomethadone induced discrete stereo-selective effects on Na(v)1.5 channels. CONCLUSIONS AND IMPLICATIONS: Methadone interacted with the LA-binding site to inhibit Na(v)1.5 channels. Our data suggest that these channels are a hitherto unrecognized molecular component contributing to cardiac arrhythmias induced by methadone.
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