The opioid methadone induces a local anaesthetic‐like inhibition of the cardiac Na+ channel, Nav1.5. (January 2014)

• Record Type: Journal Article
• Authors: Schulze, V; Stoetzer, C; O'Reilly, A O; Eberhardt, E; Foadi, N; Ahrens, J; Wegner, F; Lampert, A; de la, J; Leffler, A
• Is Part Of: British journal of pharmacology. Volume 171:Number 2(2014:Jan.)
• Page Start: 427
• Page End: 437
• Publication Date: 2014-01
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12465
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12465-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Treatment with methadone is associated with severe cardiac arrhythmias, a side effect that seems to result from an inhibition of cardiac hERG K<sup>+</sup> channels. However, several other opioids are inhibitors of voltage‐gated Na<sup>+</sup> channels. Considering the common assumption that an inhibition of the cardiac Na<sup>+</sup> channel Na<sub>v</sub>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<sub>v</sub>1.5 channels.</p> </sec> <sec id="bph12465-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>The whole‐cell patch clamp technique was applied to investigate the effects of methadone on wild‐type and mutant human Na<sub>v</sub>1.5 channels expressed in HEK293 cells. A homology model of human Na<sub>v</sub>1.5 channels was used to perform automated ligand‐docking studies.</p> </sec> <sec id="bph12465-sec-0003" sec-type="section"> <title>Key Results</title> <p>Methadone inhibited Na<sub>v</sub>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<sub>v</sub>1.5 channels.</p> </sec> <sec id="bph12465-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Methadone interacted with the LA‐binding site to inhibit Na<sub>v</sub>1.5 channels. Our data suggest that these channels are a hitherto unrecognized molecular component contributing to cardiac arrhythmias induced by methadone.</p> </sec> </abstract>