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However, several other opioids are inhibitors of voltage\u2010gated<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sup>+<\/jats:sup>channels. Considering the common assumption that an inhibition of the cardiac<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sup>+<\/jats:sup>channel<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>v<\/jats:sub>1.5, is the primary mechanism for local anaesthetic (<jats:styled-content style=\"fixed-case\">LA<\/jats:styled-content>)\u2010induced cardiotoxicity, we hypothesized that methadone has<jats:styled-content style=\"fixed-case\">LA\u2010like<\/jats:styled-content>properties leading to a modulation of<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>v<\/jats:sub>1.5 channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The whole\u2010cell patch clamp technique was applied to investigate the effects of methadone on wild\u2010type and mutant human<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>v<\/jats:sub>1.5 channels expressed in<jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells. A homology model of human Na<jats:sub>v<\/jats:sub>1.5 channels was used to perform automated ligand\u2010docking studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Methadone inhibited<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>v<\/jats:sub>1.5 channels in a state\u2010dependent manner, that is, tonic block was stronger with inactivated channels than with resting channels and a use\u2010dependent block at 10\u2009Hz. Methadone induced a concentration\u2010dependent shift of the voltage dependency of both fast and slow inactivation towards more hyperpolarized potentials, and impaired recovery from fast and slow inactivation. The<jats:styled-content style=\"fixed-case\">LA<\/jats:styled-content>\u2010insensitive mutants<jats:styled-content style=\"fixed-case\">N406K<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">F1760A<\/jats:styled-content>exhibited reduced tonic and use\u2010dependent block by methadone, and docking predictions positioned methadone in a cavity that was delimited by the residue<jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>1760. Dextromethadone and levomethadone induced discrete stereo\u2010selective effects on<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>v<\/jats:sub>1.5 channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Methadone interacted with the<jats:styled-content style=\"fixed-case\">LA<\/jats:styled-content>\u2010binding site to inhibit<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>v<\/jats:sub>1.5 channels. Our data suggest that these channels are a hitherto unrecognized molecular component contributing to cardiac arrhythmias induced by methadone.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12465","type":"journal-article","created":{"date-parts":[[2013,10,14]],"date-time":"2013-10-14T11:11:21Z","timestamp":1381749081000},"page":"427-437","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The opioid methadone induces a local anaesthetic\u2010like inhibition of the cardiac<scp>N<\/scp>a<sup>+<\/sup>channel,<scp>N<\/scp>a<sub>v<\/sub>1.5"],"prefix":"10.1111","volume":"171","author":[{"given":"V","family":"Schulze","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Stoetzer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and 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