title: Inhibition of the cardiac Na⁺ channel α-subunit Nav1.5 by propofol and dexmedetomidine.
abstract: Propofol and dexmedetomidine are very commonly used sedative agents. However, several case reports demonstrated cardiovascular adverse effects of these two sedatives. Both substances were previously demonstrated to quite potently inhibit neuronal voltage-gated Na(+) channels. Thus, a possible molecular mechanism for some of their cardiac side effects is an inhibition of cardiac voltage gated Na(+) channels. In this study, we therefore explored the effects of propofol and dexmedetomidine on the cardiac predominant Na(+) channel α-subunit Nav1.5. Effects of propofol and dexmedetomidine were investigated on constructs of the human α-subunit Nav1.5 stably expressed in HEK-293 cells by means of whole-cell patch clamp recordings. Both agents induced a concentration-dependent tonic inhibition of Nav1.5. The calculated IC50 value for propofol was 228 ± 10 μM, and for dexmedetomidine 170 ± 20 μM. Tonic block only marginally increased on inactivated channels, and a weak use-dependent block at 10 Hz was observed for dexmedetomidine (16 ± 2 % by 100 μM). The voltage dependencies of fast and slow inactivation as well as the time course of recovery from inactivation were shifted by both propofol and dexmedetomidine. Propofol (IC50 126 ± 47 μM) and dexmedetomidine (IC50 182 ± 27 μM) blocked the persistent sodium current induced by veratradine. Finally, the local-anesthetic (LA)-insensitive mutant Nav1.5-F1760A exhibited reduced tonic and use-dependent block by both substances. Dexmedetomidine was generally more potent as compared to propofol. Propofol and dexmedetomidine seem to interact with the LA-binding site to inhibit the cardiac Na(+) channel Nav1.5 in a state-dependent manner. These data suggest that Nav1.5 is a hitherto unrecognized molecular component of some cardiovascular side effects of these sedative agents.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany. stoetzer.carsten@mh-hannover.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Stoetzer
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.
authors.forename: Thorben
authors.initials: T
authors.lastname: Doll
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Foadi
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
mesh_terms: D020927:Dexmedetomidine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D006993:Hypnotics and Sedatives; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D020927:Dexmedetomidine; D015742:Propofol
keywords: Cardiac sodium channel; Dexmedetomidine; Electrophysiology; Nav1.5; Patch-clamp; Propofol