Inhibition of the cardiac Na+ channel α-subunit Nav1.5 by propofol and dexmedetomidine

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• 作者：Carsten Stoetzer ; Svenja Reuter…
• 关键词：Propofol ; Dexmedetomidine ; Patch ; clamp ; Cardiac sodium channel ; Nav1.5 ; Electrophysiology
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：389
• 期：3
• 页码：315-325
• 全文大小：1,202 KB
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• 作者单位：Carsten Stoetzer (1)
  Svenja Reuter (1)
  Thorben Doll (1)
  Nilufar Foadi (1)
  Florian Wegner (2)
  Andreas Leffler (1)
  
  1. Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany
  2. Department of Neurology, Hannover Medical School, Hannover, Germany
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Neurosciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1912

文摘

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. Keywords Propofol Dexmedetomidine Patch-clamp Cardiac sodium channel Nav1.5 Electrophysiology