title: Long QT 1 mutation KCNQ1A344V increases local anesthetic sensitivity of the slowly activating delayed rectifier potassium current.
abstract: BACKGROUND
  Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a position corresponding to the local anesthetic binding site in HERG, may render drug insensitive KCNQ1 channels into a toxicologically relevant target of these pharmacologic agents. This may suggest that LQTS constitutes not only a nonspecific but also a specific pharmacogenetic risk factor for anesthesia.
  
  
  METHODS
  The authors examined electrophysiologic and pharmacologic properties of wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, and mepivacaine were investigated using two-electrode voltage clamp and whole cell patch clamp recordings.
  
  
  RESULTS
  The mutation A344V induced voltage-dependent inactivation in homomeric KCNQ1 channels and shifted the voltage dependence of KCNQ1/KCNE1 channel activation by +30 mV. The mutation furthermore increased the sensitivity of KCNQ1/KCNE1 channels for bupivacaine 22-fold (KCNQ1wt/KCNE1: IC50 = 2,431 +/- 582 microM, n = 20; KCNQ1A344V/KCNE1: IC50 = 110 +/- 9 microM, n = 24). Pharmacologic effects of the mutant channels were dominant when mutant and wild-type channels were coexpressed. Simulation of cardiac action potentials with the Luo-Rudy model yielded a prolongation of the cardiac action potential duration and induction of early afterdepolarizations by the mutation A344V that were aggravated by local anesthetic intoxication.
  
  
  CONCLUSIONS
  The results indicate that certain forms of the LQTS may constitute a specific pharmacogenetic risk factor for regional anesthesia.
authors.affiliation: Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Siebrands
authors.forename: Stephan
authors.initials: S
authors.lastname: Binder
authors.forename: Ulrike
authors.initials: U
authors.lastname: Eckhoff
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.forename: Patrick
authors.initials: P
authors.lastname: Friederich
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics*; D009154:Mutation; D029597:Romano-Ward Syndrome / Q000235:genetics*; D016593:Terfenadine / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D051668:Delayed Rectifier Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D016593:Terfenadine