title: Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels.
abstract: BACKGROUND
  Inward rectifier K channels of the Kir2.x subfamily are widely expressed in neuronal tissues, controlling neuronal excitability. Previous studies reported that local anesthetics (LAs) do not affect Kir2 channels. However, the effects have not been studied at large concentrations used in regional anesthesia.
  
  
  METHODS
  This study used the patch-clamp technique to examine the effects of bupivacaine and lidocaine on Kir2.1, Kir2.2, and Kir2.3 channels expressed in human embryonic kidney 293 cells.
  
  
  RESULTS
  When applied extracellularly in whole-cell recordings, both LAs inhibited Kir2.x currents in a voltage-independent manner. Inhibition with bupivacaine was slow and irreversible, whereas that with lidocaine was fast and reversible. Kir2.3 displayed a greater sensitivity to bupivacaine than Kir2.1 and Kir2.2 (50% inhibitory concentrations at approximately 5 minutes, 0.6 vs 8-10 mM), whereas their sensitivities to lidocaine were similar (50% inhibitory concentrations, 1.5-2.7 mM). Increases in the charged/neutral ratio of the LAs at an acidic extracellular pH attenuated their inhibitory effects, and a permanently charged lidocaine derivative QX-314 exhibited no effects when applied extracellularly. Inside-out experiments demonstrated that inhibition of Kir2.1 with cytoplasmic lidocaine and QX-314 was rapid and reversible, whereas that induced by bupivacaine was slow and irreversible. Furthermore, dose-inhibition relations for the charged form of bupivacaine and lidocaine obtained at different cytoplasmic pHs could be approximated by a single relation for each LA.
  
  
  CONCLUSIONS
  The results indicate that both LAs at clinical concentrations equilibrated rapidly with the intracellular milieu, differentially inhibiting Kir2.x channel function from the cytoplasmic side.
authors.affiliation: From the *Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Saga University, Saga, Japan; and †Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nakahira
authors.forename: Kensuke
authors.initials: K
authors.lastname: Oshita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Sakaguchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishihara
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism* / Q000494:pharmacology; D002045:Bupivacaine / Q000378:metabolism* / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008012:Lidocaine / Q000378:metabolism* / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*
chemical_list: D000779:Anesthetics, Local; C489457:KCNJ2 protein, human; C099489:KCNJ4 protein, human; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D008012:Lidocaine; D002045:Bupivacaine