title: Lidocaine increases intracellular sodium concentration through a Na+-H+ exchanger in an identified Lymnaea neuron.
abstract: BACKGROUND
  The intracellular sodium concentration ([Na(+)]in) is related to neuron excitability. For [Na(+)]in, a Na(+)-H(+) exchanger plays an important role, which is affected by intracellular pH ([pH]in). However, the effect of lidocaine on [pH]in and a Na(+)-H(+) exchanger is unclear. We used neuron from Lymnaea stagnalis to determine how lidocaine affects [pH]in, Na(+)-H(+) exchanger, and [Na(+)]in.
  
  
  METHODS
  Intracellular sodium imaging by sodium-binding benzofuran isophthalate and intracellular pH imaging by 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein were used to measure [Na(+)]in and [pH]in. Measurements for [Na(+)]in were made in normal, Na(+) free saline, with modified extracellular pH, and a Na(+)-H(+) exchanger antagonist [(5-N-ethyl-N-isopropyl amiloride, N-methylisopropylamiloride, and 5-(N,N-hexamethylene)-amiloride) pretreatment trials. Furthermore, [Na(+)]in and [pH]in were recorded simultaneously. From 0.1 to 10 mM, lidocaine, mepivacaine, bupivacaine, prilocaine, and QX-314 were evaluated.
  
  
  RESULTS
  Lidocaine, mepivacaine, and prilocaine increased the [Na(+)]in in a dose-dependent manner. In contrast, QX-314 did not change the [Na(+)]in at each dose. In the Na(+) free saline or in the presence of each Na(+)-H(+) exchanger antagonist, lidocaine failed to increase [Na(+)]in. Lidocaine, mepivacaine, and prilocaine induced a significant decrease in [pH]in below baseline with an increase in [Na(+)]in. In contrast, QX-314 did not change the [pH]in. These results demonstrated that lidocaine increases [Na(+)]in through Na(+)-H(+) exchanger activated by intracellular acidification, which is induced by the proton trapping of lidocaine. This [Na(+)]in increase and [pH]in change induces cell toxicity.
  
  
  CONCLUSIONS
  Lidocaine increases the [Na(+)] through a Na(+)-H(+) exchanger by proton trapping.
authors.affiliation: Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Miyazaki, Kiyotake-Cho, Miyazaki 889-1692, Japan. pirotann@med.miyazaki-u.ac.jp
authors.forename: Shin
authors.initials: S
authors.lastname: Onizuka
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Kasaba
authors.forename: Ryuji
authors.initials: R
authors.lastname: Tamura
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takasaki
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity; D008195:Lymnaea / Q000187:drug effects* / Q000378:metabolism; D008619:Mepivacaine / Q000494:pharmacology; D008856:Microscopy, Fluorescence / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011318:Prilocaine / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000779:Anesthetics, Local; D017923:Sodium-Hydrogen Exchangers; D011318:Prilocaine; C057360:5-(N,N-hexamethylene)amiloride; C012647:QX-314; D000584:Amiloride; D008012:Lidocaine; D012964:Sodium; D008619:Mepivacaine; C039614:ethylisopropylamiloride