Canadian Journal of Anesthesia

, Volume 46, Issue 12, pp 1156–1163 | Cite as

Intra-axonal continuous measurement of lidocaine concentration and pH in squid giant axon

  • Shigeru SanoEmail author
  • Satoshi Yokono
  • Hiroyuki Kinoshita
  • Kenji Ogli
  • Hiromu Satake
  • Takuo Kageyama
  • Shoji Kaneshina
Laboratory Investigations



To measure the dynamic penetration process of lidocaine, lidocaine concentration (Ci) and pH (pHi) in squid giant axon, and to determine the times and Ci of disappearance and reappearance of action potentials (AP).


Lidocaine solutions adjusted to four different pHs (pH = 5.5, 6.8, 7.8 and 9.0) were externally administered to the axon and Ci and pHi were measured using lidocaine and pH microsensors. The times and Ci when the AP just disappeared and reappeared were recorded. In addition, for comparison with Ci, the lidocaine content in the whole axon (Cw) was measured with high-performance liquid chromatography (HPLC).


The Ci (charged plus uncharged) was 1.5 times greater than the uncharged form of administered lidocaine. The changes in pHi depended on the increase in Ci. The AP disappeared only after administration of high pH lidocaine solutions (pH = 7.8, 9.0) and reappeared by washing out the solution in the chamber. Nerve block occurred more rapidly at pH 9.0 than at pH 7.8, and the time after washing out the lidocaine was longer at pH 9.0 than at pH 7.8. The mean Ci and charged lidocaine concentration in the axoplasm, when the AP disappeared or reappeared, were lower at pH 9.0 than at pH 7.8 (P < 0.05).


Uncharged lidocaine penetrates the axon membrane to the axoplasm where it changes to the charged form and is concentrated in the axon membrane and axoplasm. External application of uncharged lidocaine plays a role in modulating nerve conduction.


Lidocaine Nerve Conduction Charged Form Giant Axon Axon Membrane 
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Mesurer le processus de pénétration dynamique de la lidocaïne, la concentration de lidocaïne (Ci) et le pH (pHi) dans un axone géant de calmar et déterminer les temps et la Ci de disparition et de réapparition des potentiels d’action (PA).


Les solutions de lidocaïne, préparées selon quatre pH différents (pH = 5,5; 6,8; 7,8 et 9,0), ont été administrées sur la paroi externe de l’axone et la Ci et le pHi ont été mesurés en utilisant de la lidocaïne et des microdétecteurs de pH. Les temps et les Ci correspondants au moment de disparition et de réapparition du PA ont été enregistrés. De plus, pour comparer avec la Ci, le contenu de lidocaïne de l’axone complet (Cc) a été mesuré par Chromatographie liquide à haute pression (CLHP).


La Ci (ionisée plus non ionisée) a été 1,5 fois plus élevée que la forme non ionisée de lidocaïne administrée. Les changements de pHi dépendaient de l’augmentation de Ci. Le PA a disparu seulement après l’administration de solutions de lidocaïne à pH élevé (pH = 7,8; 9,0) et a réapparu quand on a rincé la solution dans la cuve. Le blocage nerveux est survenu plus rapidement sous un pH de 9,0 que sous un pH de 7,8 et le temps après le rinçage de la lidocaïne a été plus long sous un pH de 9,0 que sous un pH de 7,8. La Ci moyenne et la concentration de lidocaïne ionisée dans l’axoplasme, au moment où le PA disparaissait ou réapparaissait, ont été plus faibles sous un pH de 9,0 que sous un pH de 7,8 (P < 0,05).


La lidocaïne non ionisée pénètre la membrane axonale jusqu’à l’axoplasme où elle se transforme en lidocaïne ionisée et est concentrée dans la membrane axonale et l’axoplasme. L’application externe de lidocaïne non ionisée joue un rôle en modulant la conduction nerveuse.


  1. 1.
    Narahashi T, Frazier DT, Yamada M. The site of action and active form of local anesthetics. I. Theory and pH experiments with tertiary compound. J Pharmacol Exp Ther 1970; 171: 32–44.PubMedGoogle Scholar
  2. 2.
    Hille B. The pH-dependent rate of action of local anesthetics on the node of ranvier. J Gen Physiol 1977; 69: 475–96.PubMedCrossRefGoogle Scholar
  3. 3.
    Dettbarn WD, Heilbronn E, Hoskin FCG, Kitz R. The effects of pH on penetration and action of procaine14C, atropine3H, n-butanol14C and halothane14C in single giant axons of the squid. Neuropharmacology 1972; 11: 727–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Ohki S, Gravis C, Pant H. Permeability of axon membranes to local anesthetics. Biochim Biophys Acta 1981; 643: 495–507.PubMedCrossRefGoogle Scholar
  5. 5.
    Satake H, Miyata T, Kaneshina S. Coated wire electrodes sensitive to local anesthetic cations and their application to potentiometric determination. Bull Chem Soc Jpn 1991; 64: 3029–34.CrossRefGoogle Scholar
  6. 6.
    Yokono A, Satake H, Kaneshina S, Yokono S, Ogli K. Local anesthetic-scnsit ive electrodes: preparation of coated-wire electrodes and their basic properties in vitro. Anesth Analg 1992; 75: 1063–69.PubMedCrossRefGoogle Scholar
  7. 7.
    Kamaya H, Hayes JJ Jr, Ueda I. Dissociation constants of local anesthetics and their temperature dependence. Anesth Analg 1983; 62: 1025–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Satake H, Kageyama T, Kaneshina S, Sana S, Kinoshita H, Ogli K. Monitoring of intracellular pH on the uptake of lidocaine in squid giant axon. (Japanese) Anesth Resus 1996; 32: 61–5.Google Scholar
  9. 9.
    Satake H, Yajima M, Ikeda S, Kaneshina S. Determination of local anesthetic, lidocaine, in human whole blood. (Japanese) BUNSEKI KAGAKU 1994; 43: 799–803.Google Scholar
  10. 10.
    Ueda I, Oguchi K, Arakawa K. True oil/ water partition coefficients of procaine and lidocaine and estimation of their dissociation constants in organic solvents. Anesth Analg 1982; 61: 56–61.PubMedCrossRefGoogle Scholar
  11. 11.
    Boron WF. Intracellular pH-regulating mechanism of the squid axon. J Gen Physiol 1985; 85: 325–45.PubMedCrossRefGoogle Scholar
  12. 12.
    Walz W, Hinks EC. Extracellular hydrogen ions influence channel-mediated and carrier-mediated K+ fluxes in cultured mouse astrocytes. Neuroscience 1987; 20: 341–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Tombaugh GG, Somjen GG. Effects of extracellular pH on voltagegated Na+, K+ and Ca2+ currents in isolated rat CA1 neurons. J Physiol (Lond) 1996; 493: 719–32.Google Scholar
  14. 14.
    Bokesch PM, Raymond SA, Strichartz GR. Dependence of lidocaine potency on pH and PCO2. Anesth Analg 1987; 66: 9–17.PubMedGoogle Scholar
  15. 15.
    Richie JM, Green NM. Local anesthetics.In: Oilman AG, Goodman LS, Gilman A. (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 6th ed. New York: Macmillan Publishing Co. Inc., 1980: 300–20.Google Scholar

Copyright information

© Canadian Anesthesiologists 1999

Authors and Affiliations

  • Shigeru Sano
    • 4
    Email author
  • Satoshi Yokono
    • 4
  • Hiroyuki Kinoshita
    • 1
  • Kenji Ogli
    • 4
  • Hiromu Satake
    • 2
  • Takuo Kageyama
    • 3
  • Shoji Kaneshina
    • 3
  1. 1.Department of AnesthesiologyAsa Municipal HospitalHiroshima
  2. 2.Institute for Cooperative ResearchUniversity of TokushimaTokushimaJapan
  3. 3.Department of Biological Science and TechnologyUniversity of TokushimaTokushimaJapan
  4. 4.Department of Anesthesiology and Emergency MedicineKagawa Medical UniversityKagawaJapan

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