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Local anesthetics: hydrophilic and hydrophobic pathways for the drug- receptor reaction

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PMCID: PMC2215053  PMID:300786

Abstract

The properties of Na channels of the node of Ranvier are altered by neutral, amine, and quaternary local anesthetic compounds. The kinetics of the Na currents are governed by a composite of voltage- and time- dependent gating processes with voltage- and time-dependent block of channels by drug. Conventional measurements of steady-state sodium inactivation by use of 50-ms prepulses show a large negative voltage shift of the inactivation curve with neutral benzocaine and with some ionizable amines like lidocaine and tetracaine, but no shift is seen with quaternary OX-572. However, when the experiment is done with repetitive application of a prepulse-testpulse waveform, a shift with the quaternary cations (applied internally) is seen as well. 1-min hyperpolarizations of lidocaine- or tetracaine-treated fibers restore two to four times as many channels to the conducting pool as 50-ms hyperpolarizations. Raising the external Ca++ concentration also has a strong unblocking effect. These manipulations do not relieve block in fibers treated with internal quaternary drugs. The results are interpreted in terms of a single receptor in Na channels for the different drug types. Lipid-soluble drug forms are thought to come and go from the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass via a hydrophilic region (the inner channel mouth). The hydrophilic pathway is open only when the gates of the channel are open. Any drug form in the channel increases the probability of closing the inactivation gate which, in effect, is equivalent to a negative shift of the voltage dependence of inactivation.

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Selected References

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  1. ACEVES J., MACHNE X. The action of calcium and of local anesthetics on nerve cells, and their interaction during excitation. J Pharmacol Exp Ther. 1963 May;140:138–148. [PubMed] [Google Scholar]
  2. Armstrong C. M. Time course of TEA(+)-induced anomalous rectification in squid giant axons. J Gen Physiol. 1966 Nov;50(2):491–503. doi: 10.1085/jgp.50.2.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blaustein M. P., Goldman D. E. Competitive action of calcium and procaine on lobster axon. A study of the mechanism of action of certain local anesthetics. J Gen Physiol. 1966 May;49(5):1043–1063. doi: 10.1085/jgp.49.5.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cahalan M. D. Modification of sodium channel gating in frog myelinated nerve fibres by Centruroides sculpturatus scorpion venom. J Physiol. 1975 Jan;244(2):511–534. doi: 10.1113/jphysiol.1975.sp010810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Courtney K. R. Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther. 1975 Nov;195(2):225–236. [PubMed] [Google Scholar]
  6. FRANKENHAEUSER B. Quantitative description of sodium currents in myelinated nerve fibres of Xenopus laevis. J Physiol. 1960 Jun;151:491–501. doi: 10.1113/jphysiol.1960.sp006455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fox J. M. Ultra-slow inactivation of the ionic currents through the membrane of myelinated nerve. Biochim Biophys Acta. 1976 Mar 5;426(2):232–244. doi: 10.1016/0005-2736(76)90334-5. [DOI] [PubMed] [Google Scholar]
  8. Gettes L. S., Reuter H. Slow recovery from inactivation of inward currents in mammalian myocardial fibres. J Physiol. 1974 Aug;240(3):703–724. doi: 10.1113/jphysiol.1974.sp010630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. HODGKIN A. L., HUXLEY A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500–544. doi: 10.1113/jphysiol.1952.sp004764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hille B. Charges and potentials at the nerve surface. Divalent ions and pH. J Gen Physiol. 1968 Feb;51(2):221–236. doi: 10.1085/jgp.51.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hille B. Common mode of action of three agents that decrease the transient change in sodium permeability in nerves. Nature. 1966 Jun 18;210(5042):1220–1222. doi: 10.1038/2101220a0. [DOI] [PubMed] [Google Scholar]
  12. Hille B. The pH-dependent rate of action of local anesthetics on the node of Ranvier. J Gen Physiol. 1977 Apr;69(4):475–496. doi: 10.1085/jgp.69.4.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hille B., Woodhull A. M., Shapiro B. I. Negative surface charge near sodium channels of nerve: divalent ions, monovalent ions, and pH. Philos Trans R Soc Lond B Biol Sci. 1975 Jun 10;270(908):301–318. doi: 10.1098/rstb.1975.0011. [DOI] [PubMed] [Google Scholar]
  14. KHODOROV B. I., BELIAEV V. I. O VOSSTANAVLIVAIUSHCHEM VLIIANII IONOV NIKELIA I KADMIIA NA AL'TERIROVANNYE PEREKHVATY RANV'E. Tsitologiia. 1964 Nov-Dec;6(6):680–687. [PubMed] [Google Scholar]
  15. Narahashi T., Frazier D. T., Takeno K. Effects of calcium on the local anesthetic suppression of ionic conductances in squid axon membranes. J Pharmacol Exp Ther. 1976 May;197(2):426–438. [PubMed] [Google Scholar]
  16. Neumcke B., Fox J. M., Drouin H., Schwarz W. Kinetics of the slow variation of peak sodium current in the membrane of myelinated nerve following changes of holding potential or extracellular pH. Biochim Biophys Acta. 1976 Mar 5;426(2):245–257. doi: 10.1016/0005-2736(76)90335-7. [DOI] [PubMed] [Google Scholar]
  17. POSTERNAK J., ARNOLD E. Action de l'anélectrotonus et d'une solution hypersodique sur la conduction dans un nerf narcotisé. J Physiol (Paris) 1954;46(1):502–505. [PubMed] [Google Scholar]
  18. Peganov E. M., Khodorov B. I., Shishkova L. D. Medlennaia natrievaia inaktivatsiia v membrane perekhvata Ranve. Rol' naruzhnogo kaliia. Biull Eksp Biol Med. 1973 Sep;76(9):15–19. [PubMed] [Google Scholar]
  19. Seeman P., Chen S. S., Chau-Wong M., Staiman A. Calcium reversal of nerve blockade by alcohols, anesthetics, tranquilizers, and barbiturates. Can J Physiol Pharmacol. 1974 Jun;52(3):526–534. doi: 10.1139/y74-070. [DOI] [PubMed] [Google Scholar]
  20. TAYLOR R. E. Effect of procaine on electrical properties of squid axon membrane. Am J Physiol. 1959 May;196(5):1071–1078. doi: 10.1152/ajplegacy.1959.196.5.1071. [DOI] [PubMed] [Google Scholar]
  21. Vogel W. Calcium and lanthanum effects at the nodal membrane. Pflugers Arch. 1974;350(1):25–39. doi: 10.1007/BF00586736. [DOI] [PubMed] [Google Scholar]
  22. WEIDMANN S. Effects of calcium ions and local anesthetics on electrical properties of Purkinje fibres. J Physiol. 1955 Sep 28;129(3):568–582. doi: 10.1113/jphysiol.1955.sp005379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Yeh J. Z., Oxford G. S., Wu C. H., Narahashi T. Interactions of aminopyridines with potassium channels of squid axon membranes. Biophys J. 1976 Jan;16(1):77–81. doi: 10.1016/S0006-3495(76)85663-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

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