The Journal of General Physiology, Vol 69, 497-515, Copyright © 1977 by The Rockefeller University Press

ARTICLES

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

B Hille

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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				H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]

				T. Narahashi Neuroreceptors and Ion Channels as the Basis for Drug Action: Past, Present, and Future J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 1 - 26. [Abstract] [Full Text]

				J C Hancox, K C R Patel, and J V Jones Antiarrhythmics---from cell to clinic: past, present, and future Heart, July 1, 2000; 84(1): 14 - 24. [Full Text] [PDF]

				Y.-F. Xiao, S. N. Wright, G. K. Wang, J. P. Morgan, and A. Leaf Coexpression with beta 1-subunit modifies the kinetics and fatty acid block of hH1alpha Na+ channels Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H35 - H46. [Abstract] [Full Text] [PDF]

				C.-J. Huang, I. Favre, and E. Moczydlowski Permeation of Large Tetra-Alkylammonium Cations through Mutant and Wild-Type Voltage-Gated Sodium Channels as Revealed by Relief of Block at High Voltage J. Gen. Physiol., April 1, 2000; 115(4): 435 - 454. [Abstract] [Full Text] [PDF]

				Z. Chen, B.-H. Ong, N. G Kambouris, E. Marban, G. F Tomaselli, and J. R Balser Lidocaine induces a slow inactivated state in rat skeletal muscle sodium channels J. Physiol., April 1, 2000; 524(1): 37 - 49. [Abstract] [Full Text] [PDF]

				H. Vais, M. S. Williamson, S. J. Goodson, A. L. Devonshire, J. W. Warmke, P. N.R. Usherwood, and C. J. Cohen Activation of Drosophila Sodium Channels Promotes Modification by Deltamethrin: Reductions in Affinity Caused by Knock-down Resistance Mutations J. Gen. Physiol., March 1, 2000; 115(3): 305 - 318. [Abstract] [Full Text] [PDF]

				J. S. Mitcheson, J. Chen, and M. C. Sanguinetti Trapping of a Methanesulfonanilide by Closure of the Herg Potassium Channel Activation Gate J. Gen. Physiol., March 1, 2000; 115(3): 229 - 240. [Abstract] [Full Text] [PDF]

				Y. Kanai, H. Katsuki, and M. Takasaki Comparisons of the Anesthetic Potency and Intracellular Concentrations of S(-) and R() Bupivacaine and Ropivacaine in Crayfish Giant Axon in Vitro Anesth. Analg., February 1, 2000; 90(2): 415 - 415. [Abstract] [Full Text] [PDF]

				J. C. Gomora, L. Xu, J. A. Enyeart, and J. J. Enyeart Effect of Mibefradil on Voltage-Dependent Gating and Kinetics of T-Type Ca2+ Channels in Cortisol-Secreting Cells J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 96 - 103. [Abstract] [Full Text]

				T. Nagatomo, C. T. January, and J. C. Makielski Preferential Block of Late Sodium Current in the LQT3 Delta KPQ Mutant by the Class IC Antiarrhythmic Flecainide Mol. Pharmacol., January 1, 2000; 57(1): 101 - 107. [Abstract] [Full Text]

				J. C. Gomora, J. A. Enyeart, and J. J. Enyeart Mibefradil Potently Blocks ATP-Activated K+ Channels in Adrenal Cells Mol. Pharmacol., December 1, 1999; 56(6): 1192 - 1197. [Abstract] [Full Text]

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