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J Gen Physiol. 1983 May 1; 81(5): 613–642.
PMCID: PMC2216565

Lidocaine block of cardiac sodium channels

Abstract

Lidocaine block of cardiac sodium channels was studied in voltage-clamped rabbit purkinje fibers at drug concentrations ranging from 1 mM down to effective antiarrhythmic doses (5-20 μM). Dose-response curves indicated that lidocaine blocks the channel by binding one-to-one, with a voltage-dependent K(d). The half-blocking concentration varied from more than 300 μM, at a negative holding potential where inactivation was completely removed, to approximately 10 μM, at a depolarized holding potential where inactivation was nearly complete. Lidocaine block showed prominent use dependence with trains of depolarizing pulses from a negative holding potential. During the interval between pulses, repriming of I (Na) displayed two exponential components, a normally recovering component (τless than 0.2 s), and a lidocaine-induced, slowly recovering fraction (τ approximately 1-2 s at pH 7.0). Raising the lidocaine concentration magnified the slowly recovering fraction without changing its time course; after a long depolarization, this fraction was one-half at approximately 10 μM lidocaine, just as expected if it corresponded to drug-bound, inactivated channels. At less than or equal to 20 μM lidocaine, the slowly recovering fraction grew exponentially to a steady level as the preceding depolarization was prolonged; the time course was the same for strong or weak depolarizations, that is, with or without significant activation of I(Na). This argues that use dependence at therapeutic levels reflects block of inactivated channels, rather than block of open channels. Overall, these results provide direct evidence for the “modulated-receptor hypothesis” of Hille (1977) and Hondeghem and Katzung (1977). Unlike tetrodotoxin, lidocaine shows similar interactions with Na channels of heart, nerve, and skeletal muscle.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allen JD, Brennan FJ, Wit AL. Actions of lidocaine on transmembrane potentials of subendocardial Purkinje fibers surviving in infarcted canine hearts. Circ Res. 1978 Sep;43(3):470–481. [PubMed]
  • Armstrong CM, Bezanilla F. Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol. 1977 Nov;70(5):567–590. [PMC free article] [PubMed]
  • Arnsdorf MF. Electrophysiologic properties of antidysrhythmic drugs as a rational basis for therapy. Med Clin North Am. 1976 Mar;60(2):213–232. [PubMed]
  • Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady state TTX-sensitive ("window") sodium current in cardiac Purkinje fibres. Pflugers Arch. 1979 Mar 16;379(2):137–142. [PubMed]
  • Baer M, Best PM, Reuter H. Voltage-dependent action of tetrodotoxin in mammalian cardiac muscle. Nature. 1976 Sep 23;263(5575):344–345. [PubMed]
  • Bellet S, Roman L, Kostis JB, Fleischmann D. Intramuscular lidocaine in the therapy of ventricular arrhythmias. Am J Cardiol. 1971 Mar;27(3):291–293. [PubMed]
  • Bigger JT, Jr, Mandel WJ. Effect of lidocaine on the electrophysiological properties of ventricular muscle and purkinje fibers. J Clin Invest. 1970 Jan;49(1):63–77. [PMC free article] [PubMed]
  • Brennan FJ, Cranefield PF, Wit AL. Effects of lidocaine and on slow response and depressed fast response action potentials of canine cardiac Purkinje fibers. J Pharmacol Exp Ther. 1978 Feb;204(2):312–324. [PubMed]
  • Brown AM, Lee KS, Powell T. Sodium current in single rat heart muscle cells. J Physiol. 1981 Sep;318:479–500. [PubMed]
  • Cardinal R, Janse MJ, van Eeden I, Werner G, d'Alnoncourt CN, Durrer D. The effects of lidocaine on intracellular and extracellular potentials, activation, and ventricular arrhythmias during acute regional ischemia in the isolated porcine heart. Circ Res. 1981 Sep;49(3):792–806. [PubMed]
  • Carmeliet E, Saikawa T. Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac purkinje fibers. An effect on Na or K currents? Circ Res. 1982 Feb;50(2):257–272. [PubMed]
  • Chen C, Gettes LS. Combined effects of rate membrane potential, and drugs on maximum rate of rise (Vmax) of action potential upstroke of guinea pig papillary muscle. Circ Res. 1976 Jun;38(6):464–469. [PubMed]
  • Chen CM, Gettes LS, Katzung BG. Effect of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)max in guinea pig ventricular myocardium. Circ Res. 1975 Jul;37(1):20–29. [PubMed]
  • Chiu SY. Inactivation of sodium channels: second order kinetics in myelinated nerve. J Physiol. 1977 Dec;273(3):573–596. [PubMed]
  • Cohen CJ, Bean BP, Colatsky TJ, Tsien RW. Tetrodotoxin block of sodium channels in rabbit Purkinje fibers. Interactions between toxin binding and channel gating. J Gen Physiol. 1981 Oct;78(4):383–411. [PMC free article] [PubMed]
  • Cohen I, Attwell D, Strichartz G. The dependence of the maximum rate of rise of the action potential upstroke on membrane properties. Proc R Soc Lond B Biol Sci. 1981 Dec 9;214(1194):85–98. [PubMed]
  • Cohen IS, Strichartz GR. On the voltage-dependent action of tetrodotoxin. Biophys J. 1977 Mar;17(3):275–279. [PubMed]
  • Colatsky TJ. Voltage clamp measurements of sodium channel properties in rabbit cardiac Purkinje fibres. J Physiol. 1980 Aug;305:215–234. [PubMed]
  • Colatsky TJ. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. An effect on steady state sodium currents? Circ Res. 1982 Jan;50(1):17–27. [PubMed]
  • Colatsky TJ, Tsien RW. Electrical properties associated with wide intercellular clefts in rabbit Purkinje fibres. J Physiol. 1979 May;290(2):227–252. [PubMed]
  • Colatsky JJ, Tsien RW. Sodium channels in rabbit cardiac Purkinje fibres. Nature. 1979 Mar 15;278(5701):265–268. [PubMed]
  • Colquhoun D, Neher E, Reuter H, Stevens CF. Inward current channels activated by intracellular Ca in cultured cardiac cells. Nature. 1981 Dec 24;294(5843):752–754. [PubMed]
  • Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Physiol. 1979 Apr;236(4):H561–H567. [PubMed]
  • Courtney KR. 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]
  • Courtney KR. Fast frequency-dependent block of action potential upstroke in rabbit atrium by small local anesthetics. Life Sci. 1979 Apr 23;24(17):1581–1588. [PubMed]
  • Courtney KR. Extracellular pH selectively modulates recovery from sodium inactivation in frog myelinated nerve. Biophys J. 1979 Nov;28(2):363–368. [PubMed]
  • Courtney KR. Comparative actions of mexiletine on sodium channels in nerve, skeletal and cardiac muscle. Eur J Pharmacol. 1981 Aug 27;74(1):9–18. [PubMed]
  • Davis LD, Temte JV. Electrophysiological actions of lidocaine on canine ventricular muscle and Purkinje fibers. Circ Res. 1969 May;24(5):639–655. [PubMed]
  • Deitmer JW, Ellis D. The intracellular sodium activity of sheep heart Purkinje fibres: effects of local anaesthetics and tetrodotoxin. J Physiol. 1980 Mar;300:269–282. [PubMed]
  • Deitmer JW, Ellis D. Interactions between the regulation of the intracellular pH and sodium activity of sheep cardiac Purkinje fibres. J Physiol. 1980 Jul;304:471–488. [PubMed]
  • Dudel J, Peper K, Rüdel R, Trautwein W. The effect of tetrodotoxin on the membrane current in cardiac muscle (Purkinje fibers). Pflugers Arch Gesamte Physiol Menschen Tiere. 1967;295(3):213–226. [PubMed]
  • Ellis D, Thomas RC. Direct measurement of the intracellular pH of mammalian cardiac muscle. J Physiol. 1976 Nov;262(3):755–771. [PubMed]
  • Ferrier GR. Digitalis arrhythmias: role of oscillatory afterpotentials. Prog Cardiovasc Dis. 1977 May-Jun;19(6):459–474. [PubMed]
  • Gadsby DC, Cranefield PF. Two levels of resting potential in cardiac Purkinje fibers. J Gen Physiol. 1977 Dec;70(6):725–746. [PMC free article] [PubMed]
  • Gettes LS. Physiology and pharmacology of antiarrhythmic drugs. Hosp Pract (Off Ed) 1981 Oct;16(10):89–101. [PubMed]
  • Gianelly R, von der Groeben JO, Spivack AP, Harrison DC. Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med. 1967 Dec 7;277(23):1215–1219. [PubMed]
  • Grant AO, Strauss LJ, Wallace AG, Strauss HC. The influence of pH on th electrophysiological effects of lidocaine in guinea pig ventricular myocardium. Circ Res. 1980 Oct;47(4):542–550. [PubMed]
  • Hauswirth O, Singh BN. Ionic mechanisms in heart muscle in relation to the genesis and the pharmacological control of cardiac arrhythmias. Pharmacol Rev. 1978 Mar;30(1):5–63. [PubMed]
  • Heistracher P. Mechanism of action of antifibrillatory drugs. Naunyn Schmiedebergs Arch Pharmakol. 1971;269(2):199–212. [PubMed]
  • Hill JL, Gettes LS. Effect of acute coronary artery occlusion on local myocardial extracellular K+ activity in swine. Circulation. 1980 Apr;61(4):768–778. [PubMed]
  • Hille B. The permeability of the sodium channel to organic cations in myelinated nerve. J Gen Physiol. 1971 Dec;58(6):599–619. [PMC free article] [PubMed]
  • Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. [PMC free article] [PubMed]
  • HODGKIN AL, HUXLEY AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500–544. [PubMed]
  • Hondeghem LM, Grant AO, Jensen RA. Antiarrhythmic drug action: selective depression of hypoxic cardiac cells. Am Heart J. 1974 May;87(5):602–605. [PubMed]
  • Hondeghem LM, Katzung BG. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta. 1977 Nov 14;472(3-4):373–398. [PubMed]
  • Hondeghem L, Katzung BG. Test of a model of antiarrhythmic drug action. Effects of quinidine and lidocaine on myocardial conduction. Circulation. 1980 Jun;61(6):1217–1224. [PubMed]
  • Iven H, Brasch H. Effects of the local anesthetics brufacain and lidocaine on transmembrane action potentials, refractory period, and reactivation of the sodium system in guinea pig heart muscle. Naunyn Schmiedebergs Arch Pharmacol. 1977 Mar;297(2):153–161. [PubMed]
  • JOHNSON EA, McKINNON MG. The differential effect of quinidine and pyrilamine on the myocardial action potential at various rates of stimulation. J Pharmacol Exp Ther. 1957 Aug;120(4):460–468. [PubMed]
  • Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres. J Physiol. 1978 Aug;281:187–208. [PubMed]
  • Kass RS, Tsien RW, Weingart R. Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibres. J Physiol. 1978 Aug;281:209–226. [PubMed]
  • Kupersmith J. Electrophysiological and antiarrhythmic effects of lidocaine in canine acute myocardial ischemia. Am Heart J. 1979 Mar;97(3):360–366. [PubMed]
  • Kupersmith J, Antman EM, Hoffman BF. In vivo electrophysiological effects of lidocaine in canine acute myocardial infarction. Circ Res. 1975 Jan;36(1):84–91. [PubMed]
  • Lazzara R, Hope RR, El-Sherif N, Scherlag BJ. Effects of lidocaine on hypoxic and ischemic cardiac cells. Am J Cardiol. 1978 May 1;41(5):872–879. [PubMed]
  • Lee KS, Hume JR, Giles W, Brown AM. Sodium current depression by lidocaine and quinidine in isolated ventricular cells. Nature. 1981 May 28;291(5813):325–327. [PubMed]
  • Oshita S, Sada H, Kojima M, Ban T. Effects of tocainide and lidocaine on the transmembrane action potentials as related to external potassium and calcium concentrations in guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol. 1980 Oct;314(1):67–82. [PubMed]
  • Rosen MR, Danilo P., Jr Effects of tetrodotoxin, lidocaine, verapamil, and AHR-2666 on Ouabain-induced delayed afterdepolarizations in canine Purkinje fibers. Circ Res. 1980 Jan;46(1):117–124. [PubMed]
  • Rosen MR, Wit AL, Hoffman BF. Electrophysiology and pharmacology of cardiac arrhythmias. IV. Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J. 1975 Mar;89(3):391–399. [PubMed]
  • Rosen MR, Hoffman BF, Wit AL. Electrophysiology and pharmacology of cardiac arrhythmias. V. Cardiac antiarrhythmic effects of lidocaine. Am Heart J. 1975 Apr;89(4):526–536. [PubMed]
  • Schmidtmayer J, Ulbricht W. Interaction of lidocaine and benzocaine in blocking sodium channels. Pflugers Arch. 1980 Aug;387(1):47–54. [PubMed]
  • Schwarz W, Palade PT, Hille B. Local anesthetics. Effect of pH on use-dependent block of sodium channels in frog muscle. Biophys J. 1977 Dec;20(3):343–368. [PubMed]
  • Singh BN, Williams EM. Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res. 1971 Sep;29(3):286–295. [PubMed]
  • Ulbricht W, Wagner HH. The influence of pH on equilibrium effects of tetrodotoxin on myelinated nerve fibres of Rana esculenta. J Physiol. 1975 Oct;252(1):159–184. [PubMed]
  • Wald RW, Waxman MB, Downar E. The effect of antiarrhythmic drugs on depressed conduction and unidirectional block in sheep Purkinje fibers. Circ Res. 1980 May;46(5):612–619. [PubMed]
  • WEIDMANN S. Effects of calcium ions and local anesthetics on electrical properties of Purkinje fibres. J Physiol. 1955 Sep 28;129(3):568–582. [PubMed]
  • Weld FM, Bigger JT., Jr Effect of lidocaine on the early inward transient current in sheep cardiac Purkinje fibers. Circ Res. 1975 Nov;37(5):630–639. [PubMed]
  • Weld FM, Bigger JT., Jr The effect of lidocaine on diastolic transmembrane currents determining pacemaker depolarization in cardiac Purkinje fibers. Circ Res. 1976 Mar;38(3):203–208. [PubMed]
  • Zipes DP, Arbel E, Knope RF, Moe GK. Accelerated cardiac escape rhythms caused by ouabain intoxication. Am J Cardiol. 1974 Feb;33(2):248–253. [PubMed]

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