Summary
Guinea-pig papillary muscles were voltage-clamped using the single sucrose gap technique. The maximum upstroke velocity of the action potential (V max) was used as an indicator of the sodium conductance. Lidocaine (5 μmol/l to 40 μmol/l) reduced V max in a use-dependent fashion. Block of sodium channels developed during channel opening and while the channels were in-activated. Block of inactivated channels was not voltage-dependent over the −40 mV to +40 mV range. Recovery from block occurs upon repolarization, and for a given diastolic interval the recovery is more complete as the membrane potential is hyperpolarized over the −80 mV to −150 mV range. These results can be accounted for in terms of the modulated receptor hypothesis, where lidocaine has a low affinity for rested sodium channels, but a high affinity for open and inactivated channels.
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References
Bean BP, Cohen CJ, Tsien RW (1983) Lidocaine block of cardiac sodium channels. J Gen Physiol 81:613–642
Bigger JT, Mandel WJ (1970) Effect of lidocaine on conduction in canine Purkinje fibers and at the ventricular muscle-Purkinje fiber junction. J Pharmacol Exp Ther 172:239–254
Cahalan MD (1978) Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons. Biophys J 23:285–311
Chen C, Gettes LS, Katzung BG (1975) Effects of lidocaine and quinidine on steady-state characteristics and recovery kinetics of (dV/dt)max in guinea pig ventricular myocardium. Circ Res 37:20–29
Clarkson CW, Matsubara T, Hondeghem LM (1984) Slow inactivation of Vmax in guinea pig ventricular myocardium. Am J Physiol 247:645–654
Clarkson CW, Follmer CH, Yeh JZ, Ten Eick RE, Hondeghem LM (1985) Evidence for two components of sodium channel block by lidocaine in single isolated cardiac myocytes. Circulation 72 (Suppl III):38
Cohen CJ, Bean BP, Tsien RW (1984) Maximal upstroke velocity as an index of available sodium conductance: Comparison of maximal upstroke velocity and voltage clamp measurements of sodium current in rabbit Purkinje fibers. Circ Res 54:636–651
Courtney KR (1975) Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA 968. J Pharmacol Exp Ther 195:225–236
Covino BG, D'Amato HE (1968) Current status of antiarrhythmic drug therapy. J Electrocardiol 1:129–134
Davis LD, Temte JV (1969) Electrophysiological actions of lidocaine on canine ventricular muscle and Purkinje fibers. Circ Res 24:639–655
Fozzard HA, Hanck DA, Sheets MF (1987) Nonlinear relationship of maximal upstroke velocity to the sodium current in single canine cardiac Purkinje cells. J Physiol (Lond) 382:103P
Grant AO, Strauss LJ, Wallace AG, Strauss HC (1980) The influence of pH on the electrophysiological effects of lidocaine in guinea pig ventricular myocardium. Circ Res 47:542–550
Grant AO, Starmer CF, Strauss HC (1984) Antiarrhythmic drug action: Blockade of the inward sodium current. Circ Res 55:427–439
Heistracher P (1971) Mechanism of action of antifibrillatory drugs. Naunyn-Schmiedeberg's Arch Pharmacol 269:199–212
Hille B (1977) Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515
Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (Lond) 117:500–544
Hondeghem LM, Cotner CL (1978) Measurement of Vmax of the cardiac action potential with a sample/hold peak detector. Am J Physiol 234 (Heart Circ Physiol 3):H312-H314
Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398
Hondeghem LM, Katzung BG (1980) Test of a model of antiarrhythmic drug action: Effects of quinidine and lidocaine on myocardial conduction. Circulation 61:1217–1224
Hondeghem LM, Katzung BG (1984) Antiarrhythmic agents: The modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Ann Rev Pharmacol Toxicol 24:387–423
Hondeghem LM, Mason JW (1987) Agents used in cardiac arrhythmias. In: Katzung BG (ed) Basic and clinical pharmacology. Lange Publications. Los Altos, CA, USA
Lee KS, Hume JR, Giles W, Brown AM (1981) Sodium current depression by lidocaine and quinidine in isolated ventricular cells. Nature 291:325–327
Mason JW, Hondeghem LM, Katzung BG (1984) Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by aminodarone. Circ Res 55:277–285
Moyer JW (1985) The interaction of a series of aprindine derivatives with cardiac sodium channel. Dissertation, University of California San Francisco, San Francisco, CA, USA
New W, Trautwein W (1972) The ionic nature of slow inward current and its relation to contraction. Pflügers Arch 334:24–38
Obayashi K, Hayakawa H, Mandel WJ (1975) Interrelationships between external potassium concentration and lidocaine: effects on canine Purkinje fiber. Am Heart J 89:221–226
Oshita S, Sada H, Kojima M, Ban T (1980) Effects of tocainide and lidocaine on the transmembrane action potentials as related to external potassium and calcium concentrations in guinea pig papillary muscles. Naunyn-Schmiedeberg's Arch Pharmacol 314:67–82
Sanchez-Chapula J, Tsuda Y, Josephson IR (1983) Voltage- and use-dependent effects of lidocaine on sodium current in rat single ventricular cells. Circ Res 52: 557–565
Sanchez-Chapula J (1985) Interaction of lidocaine and benzocaine in depressing Vmax of ventricular action potentials. J Mol Cell Cardiol 17:495–503
Singh BN, Vaughan Williams EM (1971) Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res 29:286–295
Strichartz GR (1973) The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol 62:37–57
Walton M, Fozzard HA (1979) The relation of Vmax to I Na, 231–1 and h 00, in a model of the cardiac Purkinje fiber. Biophys J 25:407–420
Yeh JZ, Narahashi T (1977) Kinetic analysis of pancuronium interaction with sodium channels in squid axon membranes. J Gen Physiol 69:293–323
Yeh JZ, Tanguy J (1985) Na channel activation gate modulates slow recovery from use-dependent block by local anesthetics in squid giant axons. Biophys J 47:685–694
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L. Hondeghem is an Established Investigator of the American Heart Association
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Matsubara, T., Clarkson, C. & Hondeghem, L. Lidocaine blocks open and inactivated cardiac sodium channels. Naunyn-Schmiedeberg's Arch Pharmacol 336, 224–231 (1987). https://doi.org/10.1007/BF00165809
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DOI: https://doi.org/10.1007/BF00165809