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. 1989 Jun;83(6):2109–2119. doi: 10.1172/JCI114124

Characterization of concentration- and use-dependent effects of quinidine from conduction delay and declining conduction velocity in canine Purkinje fibers.

D L Packer 1, A O Grant 1, H C Strauss 1, C F Starmer 1
PMCID: PMC303938  PMID: 2542382

Abstract

The dynamic response of squared conduction velocity, theta 2, to repetitive stimulation in canine Purkinje fibers with quinidine was studied using a double-microelectrode technique. With stimulation, a frequency-dependent monoexponential increase in conduction delay (CD) and a decline in theta 2 were observed. The exponential rates and changes in steady-state CD and theta 2 were frequency- and concentration-dependent. The overall drug uptake rates describing blockade and the interpulse recovery interval were linearly related and steady-state values of theta 2 were linearly related to an exponential function of the stimulus intervals. Based on first-order binding, the frequency- and concentration-dependent properties of quinidine were characterized by the apparent binding and unbinding rates of 14.2 +/- 5.7 X 10(6) mol-1.s-1 and 63 +/- 12 s-1 for activated and 14.8 +/- 1.0 X 10(2) mol-1.s-1 and 0.16 +/- 0.03 s-1 for resting states. The recovery time constant extracted from the pulse train interpulse interval was 5.8 +/- 1.5 s compared with 5.1 +/- 0.6 s determined from a posttrain test pulse protocol. This study demonstrates that the kinetics of drug action can be derived from measures of impulse propagation. This provides a basis for characterizing frequency-dependent properties of antiarrhythmic agents in vivo and suggests the plausibility of a quantitative assessment of drug binding and recovery rates in man.

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Selected References

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  1. Arnsdorf M. F., Sawicki G. J. Effects of quinidine sulfate on the balance among active and passive cellular properties that comprise the electrophysiologic matrix and determine excitability in sheep Purkinje fibers. Circ Res. 1987 Aug;61(2):244–255. doi: 10.1161/01.res.61.2.244. [DOI] [PubMed] [Google Scholar]
  2. Bean B. P., Cohen C. J., Tsien R. W. Lidocaine block of cardiac sodium channels. J Gen Physiol. 1983 May;81(5):613–642. doi: 10.1085/jgp.81.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Browning D. J., Strauss H. C. Effects of stimulation frequency on potassium activity and cell volume in cardiac tissue. Am J Physiol. 1981 Jan;240(1):C39–C55. doi: 10.1152/ajpcell.1981.240.1.C39. [DOI] [PubMed] [Google Scholar]
  4. Buchanan J. W., Jr, Saito T., Gettes L. S. The effects of antiarrhythmic drugs, stimulation frequency, and potassium-induced resting membrane potential changes on conduction velocity and dV/dtmax in guinea pig myocardium. Circ Res. 1985 May;56(5):696–703. doi: 10.1161/01.res.56.5.696. [DOI] [PubMed] [Google Scholar]
  5. Chen C. M., Gettes L. S., Katzung B. G. 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. doi: 10.1161/01.res.37.1.20. [DOI] [PubMed] [Google Scholar]
  6. Chen C., Gettes L. S. 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. doi: 10.1161/01.res.38.6.464. [DOI] [PubMed] [Google Scholar]
  7. Cohen C. J., Bean B. P., Tsien R. W. 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. 1984 Jun;54(6):636–651. doi: 10.1161/01.res.54.6.636. [DOI] [PubMed] [Google Scholar]
  8. Cohen I. S., Strichartz G. R. On the voltage-dependent action of tetrodotoxin. Biophys J. 1977 Mar;17(3):275–279. doi: 10.1016/S0006-3495(77)85656-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Courtney K. R. Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium. J Mol Cell Cardiol. 1980 Nov;12(11):1273–1286. doi: 10.1016/0022-2828(80)90071-1. [DOI] [PubMed] [Google Scholar]
  10. Courtney K. R., Kendig J. J., Cohen E. N. The rates of interaction of local anesthetics with sodium channels in nerve. J Pharmacol Exp Ther. 1978 Nov;207(2):594–604. [PubMed] [Google Scholar]
  11. 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]
  12. Courtney K. R. Quantifying antiarrhythmic drug blocking during action potentials in guinea-pig papillary muscle. J Mol Cell Cardiol. 1983 Nov;15(11):749–757. doi: 10.1016/0022-2828(83)90334-6. [DOI] [PubMed] [Google Scholar]
  13. Davis J., Matsubara T., Scheinman M. M., Katzung B., Hondeghem L. H. Use-dependent effects of lidocaine on conduction in canine myocardium: application of the modulated receptor hypothesis in vivo. Circulation. 1986 Jul;74(1):205–214. doi: 10.1161/01.cir.74.1.205. [DOI] [PubMed] [Google Scholar]
  14. Donati F., Kunov H. A model for studying velocity variations in unmyelinated axons. IEEE Trans Biomed Eng. 1976 Jan;23(1):23–28. doi: 10.1109/tbme.1976.324611. [DOI] [PubMed] [Google Scholar]
  15. Ellenbogen K. A., German L. D., O'Callaghan W. G., Colavita P. G., Marchese A. C., Gilbert M. R., Strauss H. C. Frequency-dependent effects of verapamil on atrioventricular nodal conduction in man. Circulation. 1985 Aug;72(2):344–352. doi: 10.1161/01.cir.72.2.344. [DOI] [PubMed] [Google Scholar]
  16. GETTES L. S., SURAWICZ B., SHIUE J. C. Effect of high K, and low K quinindine on QRS duration and ventricular action potential. Am J Physiol. 1962 Dec;203:1135–1140. doi: 10.1152/ajplegacy.1962.203.6.1135. [DOI] [PubMed] [Google Scholar]
  17. Gang E. S., Denton T. A., Oseran D. S., Mandel W. J., Peter T. Rate-dependent effects of procainamide on His-Purkinje conduction in man. Am J Cardiol. 1985 Jun 1;55(13 Pt 1):1525–1529. doi: 10.1016/0002-9149(85)90966-x. [DOI] [PubMed] [Google Scholar]
  18. Grant A. O., Starmer C. F. Mechanisms of closure of cardiac sodium channels in rabbit ventricular myocytes: single-channel analysis. Circ Res. 1987 Jun;60(6):897–913. doi: 10.1161/01.res.60.6.897. [DOI] [PubMed] [Google Scholar]
  19. Grant A. O., Trantham J. L., Brown K. K., Strauss H. C. PH-Dependent effects of quinidine on the kinetics of dV/dtmax in guinea pig ventricular myocardium. Circ Res. 1982 Feb;50(2):210–217. doi: 10.1161/01.res.50.2.210. [DOI] [PubMed] [Google Scholar]
  20. Heistracher P. Mechanism of action of antifibrillatory drugs. Naunyn Schmiedebergs Arch Pharmakol. 1971;269(2):199–212. doi: 10.1007/BF01003037. [DOI] [PubMed] [Google Scholar]
  21. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hondeghem L. M., Cotner C. L. Measurement of Vmax of the cardiac action potential with a sample/hold peak detector. Am J Physiol. 1978 Mar;234(3):H312–H314. doi: 10.1152/ajpheart.1978.234.3.H312. [DOI] [PubMed] [Google Scholar]
  23. Hondeghem L. M., Katzung B. G. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta. 1977 Nov 14;472(3-4):373–398. doi: 10.1016/0304-4157(77)90003-x. [DOI] [PubMed] [Google Scholar]
  24. Hondeghem L. M., Matsubara T. Quinidine and lidocaine: activation and inactivation block. Proc West Pharmacol Soc. 1984;27:19–21. [PubMed] [Google Scholar]
  25. Hondeghem L. M. Validity of Vmax as a measure of the sodium current in cardiac and nervous tissues. Biophys J. 1978 Jul;23(1):147–152. doi: 10.1016/S0006-3495(78)85439-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. JOHNSON E. A., McKINNON M. G. 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] [Google Scholar]
  27. Kline R., Morad M. Potassium efflux and accumulation in heart muscle. Evidence from K +/- electrode experiments. Biophys J. 1976 Apr;16(4):367–372. doi: 10.1016/S0006-3495(76)85694-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kohlhardt M., Seifert C. Inhibition of Vmax of the action potential by propafenone and its voltage-, time- and pH-dependence in mammalian ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol. 1980;315(1):55–62. doi: 10.1007/BF00504230. [DOI] [PubMed] [Google Scholar]
  29. Kojima M., Ban T. Nicorandil shortens action potential duration and antagonises the reduction of Vmax by lidocaine but not by disopyramide in guinea-pig papillary muscles. Naunyn Schmiedebergs Arch Pharmacol. 1988 Feb;337(2):203–212. doi: 10.1007/BF00169249. [DOI] [PubMed] [Google Scholar]
  30. Kunze D. L. Rate-dependent changes in extracellular potassium in the rabbit atrium. Circ Res. 1977 Jul;41(1):122–127. doi: 10.1161/01.res.41.1.122. [DOI] [PubMed] [Google Scholar]
  31. Morady F., DiCarlo L. A., Jr, Baerman J. M., Krol R. B. Rate-dependent effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction. J Am Coll Cardiol. 1985 Jul;6(1):179–185. doi: 10.1016/s0735-1097(85)80272-2. [DOI] [PubMed] [Google Scholar]
  32. Nattel S., Elharrar V., Zipes D. P., Bailey J. C. pH-dependent electrophysiological effects of quinidine and lidocaine on canine cardiac purkinje fibers. Circ Res. 1981 Jan;48(1):55–61. doi: 10.1161/01.res.48.1.55. [DOI] [PubMed] [Google Scholar]
  33. Nattel S. Frequency-dependent effects of amitriptyline on ventricular conduction and cardiac rhythm in dogs. Circulation. 1985 Oct;72(4):898–906. doi: 10.1161/01.cir.72.4.898. [DOI] [PubMed] [Google Scholar]
  34. Nattel S. Interval-dependent effects of lidocaine on conduction in canine cardiac Purkinje fibers: experimental observations and theoretical analysis. J Pharmacol Exp Ther. 1987 Apr;241(1):275–281. [PubMed] [Google Scholar]
  35. Nattel S. Relationship between use-dependent effects of antiarrhythmic drugs on conduction and Vmax in canine cardiac Purkinje fibers. J Pharmacol Exp Ther. 1987 Apr;241(1):282–288. [PubMed] [Google Scholar]
  36. Schwarz W., Palade P. T., 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. doi: 10.1016/S0006-3495(77)85554-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Starmer C. F., Grant A. O. Phasic ion channel blockade. A kinetic model and parameter estimation procedure. Mol Pharmacol. 1985 Oct;28(4):348–356. [PubMed] [Google Scholar]
  38. Starmer C. F., Grant A. O., Strauss H. C. Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J. 1984 Jul;46(1):15–27. doi: 10.1016/S0006-3495(84)83994-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Starmer C. F., Hollett M. D. Mechanisms of apparent affinity variation of guarded receptors. J Theor Biol. 1985 Aug 7;115(3):337–349. doi: 10.1016/s0022-5193(85)80196-x. [DOI] [PubMed] [Google Scholar]
  40. Starmer C. F., Kerr R. B. Simulation of use-dependent uptake of ion channel blocking agents by excitable membranes. IEEE Trans Biomed Eng. 1985 Oct;32(10):770–774. doi: 10.1109/TBME.1985.325492. [DOI] [PubMed] [Google Scholar]
  41. Starmer C. F., Packer D. L., Grant A. O. Ligand binding to transiently accessible sites: mechanisms for varying apparent binding rates. J Theor Biol. 1987 Feb 7;124(3):335–341. doi: 10.1016/s0022-5193(87)80120-0. [DOI] [PubMed] [Google Scholar]
  42. Starmer C. F. Theoretical characterization of ion channel blockade: ligand binding to periodically accessible receptors. J Theor Biol. 1986 Mar 21;119(2):235–249. doi: 10.1016/s0022-5193(86)80077-7. [DOI] [PubMed] [Google Scholar]
  43. Starmer C. F., Yeh J. Z., Tanguy J. A quantitative description of QX222 blockade of sodium channels in squid axons. Biophys J. 1986 Apr;49(4):913–920. doi: 10.1016/S0006-3495(86)83719-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Strichartz G. R. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol. 1973 Jul;62(1):37–57. doi: 10.1085/jgp.62.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Talajic M., Nattel S. Frequency-dependent effects of calcium antagonists on atrioventricular conduction and refractoriness: demonstration and characterization in anesthetized dogs. Circulation. 1986 Nov;74(5):1156–1167. doi: 10.1161/01.cir.74.5.1156. [DOI] [PubMed] [Google Scholar]
  46. Vassalle M. Electrogenic suppression of automaticity in sheep and dog purkinje fibers. Circ Res. 1970 Sep;27(3):361–377. doi: 10.1161/01.res.27.3.361. [DOI] [PubMed] [Google Scholar]
  47. 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]
  48. Wallace A. G., Cline R. E., Sealy W. C., Young W. G., Jr, Troyer W. G., Jr Electrophysiologic effects of quinidine. Studies using chronically implanted electrodes in awake dogs with and without cardiac denervation. Circ Res. 1966 Nov;19(5):960–969. doi: 10.1161/01.res.19.5.960. [DOI] [PubMed] [Google Scholar]
  49. Walton M. K., Fozzard H. A. Experimental study of the conducted action potential in cardiac Purkinje strands. Biophys J. 1983 Oct;44(1):1–8. doi: 10.1016/S0006-3495(83)84272-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Walton M. K., Fozzard H. A. The conducted action potential. Models and comparison to experiments. Biophys J. 1983 Oct;44(1):9–26. doi: 10.1016/S0006-3495(83)84273-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wang G. K., Brodwick M. S., Eaton D. C., Strichartz G. R. Inhibition of sodium currents by local anesthetics in chloramine-T-treated squid axons. The role of channel activation. J Gen Physiol. 1987 Apr;89(4):645–667. doi: 10.1085/jgp.89.4.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Weld F. M., Bigger J. T., Jr Effect of lidocaine on the early inward transient current in sheep cardiac Purkinje fibers. Circ Res. 1975 Nov;37(5):630–639. doi: 10.1161/01.res.37.5.630. [DOI] [PubMed] [Google Scholar]
  53. Weld F. M., Coromilas J., Rottman J. N., Bigger J. T., Jr Mechanisms of quinidine-induced depression of maximum upstroke velocity in ovine cardiac Purkinje fibers. Circ Res. 1982 Mar;50(3):369–376. doi: 10.1161/01.res.50.3.369. [DOI] [PubMed] [Google Scholar]
  54. Yeh J. Z., Tanguy J. Na channel activation gate modulates slow recovery from use-dependent block by local anesthetics in squid giant axons. Biophys J. 1985 May;47(5):685–694. doi: 10.1016/S0006-3495(85)83965-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

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