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. 1990 Mar;57(3):589–599. doi: 10.1016/S0006-3495(90)82574-1

Characterization of cocaine-induced block of cardiac sodium channels.

W J Crumb Jr 1, C W Clarkson 1
PMCID: PMC1280752  PMID: 2155033

Abstract

Recent evidence suggests that cocaine can produce marked cardiac arrhythmias and sudden death. A possible mechanism for this effect is slowing of impulse conduction due to block of cardiac Na channels. We therefore investigated its effects on Na channels in isolated guinea pig ventricular myocytes using the whole-cell variant of the patch clamp technique. Cocaine (10-50 microM) was found to reduce Na current in a use-dependent manner. The time course for block development and recovery were characterized. At 30 microM cocaine, two phases of block development were defined: a rapid phase (tau = 5.7 +/- 4.9 ms) and a slower phase (tau = 2.3 +/- 0.7 s). Recovery from block at -140 mV was also defined by two phases: (tau f = 136 +/- 61 ms, tau s = 8.5 +/- 1.7 s) (n = 6). To further clarify the molecular mechanisms of cocaine action on cardiac Na channels, we characterized its effects using the guarded receptor model, obtaining estimated Kd values of 328, 19, and 8 microM for channels predominantly in the rested, activated, and inactivated states. These data indicate that cocaine can block cardiac Na channels in a use-dependent manner and provides a possible cellular explanation for its cardiotoxic effects.

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Selected References

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  1. 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]
  2. Benchimol A., Bartall H., Desser K. B. Accelerated ventricular rhythm and cocaine abuse. Ann Intern Med. 1978 Apr;88(4):519–520. doi: 10.7326/0003-4819-88-4-519. [DOI] [PubMed] [Google Scholar]
  3. Cahalan M. D., Almers W. Interactions between quaternary lidocaine, the sodium channel gates, and tetrodotoxin. Biophys J. 1979 Jul;27(1):39–55. doi: 10.1016/S0006-3495(79)85201-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cahalan M. D. Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons. Biophys J. 1978 Aug;23(2):285–311. doi: 10.1016/S0006-3495(78)85449-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clarkson C. W., Follmer C. H., Ten Eick R. E., Hondeghem L. M., Yeh J. Z. Evidence for two components of sodium channel block by lidocaine in isolated cardiac myocytes. Circ Res. 1988 Nov;63(5):869–878. doi: 10.1161/01.res.63.5.869. [DOI] [PubMed] [Google Scholar]
  6. Clarkson C. W. Stereoselective block of cardiac sodium channels by RAC109 in single guinea pig ventricular myocytes. Circ Res. 1989 Nov;65(5):1306–1323. doi: 10.1161/01.res.65.5.1306. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Courtney K. R. Size-dependent kinetics associated with drug block of sodium current. Biophys J. 1984 Jan;45(1):42–44. doi: 10.1016/S0006-3495(84)84100-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Follmer C. H., ten Eick R. E., Yeh J. Z. Sodium current kinetics in cat atrial myocytes. J Physiol. 1987 Mar;384:169–197. doi: 10.1113/jphysiol.1987.sp016449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fozzard H. A., Hanck D. A., Makielski J. C., Scanley B. E., Sheets M. F. Sodium channels in cardiac Purkinje cells. Experientia. 1987 Dec 1;43(11-12):1162–1168. doi: 10.1007/BF01945516. [DOI] [PubMed] [Google Scholar]
  11. Gintant G. A., Hoffman B. F. Use-dependent block of cardiac sodium channels by quaternary derivatives of lidocaine. Pflugers Arch. 1984 Feb;400(2):121–129. doi: 10.1007/BF00585029. [DOI] [PubMed] [Google Scholar]
  12. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Hondeghem L., Katzung B. G. Test of a model of antiarrhythmic drug action. Effects of quinidine and lidocaine on myocardial conduction. Circulation. 1980 Jun;61(6):1217–1224. doi: 10.1161/01.cir.61.6.1217. [DOI] [PubMed] [Google Scholar]
  16. Isner J. M., Estes N. A., 3rd, Thompson P. D., Costanzo-Nordin M. R., Subramanian R., Miller G., Katsas G., Sweeney K., Sturner W. Q. Acute cardiac events temporally related to cocaine abuse. N Engl J Med. 1986 Dec 4;315(23):1438–1443. doi: 10.1056/NEJM198612043152302. [DOI] [PubMed] [Google Scholar]
  17. Jonsson S., O'Meara M., Young J. B. Acute cocaine poisoning. Importance of treating seizures and acidosis. Am J Med. 1983 Dec;75(6):1061–1064. doi: 10.1016/0002-9343(83)90889-6. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Kossowsky W. A., Lyon A. F. Cocaine and acute myocardial infarction. A probable connection. Chest. 1984 Nov;86(5):729–731. doi: 10.1378/chest.86.5.729. [DOI] [PubMed] [Google Scholar]
  20. Kunze D. L., Lacerda A. E., Wilson D. L., Brown A. M. Cardiac Na currents and the inactivating, reopening, and waiting properties of single cardiac Na channels. J Gen Physiol. 1985 Nov;86(5):691–719. doi: 10.1085/jgp.86.5.691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mitra R., Morad M. A uniform enzymatic method for dissociation of myocytes from hearts and stomachs of vertebrates. Am J Physiol. 1985 Nov;249(5 Pt 2):H1056–H1060. doi: 10.1152/ajpheart.1985.249.5.H1056. [DOI] [PubMed] [Google Scholar]
  22. Mittleman R. E., Wetli C. V. Death caused by recreational cocaine use. An update. JAMA. 1984 Oct 12;252(14):1889–1893. [PubMed] [Google Scholar]
  23. Nanji A. A., Filipenko J. D. Asystole and ventricular fibrillation associated with cocaine intoxication. Chest. 1984 Jan;85(1):132–133. doi: 10.1378/chest.85.1.132. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Spiehler V. R., Reed D. Brain concentrations of cocaine and benzoylecgonine in fatal cases. J Forensic Sci. 1985 Oct;30(4):1003–1011. [PubMed] [Google Scholar]
  26. Starmer C. F., Courtney K. R. Modeling ion channel blockade at guarded binding sites: application to tertiary drugs. Am J Physiol. 1986 Oct;251(4 Pt 2):H848–H856. doi: 10.1152/ajpheart.1986.251.4.H848. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Starmer C. F. Theoretical characterization of ion channel blockade. Competitive binding to periodically accessible receptors. Biophys J. 1987 Sep;52(3):405–412. doi: 10.1016/S0006-3495(87)83229-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. 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]
  32. Wang G. K. Cocaine-induced closures of single batrachotoxin-activated Na+ channels in planar lipid bilayers. J Gen Physiol. 1988 Dec;92(6):747–765. doi: 10.1085/jgp.92.6.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wetli C. V., Wright R. K. Death caused by recreational cocaine use. JAMA. 1979 Jun 8;241(23):2519–2522. [PubMed] [Google Scholar]
  34. Woodhull A. M. Ionic blockage of sodium channels in nerve. J Gen Physiol. 1973 Jun;61(6):687–708. doi: 10.1085/jgp.61.6.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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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