The Journal of Membrane Biology

, Volume 122, Issue 3, pp 267–278 | Cite as

Responsiveness of cardiac Na+ channels to antiarrhythmic drugs: The role of inactivation

  • I. Benz
  • M. Kohlhardt


Elementary Na+ currents were recorded at 9°C in inside-out patches from cultured neonatal rat heart myocytes. In characterizing the sensitivity of cooled, slowly inactivating cardiac Na+ channels to several antiarrhythmic drugs including propafenone, lidocaine and quinidine, the study aimed to define the role of Na+ inactivation for open channel blockade.

In concentrations (1–10 μmol/liter) effective to depressNP o significantly, propafenone completely failed to influence the open state of slowly inactivating Na+ channels. With 1 μmol/liter, τopen changed insignificantly to 96±7% of the control. Even a small number of ultralong openings of 6 msec or longer exceeding τopen of the whole ensemble several-fold and attaining τopen (at −45 mV) in cooled, (-)-DPI-modified, noninactivating Na+ channels proved to be drug resistant and could not be flicker-blocked by 10 μmol/liter propafenone. The same drug concentration induced in(-)-DPI-modified Na+ channels a discrete block with association and dissociation rate constants of 16.1 ± 5.3 × 106 mol−1 sec−1 and 675 ± 25 sec−1, respectively. Quinidine, known to have a considerable affinity for activated Na+ channels, in lower concentrations (5 μmol/liter) left τopen unchanged or reduced, in higher concentrations (10 μmol/liter) τopen only slightly to 81% of the predrug value whereasNP o declined to 30%, but repetitive blocking events during the conducting state could never be observed. Basically the same drug resistance of the open state was seen in cardiac Na+ channels whose open-state kinetics had been modulated by the cytoplasmic presence of F ions. But in this case, propafenone reduced reopening and selectively abolished a long-lasting open state. This drug action is unlikely related to the inhibitory effect onNP o since hyperpolarization and the accompanying block attenuation did not restore the channel kinetics. It is concluded that cardiac Na+ channels cannot be flicker-blocked by antiarrhythmic drugs unless Na+ inactivation is removed.

Key Words

single cardiac Na+ channels open-state kinetics drug-induced blockade (-)-DPI 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Alpert, L.A., Fozzard, H.A., Hanck, D.A., Makielski, J.C. 1989. Is there a second external lidocaine binding site on mammalian cardiac cells.Am. J. Physiol. 257:H79-H84PubMedGoogle Scholar
  2. 2.
    Bigay, J., Deterre, P., Pfister, D., Chabre, M., 1985. Fluoroaluminates activate transducin-GMP by mimicking the gamma-phosphate of GTP in its binding site.FEBS Lett. 191:181–185CrossRefPubMedGoogle Scholar
  3. 3.
    Catterall, W.A. 1988. Structure and function of voltage-sensitive ion channels.Science 242:50–61PubMedGoogle Scholar
  4. 4.
    Colquhoun, D., Sigworth, F. 1983. Fitting and statistical analysis of single channel records.In: Single Channel Recordings. B. Sakmann and E. Neher, editors. pp. 191–264, Plenum. New YorkGoogle Scholar
  5. 5.
    Cukierman, S., Zinkand, W.C., French, R.J., Krueger, B.K. 1988. Effects of membrane surface charge and calcium on the gating of rat brain sodium channels in planar bilayers.J. Gen. Physiol. 92:431–447CrossRefPubMedGoogle Scholar
  6. 6.
    Fenwick, E.M., Marty, A., Neher, E. 1982. Sodium and calcium channels in bovine chromaffin cells.J. Physiol. 331:599–635PubMedGoogle Scholar
  7. 7.
    Grant, A.O., Dietz, M.A., Gilliam, F.R., Starmer, C.F. 1989. Blockade of cardiac sodium channels by lidocaine. Single channel analysis.Circ. Res. 65:1247–1262PubMedGoogle Scholar
  8. 8.
    Hamill, O.P., Marty, A., Neher, E., Sakmann, B., Sigworth, F.J. 1981. Improved patch-clamp techniques for high resolution current recordings from cell and cell-free membrane patches.Pfluegers Arch. 391:85–100CrossRefGoogle Scholar
  9. 9.
    Hille, B. 1984. Ionic channels of excitable membranes. Sinauer, Sunderland, (MA)Google Scholar
  10. 10.
    Hille, B., 1975. Ionic selectivity, saturation, and block in sodium channels. A four barrier model.J. Gen. Physiol. 66:535–560PubMedGoogle Scholar
  11. 11.
    Hille, B. 1977. Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction.J. Gen. Physiol. 69:497–515PubMedGoogle Scholar
  12. 12.
    Hondeghem, L.M., Katsung, B.G. 1977. Time- and voltagedependent interactions of antiarrhythmic drugs with cardiac sodium channels.Biochim. Biophys. Acta 472:373–398PubMedGoogle Scholar
  13. 13.
    Kodama, I., Toyama, J., Takanaka, C., Yamada, K. 1987. Block of activated and inactivated sodium channels by class-1 antiarrhythmic drugs studied by using the maximum upstroke velocity (V max) of action potential in guinea-pig cardiac muscles.J. Mol. Cell. Cardiol. 19:367–377PubMedGoogle Scholar
  14. 14.
    Kohlhardt, M. 1990. Different temperature sensitivity of cardiac Na+ channels in cell-attached and cell-free conditions.Am. J. Physiol. 259:C599-C604PubMedGoogle Scholar
  15. 15.
    Kohlhardt, M., Fichtner, H. 1988. Block of single cardiac Na+ channels by antiarrhythmic drugs: The effect of amiodarone, propafenone and diprafenone.J. Membrane Biol. 102:105–119Google Scholar
  16. 16.
    Kohlhardt, M., Fichtner, H., Fröbe, U. 1988. Predominance of poorly reopening single Na+ channels and lack of slow Na+ inactivation in neonatal cardioytes.J. Membrane Biol. 103:283–291Google Scholar
  17. 17.
    Kohlhardt, M., Fichtner, H., Fröbe, U., Herzig, J.W. 1989. On the mechanism of drug-induced blockade of Na+ cur-Interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.Circ. Res. 64:867–881PubMedGoogle Scholar
  18. 18.
    Kohlhardt, M., Fröbe, U., Herzig, J.W. 1986. Modification of single cardiac Na+ channels by DPI 201-106.J. Membrane Biol. 89:163–172Google Scholar
  19. 19.
    Kohlhardt, M., Seifert, C. 1985. Properties of\(\dot V\) max block ofI Na-mediated action potentials during combined application of antiarrhythmic drugs in cardiac muscle}.Naunyn Schmiedebergs Arch. Pharmacol. 330:235–244PubMedGoogle Scholar
  20. 20.
    Kohlhardt, M., Seifert, C. 1983. Tonic and phasicI Na blockade by antiarrhythmics. Different properties of drug binding to fast sodium channels as judged from278-2 studies with propafenone and derivatives in mammalian ventricular myocardium.Pfluegers Arch. 396:199–209Google Scholar
  21. 21.
    Lansman, J.B., Hess, P., Tsien, R.W. 1986. Blockade of current through single calcium channels by Cd++, Mg++, and Ca++. Voltage and concentration dependence of calcium entry into the pore.J. Gen. Physiol. 88:321–347PubMedGoogle Scholar
  22. 22.
    McDonald, T., Pelzer, D., Trautwein, W. 1989. Dual action (stimulation, inhibition) of D600 on contractility and calcium channels in guinea-pig and cat heart cells.J. Physiol. 414:569–586PubMedGoogle Scholar
  23. 23.
    Meves, H. 1978. Inactivation of the sodium permeability in squid giant nerve fibres.Prog. Biophys. Mol. Biol. 33:207–320PubMedGoogle Scholar
  24. 24.
    Modczydlowski, E., Uehara, A., Guo, X., Heiny, J. 1986. Isochannels and blocking modes of voltage-dependent sodium channels.Ann. NY Acad. Sci. 479:269–292PubMedGoogle Scholar
  25. 25.
    Neher, E. 1983. The charge carried by single-channel currents of rat cultured muscle cells in the presence of local anesthetics.J. Physiol. 339:663–678PubMedGoogle Scholar
  26. 26.
    Neher, E., Steinbach, J.H. 1978. Local anesthetics transiently block currents through single acetylcholine-receptor channels.J. Physiol. 277:153–176PubMedGoogle Scholar
  27. 27.
    Nilius, B., Benndorf, K., Markwardt, F. 1987. Effects of lidocaine on single cardiac sodium channels.J. Mol. Cell. Cardiol. 19:865–874PubMedGoogle Scholar
  28. 28.
    Patlak, J.B., Ortiz, M. 1985. Slow currents through single sodium channels of the adult rat heart.J. Gen. Physiol. 86:89–104PubMedGoogle Scholar
  29. 29.
    Postma, S.W., Catterall, W.A. 1984. Inhibition of binding of 3H batrachotoxin A20-α-benzoate to sodium channels by local anesthetics.Mol. Pharmacol. 25:219–227PubMedGoogle Scholar
  30. 30.
    Quandt, F.N., Yeh, J.Z., Narahashi, T. 1985. All or none block of single Na+ channels by tetrodotoxin.Neurosci. Lett. 54:77–83PubMedGoogle Scholar
  31. 31.
    Romey, G., Quast, U., Pauron, D., Frelin, C., Renaud, J.F., Laxdunski, M. 1987. Na channels as sites of action of the cardioactive agent DPI 201-106 with agonist and antagonist enantiomers.Proc. Natl. Acad. Sci. USA 84:896–900PubMedGoogle Scholar
  32. 32.
    Sheets, M.F., Scanley, B.E., Hanck, D.A., Makielski, J.C., Fozzard, H.A. 1987. Open sodium channel properties of single canine cardiac Purkinje cells.Biophys. J. 52:13–22PubMedGoogle Scholar
  33. 33.
    Sheldon, R.S., Hill, R.J., Cannon, N.J., Duff, H.J. 1989. Amiodarone: Biochemical evidence for binding to a receptor for class 1 drugs associated with the rat cardiac sodium channel.Circ. Res. 65:477–482PubMedGoogle Scholar
  34. 34.
    Snyders, D.J., Hondeghem, L.M. 1990. Effects of quinidine on the sodium current of guinea pig ventricular myocytes. Evidence for a drug-associated rested state with altered kinetics.Circ. Res. 66:565–579PubMedGoogle Scholar
  35. 35.
    Stamer, C.F., Grant, A.O., Strauss, H.C. 1984. Mechanism of use-dependent block of sodium channels in excitable membranes by local anesthetics.Biophys. J. 46:15–27PubMedGoogle Scholar
  36. 36.
    Tanabe, T., Takeshima, H., Mikami, A., Flockerzi, V., Takahashi, H., Kangawa, K., Kojima, M., Matsuo, H., Hirose, T., Numa, S. 1987. Primary structure of the receptor for calcium channel blockers from skeletal muscle.Nature 328:313–318CrossRefGoogle Scholar
  37. 37.
    Wang, G.K. 1988. Cocaine-induced closures of single batrachotoxin-activated Na+ channels in planar lipid bilayers.J. Gen. Physiol. 92:747–765PubMedGoogle Scholar
  38. 38.
    Yamamoto, D., Yeh, J.Z. 1984. Kinetics of 9-aminoacridine block of single Na channels.J. Gen. Physiol. 84:361–377PubMedGoogle Scholar
  39. 39.
    Yamamoto, D., Yeh, J.Z., Narahashi, T. 1984. Voltage-dependent calcium block of normal and tetramethrin-modified single sodium channels.Biophys. J. 45:337–344PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1991

Authors and Affiliations

  • I. Benz
    • 1
  • M. Kohlhardt
    • 1
  1. 1.Physiological Institute of the University FreiburgFreiburg/Br.Germany

Personalised recommendations