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. 1991 Apr;435:65–81. doi: 10.1113/jphysiol.1991.sp018498

Dual effect of the local anaesthetic penticainide on the Na+ current of guinea-pig ventricular myocytes.

R Gruber 1, J Vereecke 1, E Carmeliet 1
PMCID: PMC1181450  PMID: 1663162

Abstract

1. The effect of the local anaesthetic penticainide (2-alkyl-(4-dialkylamino)-2-pyridyl-butyramide) on macroscopic and single-channel sodium current (INa) of guinea-pig ventricular myocytes was studied with the patch-clamp technique in the cell-attached and inside-out mode. 2. Penticainide (3-60 microM) affected the INa from the outside as well as from the cytoplasmic side. 3. Peak INa was reduced by penticainide at concentrations of 6, 30 and 60 microM, and this decrease of peak INa was more pronounced when the holding potential was more negative. Despite a reduction of peak INa, the time integral of the Na+ current was not changed (60 microM) or was even enhanced (6 microM), and this enhancement became more pronounced at less negative potentials. 4. At a concentration of 3 microM, penticainide increased both the time integral of the current and peak INa. 5. The shape of the steady-state current-voltage relationship and the steady-state inactivation curve were not influenced by penticainide. 6. In pronase-modified inside-out patches penticainide reduced INa at the beginning of a depolarizing pulse to the same extent as at the end (400 ms), indicating a very fast blockade of the bursting Na+ channel. The most prominent effects on pronase-modified single-channel INa were an increase of sweeps without activity, and a fast, repeatedly occurring block (flickering) of the bursting Na+ channel. 7. The amplitude of the unitary current was not altered. 8. It is concluded that penticainide blocks the open Na+ channel, and in addition shows the macroscopic inactivation.

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Selected References

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  1. Alpert L. A., Fozzard H. A., Hanck D. A., Makielski J. C. Is there a second external lidocaine binding site on mammalian cardiac cells? Am J Physiol. 1989 Jul;257(1 Pt 2):H79–H84. doi: 10.1152/ajpheart.1989.257.1.H79. [DOI] [PubMed] [Google Scholar]
  2. Anno T., Hondeghem L. M. Interactions of flecainide with guinea pig cardiac sodium channels. Importance of activation unblocking to the voltage dependence of recovery. Circ Res. 1990 Mar;66(3):789–803. doi: 10.1161/01.res.66.3.789. [DOI] [PubMed] [Google Scholar]
  3. Berman M. F., Camardo J. S., Robinson R. B., Siegelbaum S. A. Single sodium channels from canine ventricular myocytes: voltage dependence and relative rates of activation and inactivation. J Physiol. 1989 Aug;415:503–531. doi: 10.1113/jphysiol.1989.sp017734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernhart C. A., Condamine C., Demarne H., Roncucci R., Gagnol J. P., Gautier P. J., Serre M. A. Synthesis and antiarrhythmic activity of new [(dialkylamino)alkyl]pyridylacetamides. J Med Chem. 1983 Mar;26(3):451–455. doi: 10.1021/jm00357a026. [DOI] [PubMed] [Google Scholar]
  5. Cachelin A. B., De Peyer J. E., Kokubun S., Reuter H. Sodium channels in cultured cardiac cells. J Physiol. 1983 Jul;340:389–401. doi: 10.1113/jphysiol.1983.sp014768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Carmeliet E. Activation block and trapping of penticainide, a disopyramide analogue, in the Na+ channel of rabbit cardiac Purkinje fibers. Circ Res. 1988 Jul;63(1):50–60. doi: 10.1161/01.res.63.1.50. [DOI] [PubMed] [Google Scholar]
  8. Carmeliet E., Nilius B., Vereecke J. Properties of the block of single Na+ channels in guinea-pig ventricular myocytes by the local anaesthetic penticainide. J Physiol. 1989 Feb;409:241–262. doi: 10.1113/jphysiol.1989.sp017495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Fernandez J. M., Fox A. P., Krasne S. Membrane patches and whole-cell membranes: a comparison of electrical properties in rat clonal pituitary (GH3) cells. J Physiol. 1984 Nov;356:565–585. doi: 10.1113/jphysiol.1984.sp015483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gautier P., Escande D., Bertrand J. P., Seguin J., Guiraudou P. Electrophysiological effects of penticainide (CM 7857) in isolated human atrial and ventricular fibers. J Cardiovasc Pharmacol. 1989 Feb;13(2):328–335. doi: 10.1097/00005344-198902000-00024. [DOI] [PubMed] [Google Scholar]
  12. Gautier P., Guiraudou P., Pezziardi F., Bertrand J. P., Gagnol J. P. Electrophysiological studies of penticainide (CM 7857), a new antiarrhythmic agent, in mammalian myocardium. J Cardiovasc Pharmacol. 1987 May;9(5):601–610. doi: 10.1097/00005344-198705000-00015. [DOI] [PubMed] [Google Scholar]
  13. Grissmer S., Cahalan M. TEA prevents inactivation while blocking open K+ channels in human T lymphocytes. Biophys J. 1989 Jan;55(1):203–206. doi: 10.1016/S0006-3495(89)82793-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gruber R., Carmeliet E. The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres. Br J Pharmacol. 1989 May;97(1):41–50. doi: 10.1111/j.1476-5381.1989.tb11921.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Kimitsuki T., Mitsuiye T., Noma A. Negative shift of cardiac Na+ channel kinetics in cell-attached patch recordings. Am J Physiol. 1990 Jan;258(1 Pt 2):H247–H254. doi: 10.1152/ajpheart.1990.258.1.H247. [DOI] [PubMed] [Google Scholar]
  18. Kohlhardt M., Fröbe U., Herzig J. W. Modification of single cardiac Na+ channels by DPI 201-106. J Membr Biol. 1986;89(2):163–172. doi: 10.1007/BF01869712. [DOI] [PubMed] [Google Scholar]
  19. Makielski J. C., Sheets M. F., Hanck D. A., January C. T., Fozzard H. A. Sodium current in voltage clamped internally perfused canine cardiac Purkinje cells. Biophys J. 1987 Jul;52(1):1–11. doi: 10.1016/S0006-3495(87)83182-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. McDonald T. V., Courtney K. R., Clusin W. T. Use-dependent block of single sodium channels by lidocaine in guinea pig ventricular myocytes. Biophys J. 1989 Jun;55(6):1261–1266. doi: 10.1016/S0006-3495(89)82921-2. [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. Nilius B., Vereecke J., Carmeliet E. Properties of the bursting Na channel in the presence of DPI 201-106 in guinea-pig ventricular myocytes. Pflugers Arch. 1989 Jan;413(3):234–241. doi: 10.1007/BF00583535. [DOI] [PubMed] [Google Scholar]
  23. 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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