Cardiovascular Drugs and Therapy

, Volume 6, Supplement 1, pp 321–327 | Cite as

The mode of action of tedisamil on voltage-dependent K+ channels

  • Iain D. Dukes
  • Martin Morad


The mechanism of the interaction of tedisamil with voltage-dependent K+ channels was studied using whole-cell and single-channel recordings in a variety of species and cell types. In K+ channels with rapid activation kinetics (Ito of rat ventricular myocytes; IA of mouse astroglial cells), tedisamil enhanced the kinetics of inactivation of the current without significantly suppressing the amplitude of the initial current. In K+ channels with slower activation/inactivation kinetics, tedisamil had a divergent effect. On IK of the glial cells, which have slow activation and inactivation kinetics, the kinetics of inactivation were enhanced and the initial peak current was reduced. On the other hand, in IK of guinea-pig ventricular myocytes, which have even slower activation kinetics with no inactivation, tedisamil slowed or completely suppressed the activation of the current. Finally, in K+ channels with rapid activation but slow inactivation kinetics (pedestal-type current of rat ventricular myocytes), tedisamil accelerated the inactivation without affecting the initial current. Thus, the prime determinant of the blocking mode of tedisamil appeared to be the kinetics of activation of the K+ channel; that is, the slower the kinetics of activation of the channel, the greater the initial block by the drug. Unitary Ito currents recorded in rat ventricular myocytes showed that tedisamil induced a rapid flicker block of the open channel and prolonged the time between the burst of openings without any effect on the unitary conductance. These effects were modeled by assuming that the drug bound to the open channel at a finite rate. Thus, tedisamil appears to decrease K+ currents by interacting uniformly with the open state of the channel.

Key Words

tedisamil K+ channel activation kinetics Ito IK 


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  1. 1.
    Baumann A, Grupe A, Ackermann A, et al. Structure of the voltage-dependent potassium channel is highly conserved from Drosophila to vertebrate central nervous systems. EMBO J 1988;7:2457–2463.PubMedGoogle Scholar
  2. 2.
    Stuhmer W, Ruppersburg P, Schroter KH, et al. Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J 1989;8:3235–3244.PubMedGoogle Scholar
  3. 3.
    Dukes ID, Morad M. Tedisamil inactivates transient outward K+ current in rat ventricular myocytes. Am J Physiol 1989;257:H1746-H1749.PubMedGoogle Scholar
  4. 4.
    Dukes ID, Cleemann L, Morad M. Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells. J Pharmacol Exp Ther 1990;254:560–569.PubMedGoogle Scholar
  5. 5.
    Oexle B, Weirich J, Antoni H. Electrophysiological profile of tedisamil, a new bradycardic agent. J Moll Cell Cardiol 1987;19 (Suppl III):S65.Google Scholar
  6. 6.
    Beatch GN, Abraham S, Macleod BA, et al. Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker. Br J Pharmacol 1991;102:13–18.PubMedGoogle Scholar
  7. 7.
    Hamill OP, Marty A, Neher E, et al. Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches. Pflügers Arch 1981;391:85–100.CrossRefGoogle Scholar
  8. 8.
    Agus ZS, Dukes ID, Morad M. Divalent cations modulate the transient outward current in rat ventricular myocytes. Am J Physiol 1991;261:C310-C318.PubMedGoogle Scholar
  9. 9.
    Bevan S, Raff M. Voltage-dependent potassium currents in cultured astrocytes. Nature (Lond) 1985;315:229–232.CrossRefPubMedGoogle Scholar
  10. 10.
    Walsh RB, Kass RS. Regulation of a heart potassium channel by protein kinase A and C. Science 1988;242:67–69.PubMedGoogle Scholar
  11. 11.
    Dukes ID, Morad M. A maintained outward K+ current in rat ventricular myocytes (abstract). Biophys J 1991;59:279.Google Scholar
  12. 12.
    Dukes ID, Morad M. Analysis of a K+ pedestal current, Imaintained, in rat ventricular myocytes. J Physiol 1992, submitted for publication.Google Scholar
  13. 13.
    Pfrunder D, Kreye VA. Tedisamil blocks single large-conductance Ca2+-activated K+ channels in membrane patches from smooth muscle cells of the guinea-pig portal vein. Pflügers Arch 1991;418:308–312.CrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1992

Authors and Affiliations

  • Iain D. Dukes
    • 1
  • Martin Morad
    • 1
  1. 1.Department of PhysiologyUniversity of PennsylvaniaPhiladelphiaUSA

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