Українська Русский English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2001; 47(1): 17-25


The blockade of herg k+ channels expressedin xenopus oocytes by neuroleptic agents

V. N. Osipenko, V. E. Degtiar, V. G. Naidionov, Y. M. Shuba

    A. A. Bogomoletz Institute of PhysiologyNational Academy of Sciences of Ukraine;International Center of Molecular PhysiologyNational Academy of Sciences of Ukraine, Kiev


Abstract

V. N. Osipenko, V. E. Degtiar, V. G. Naidionov, Y. M. Shuba THE BLOCKADE OF HERG K+ CHANNELS EXPRESSED IN XENOPUS OOCYTES BY NEUROLEPTIC AGENTS We have investigated the effects of neuroleptic agents, haloperidol, pimozide and fluspirilen, that are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac dalayed rectifier K+ current, IKr. All three agents blocked HERG-directed IKr in Xenopus oocytes in a voltage-dependent manner. The extent of the blockade increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism. The ?N50 values for the haloperidol-, pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36, 1.74 and 2.34 mnM respectively. Neuroleptics did not affect the HERG channels steady-state activation and inactivation properties. Thus, the blockade of HERG channels may underly proarrhythmic actions of neuroleptics resulting in a slowing down of the repolarization phase of cardiac action potential, and prolongation of the electrocardiographic QT interval. A. A. Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine; International Center of Molecular Physiology National Academy of Sciences of Ukraine, Kiev

References

  1. СПИСОК ЛІТЕРАТУРИ
  2. Катцунг Б. Г. Базисная и клиническая фармакологияCIa., 1998. ? O. 1. ? C. 524-537.
  3. Busch A.E., Eigenberg B., Jurkievicz N.K. et al. Alockade of HERG nhannels by the nlass III antiarrhythmic azimilide: mode of action // Brit. J. Pharmacol. ? 1998. 123, ? 1. ? P. 23-30.
  4. Dausse E. A iutation in HERG, associated with notched T-waves in long QT Syndrom// Mol. Cell. Cardiol. ? 1996. ? 28. ? P. 1609-1615.
  5. Deal K.K., England S.H., Michael M. Tamkun Molecular physiology of cardiac potassium channels // Physiol. Rev. ? 1996. ? 76, ? 1. ? P. 49-67.
  6. Enyert J.J., Biagi D.A., Mlinar B. Preferential block of T-type calcium channels by neuroleptics in neural crest-derived rat and human C cell lines // Mol. Pharmacol. ? 1992. ? 42. ? P. 364-372.
  7. Fayer S.A. Tosades de pointes ventricular tachyarrhythmia assotiated with haloperidol // J. Clin. Psychopharmacol. ? 1986. ? 6. ? P.375-376.
  8. Goldin A.L. Maintenance of Xenopus Laevis and oocyte injection // Methods in Enzymology. ? 1992. ? 207, chapter 15. ? P. 266-279. ISSN 0201-8489 O?c?ie. ?o?i., 2001, O. 47, ? 1 25
  9. Henderson R.S., Lane S., Henry J.A. Life-threatening ventricular arrhytmia (torsadesde pointes) after haloperidol overdose // Hum. Exp. Toxicol. ? 1991. ? 10. ?P. 482-484.
  10. 9. Hunt N., Stern T.A. The assotiation between intravenous haloperidol and torsades de pointes// Psychosomatics. ? 1995. ? 36. ? P. 541-549.
  11. 10. Janse M.J., Wilde A.A. Molecular mechanisms of arrhythmias // Rev. Port. Cardiol. ? 1998. ? 17, suppl. 2. ? P. 41-46.
  12. Ogata N., Yoahii M., Narachashi T. Psychotropic drugs block voltage-gated ion channels in neuroblastoma cells//Brain Res. ? 1989. ? 476. ? P. 140-144.
  13. Roden D.M., Lazzara R. Multiple mechanisms of long QT-Syndrome. Current knowledge, gaps and future directions. Special review // Circulation. ? 1996. ? 94, ? 8. ?P.1996-2012.
  14. Roy M.L., Dumaine R. HERG, a primary human ventricular target of the nonsedating antihistamin terfenadin // Circulation. ? 1996. ? 94, ? 4. ? P. 817-823.
  15. Sah D.W.Y., Bean B.P. Inhibition of P-type and N-type calcium channels by dopamine receptor antagonists // Mol. Pharmacol. ? 1994. ? 45. ? P. 84-92.
  16. Sanguinetti M.C., Jiang C., Curran M.E. et al. A mechanistic link between an inherited and an acquired cardiac arrhytmia: HERG encodes the Ikr potassium channel //Cell.? 1995. ? 81. ? P. 299-307.
  17. Sanguinetti M.C., Jurkiewic N.K. Two components of cardiac delayed rectifier K+current: differential sensitivity to block by class III antiarrhitmic agents // j.Gen. Physiol. ? 1998. ? 96. ? P. 195-215.
  18. Seeman P., Lee T., Chau-Wang M. et al. Antipsychotic drug doses and neuroleptic/ dopamine receptors// Nature. ? 1976. ? 261. ? P. 717-719.
  19. Shonherr R.R. Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel // J. Physiol. (Lond.). ? 1996. ? 493. ?P.635-642.
  20. 19. Smith P.L., Baukrowitz T., Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel // Nature. ? 1996. ? 379. ? P. 833-836.
  21. 20. Suessbrich H., Schonherr R.R., Heinemann S.H. et.al. The inhibitory effect of the antipsihotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes // Brit. J. of Pharm. ? 1997. ? 120. ? P. 968-974.
  22. Tagliatella M., Castaldo P., Pannaccione A. et al. Human ether?a-go-go related gene (HERG) K+channels as pharmacological targets // Biochem. Pharmacology. ? 1998.? 55. ? P.1741-1746.
  23. Woosley R.L. Cardiac actions of ahtihistamins // Ann. Rev. Pharmacol. Toxicol. ?1996. ? 36. ? P. 233-252.

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2018.