Skip to main content
SpringerLink
Log in

Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of ICa,L

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The neuroleptic risperidone is an effective blocker of the rapidly activating component of the delayed rectifier current (IKr) and hence is expected to prolong cardiac action potential duration (APD). However, unlike with other typical IKr blockers we failed to demonstrate a marked prolongation of late repolarization with risperidone. It is hypothesized that the APD-prolonging effect of risperidone is masked by the high repolarization reserve due to the prominent delayed rectifier currents IKr and IKs in guinea pig papillary muscle. Action potentials and force of contraction were recorded in isolated guinea pig papillary muscles. L-type calcium current ICa,L and IKr were measured using the standard patch clamp technique in single ventricular cardiomyocytes. Reduction of the repolarization reserve by the blocking of IKs with chromanol 239B augmented the effect of the selective IKr blocker E-4031, but not of risperidone, although both drugs completely blocked IKr. In contrast to E-4031 risperidone markedly reduced the force of contraction due to the partial blocking of ICa,L in the same concentration range as required for block of IKr. Reduction of the repolarization reserve by the blocking of IKs cannot exacerbate the APD-prolonging effect of risperidone. However, even incomplete concomitant blocking of ICa,L attenuates the APD-prolonging effect of the complete blocking of IKr. This behaviour may explain the small APD-prolonging effect of risperidone despite the drug’s robust blocking of IKr.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Acri AA, Henreting FM (1998) Effects of risperidone overdose. Am J Emerg Med 16:498–501

    Article  CAS  PubMed  Google Scholar 

  • Blaschke M, Wettwer E, Ravens U (2002) Reduction of the repolarization reserve by partial inhibition of IKs with chromanol 293B reveals action potential prolonging effects of the neuroleptic risperidone in guinea-pig papillary muscle. Naunyn-Schmiedebergs Arch Pharmacol 365:R96

    Article  Google Scholar 

  • Bleich M, Briel M, Busch AE, Lang HJ, Gerlach U, Gogelein H, Greger R, Kunzelmann K (1997) KVLQT channels are inhibited by the K+ channel blocker 293B. Pflugers Arch 434:499–501

    Article  CAS  PubMed  Google Scholar 

  • Brown K, Levy H, Brenner C, Leffler S, Hamburg EL (1993) Overdose of risperidone. Ann Emerg Med 22:1908–1910

    Google Scholar 

  • Burns MJ (2001) The pharmacology and toxicology of atypical antipsychotic agents. Clin Toxicol 39:1–14

    Article  CAS  Google Scholar 

  • Camm AJ, Janse MJ, Rosen MR, Cinca J, Cobbe SM (2000) Congenital and acquired long QT syndrome. Eur Heart J 21:1232–1237

    Article  CAS  PubMed  Google Scholar 

  • Chouabe C, Drici MD, Romey G, Barhanin J, Lazdunski M (1998) HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers. Mol Pharmacol 54:695–703

    CAS  PubMed  Google Scholar 

  • Christ T, Wüst M, Matthes J, Jänchen M, Jurgens S, Herzig S, Wettwer E, Dobrev D, Matschke K, Mebs D, Ravens U (2004) An aqueous extract of the marine sponge Ectyoplasia ferox stimulates L-type Ca2+-current by direct interaction with the Cav1.2 subunit. Naunyn-Schmiedebergs Arch Pharmacol 370:474–483

    Article  CAS  PubMed  Google Scholar 

  • Davison ET (1985) Amitriptyline-induced torsade de pointes. Successful therapy with atrial pacing. J Electrocardiol 18:299–301

    CAS  PubMed  Google Scholar 

  • Drici MD, Wang WX, Liu XK, Woosley RL, Flockhart DA (1998) Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. J Clin Psychopharmacol 18:477–481

    Article  CAS  PubMed  Google Scholar 

  • Drolet B, Yang T, Daleau P, Roden DM, Turgeon J (2003) Risperidone prolongs cardiac repolarisation by blocking the rapid component of the delayed rectifier potassium current. J Cardiovasc Pharmacol 41:934–937

    Article  CAS  PubMed  Google Scholar 

  • Duenas-Laita A, Castro-Villamor MA, Martin-Escudero JC, Perez-Castrillon JL (1999) New clinical manifestations of acute risperidone poisoning. J Toxicol Clin Toxicol 37:893–895

    Article  CAS  PubMed  Google Scholar 

  • Fossa AA, Wisialowski T, Wolfgang E, Wang E, Avery M, Raunig DL, Fermini B (2004) Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig. Eur J Pharmacol 486:209–221

    Article  CAS  PubMed  Google Scholar 

  • Glassman AH, Bigger JT Jr (2001) Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 158:1774–1782

    Article  CAS  PubMed  Google Scholar 

  • Gluais P, Bastide M, Caron J, Adamantidis M (2002) Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes. Eur J Pharmacol 444:123–132

    Article  CAS  PubMed  Google Scholar 

  • Grant S, Fitton A (1994) Risperidone. A review of its pharmacology and therapeutic potential in the treatment of schizophrenia. Drugs 48:253–273

    CAS  PubMed  Google Scholar 

  • Jackson T, Ditmanson L, Phibbs B (1997) Torsade de pointes and low-dose oral haloperidol. Arch Intern Med 157:2013–2015

    Article  CAS  PubMed  Google Scholar 

  • Kongsamut S, Kang J, Chen XL, Roehr J, Rampe D (2002) A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. Eur J Pharmacol 450:37–41

    Article  CAS  PubMed  Google Scholar 

  • Laroussinie G, Zenut M, Beal M, Bernard C, Lavarenne J (1997) Intoxication aigue par la risperidone et perturbation ioniques et electrocardiographiques. Therapie 52:155–156

    CAS  PubMed  Google Scholar 

  • Lawrence KR, Nasraway SA (1997) Conduction disturbances associated with administration of butyrophenone antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 17:531–537

    CAS  PubMed  Google Scholar 

  • Lee HS, Tan CH, Au LS, Khoo YM (1997) Serum and urine risperidone concentrations in an acute overdose. J Clin Psychopharmacol 17:325–326

    Article  CAS  PubMed  Google Scholar 

  • Lo Vecchio F, Hamilton RJ, Hoffman RJ (2000) Risperidone overdose. Am J Emerg Med 14:95–96

    Article  Google Scholar 

  • Magyar J, Bányász T, Bagi Z, Pacher P, Szentandrássy N, Fülöp L, Kecskeméti V, Nánási PP (2002) Electrophysiological effects of risperidone in mammalian cardiac cells. Naunyn-Schmiedebergs Arch Pharmacol 366:350–356

    Article  CAS  PubMed  Google Scholar 

  • Missan S, Zhabyeyev P, Dyachok O, Jones SE, McDonald TF (2003) Block of cardiac delayed-rectifier and inward-rectifier K+ currents by nisoldipine. Br J Pharmacol 140:863–870

    Article  CAS  PubMed  Google Scholar 

  • Ohler A, Amos GJ, Wettwer E, Ravens U (1994) Frequency-dependent effects of E-4031, almokalant, dofetilide and tedisamil on action potential duration: no evidence for “reverse use dependent” block. Naunyn-Schmiedebergs Arch Pharmacol 349:602–610

    Article  CAS  PubMed  Google Scholar 

  • Priori SG, Napolitano C, Schwartz PJ (1999) Low penetrance in the long-QT syndrome: clinical impact. Circulation 99:529–533

    CAS  PubMed  Google Scholar 

  • Ravin DS, Levenson JW (1997) Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 31:867–870

    CAS  PubMed  Google Scholar 

  • Rocchetti M, Besana A, Gurrola GB, Possani LD, Zaza A (2001) Rate dependency of delayed rectifier currents during the guinea-pig ventricular action potential. J Physiol 534:721–732

    Article  CAS  PubMed  Google Scholar 

  • Roden DM (1998) Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes. Pacing Clin Electrophysiol 21:1029–1034

    CAS  PubMed  Google Scholar 

  • Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM (1996) Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS foundation task force on LQTS. Circulation 94:1996–2012

    CAS  PubMed  Google Scholar 

  • Sanguinetti MC, Jurkiewicz NK (1990) Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96:195–215

    Article  CAS  PubMed  Google Scholar 

  • Tamargo J (2000) Drug-induced torsade de pointes: from molecular biology to bedside. Jpn J Pharmacol 83:1–9

    Article  CAS  PubMed  Google Scholar 

  • Vieweg WV (2003) New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry 5:205–215

    PubMed  Google Scholar 

  • Weirich J, Antoni H (1998) Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs. Basic Res Cardiol 93:125–132

    Article  CAS  Google Scholar 

  • Wu L, Shryock JC, Song Y, Li Y, Antzelevitch C, Belardinelli L (2004) Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther 310:599–605

    Article  CAS  PubMed  Google Scholar 

  • Wu SN, Jan CR, Li HF, Chiang HT (2000) Characterization of inhibition by risperidone of the inwardly rectifying K+ current in pituitary GH3 cells. Neuropsychopharmacology 23:676–689

    Article  CAS  PubMed  Google Scholar 

  • Yang T, Roden DM (1996) Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 93:407–411

    CAS  PubMed  Google Scholar 

  • Yerrabolu M, Prabhudesai S, Tawam M, Winter L, Kamales M (2000) Effect of risperidone on QT interval and QT dispersion in the elderly. Heart Dis 2:10–12

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the excellent technical assistance of Konstanze Fischer, Annegret Häntzschel, Ulrike Heinrich and Trautlinde Thurm.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical Faculty, University of Technology, Dresden, Germany

    Torsten Christ, Erich Wettwer & Ursula Ravens

  2. Institut für Pharmakologie und Toxikologie, Fetscherstrasse 74, 01309, Dresden, Germany

    Ursula Ravens

Authors
  1. Torsten Christ
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erich Wettwer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ursula Ravens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ursula Ravens.

Additional information

T. Christ and E. Wettwer contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christ, T., Wettwer, E. & Ravens, U. Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of ICa,L. Naunyn Schmied Arch Pharmacol 371, 393–400 (2005). https://doi.org/10.1007/s00210-005-1063-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-005-1063-5

Keywords

Search

Navigation