Relevance of anaesthesia for dofetilide-induced torsades de pointes in α 1-adrenoceptor-stimulated rabbits

D. Vincze, A. S. Farkas, L. Rudas, P. Makra, N. Csík, I. Leprán, T. Forster, M. Csanády, J. Papp, A. Varró, A. Farkas

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Abstract

Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in α 1-adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or α-chloralose were infused simultaneously with the α 1-adrenoceptor agonist phenylephrine (15 μg kg -1 min -1, i.v.) and dofetilide (0.04 mg kg -1 min -1, i.v.). The electrocardiographic QT interval, the T peak-T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with α-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with α-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the α-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared.

Original languageEnglish
Pages (from-to)75-89
Number of pages15
JournalBritish Journal of Pharmacology
Volume153
Issue number1
DOIs
Publication statusPublished - Jan 2008

Fingerprint

Torsades de Pointes
Chloralose
Adrenergic Receptors
Propofol
Anesthesia
Rabbits
Pentobarbital
Phenylephrine
Anesthetics
Baroreflex
Anti-Arrhythmia Agents
Incidence
Cardiac Arrhythmias
Arterial Pressure
Heart Rate
dofetilide
Blood Pressure
Pharmaceutical Preparations

Keywords

  • α-chloralose
  • α -adrenoceptor stimulation
  • Dofetilide
  • Intravenous anaesthesia
  • Pentobarbital
  • Phenylephrine
  • Pro-arrhythmia
  • Propofol
  • Rabbit
  • Torsades de pointes

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{75fa86dc771e473eaef3297e0f68e483,
title = "Relevance of anaesthesia for dofetilide-induced torsades de pointes in α 1-adrenoceptor-stimulated rabbits",
abstract = "Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in α 1-adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or α-chloralose were infused simultaneously with the α 1-adrenoceptor agonist phenylephrine (15 μg kg -1 min -1, i.v.) and dofetilide (0.04 mg kg -1 min -1, i.v.). The electrocardiographic QT interval, the T peak-T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with α-chloralose (40{\%} (P=0.011) and 70{\%} (P=0.211) vs 100{\%}, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with α-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the α-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared.",
keywords = "α-chloralose, α -adrenoceptor stimulation, Dofetilide, Intravenous anaesthesia, Pentobarbital, Phenylephrine, Pro-arrhythmia, Propofol, Rabbit, Torsades de pointes",
author = "D. Vincze and Farkas, {A. S.} and L. Rudas and P. Makra and N. Cs{\'i}k and I. Lepr{\'a}n and T. Forster and M. Csan{\'a}dy and J. Papp and A. Varr{\'o} and A. Farkas",
year = "2008",
month = "1",
doi = "10.1038/sj.bjp.0707536",
language = "English",
volume = "153",
pages = "75--89",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Relevance of anaesthesia for dofetilide-induced torsades de pointes in α 1-adrenoceptor-stimulated rabbits

AU - Vincze, D.

AU - Farkas, A. S.

AU - Rudas, L.

AU - Makra, P.

AU - Csík, N.

AU - Leprán, I.

AU - Forster, T.

AU - Csanády, M.

AU - Papp, J.

AU - Varró, A.

AU - Farkas, A.

PY - 2008/1

Y1 - 2008/1

N2 - Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in α 1-adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or α-chloralose were infused simultaneously with the α 1-adrenoceptor agonist phenylephrine (15 μg kg -1 min -1, i.v.) and dofetilide (0.04 mg kg -1 min -1, i.v.). The electrocardiographic QT interval, the T peak-T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with α-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with α-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the α-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared.

AB - Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in α 1-adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or α-chloralose were infused simultaneously with the α 1-adrenoceptor agonist phenylephrine (15 μg kg -1 min -1, i.v.) and dofetilide (0.04 mg kg -1 min -1, i.v.). The electrocardiographic QT interval, the T peak-T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with α-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with α-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the α-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared.

KW - α-chloralose

KW - α -adrenoceptor stimulation

KW - Dofetilide

KW - Intravenous anaesthesia

KW - Pentobarbital

KW - Phenylephrine

KW - Pro-arrhythmia

KW - Propofol

KW - Rabbit

KW - Torsades de pointes

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U2 - 10.1038/sj.bjp.0707536

DO - 10.1038/sj.bjp.0707536

M3 - Article

C2 - 17965737

AN - SCOPUS:37849007861

VL - 153

SP - 75

EP - 89

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 1

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