Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model

Br J Pharmacol. 2008 Jul;154(5):958-70. doi: 10.1038/bjp.2008.154. Epub 2008 Apr 21.

Abstract

Background and purpose: Bradycardia is a risk factor for the development of torsade de pointes (TdP). The aim of this work was to compare the importance of changes in heart rate and arterial blood pressure in the development of drug-induced TdP and to investigate the role of vagal influences.

Experimental approach: Experiments were performed in open-chest, pentobarbital-anaesthetized, male rabbits which were given clofilium (20, 60 and 200 nmol kg(-1) min(-1)) with rising doses of either phenylephrine (75, 150, 225 and 300 nmol kg(-1) min(-1)), angiotensin II (0.25, 0.5, 0.75 and 1 nmol kg(-1) min(-1)) or saline. A fourth group received phenylephrine and cloflium after bilateral vagotomy. ECGs, haemodynamics and epicardial monophasic action potentials were recorded.

Key results: TdP occurred in 57% of rabbits given phenylephrine and clofilium. Replacement of phenylephrine with saline or angiotensin II reduced the incidence of TdP to 0 and 17%, respectively. Vagotomy prevented TdP in rabbits given phenylephrine and clofilium. Increases in blood pressure induced by phenylephrine and angiotensin II were similar. Bradycardia only occurred with phenylephrine and was reduced but not abolished by vagotomy. Neither short-term variability of repolarization nor action potential triangulation could predict TdP.

Conclusions and implications: These results indicate that reflex activation of vagal nerve activity is essential for the induction of drug-induced TdP in alpha1-adrenoceptor-stimulated anaesthetized rabbits. This implies that alterations in vagal activity may also precipitate episodes of drug-induced TdP in man and that this should be considered in selecting models used in drug development.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adrenergic alpha-Agonists / toxicity*
  • Angiotensin II / toxicity
  • Animals
  • Anti-Arrhythmia Agents / toxicity
  • Blood Pressure
  • Bradycardia / complications*
  • Bradycardia / metabolism
  • Bradycardia / physiopathology
  • Carbon Dioxide / blood
  • Disease Models, Animal
  • Electrocardiography
  • Heart / innervation*
  • Heart Rate / drug effects*
  • Hydrogen-Ion Concentration
  • Male
  • Oxygen / blood
  • Phenylephrine / toxicity*
  • Potassium / blood
  • Quaternary Ammonium Compounds / toxicity
  • Rabbits
  • Reflex
  • Time Factors
  • Torsades de Pointes / chemically induced*
  • Torsades de Pointes / metabolism
  • Torsades de Pointes / physiopathology
  • Vagotomy
  • Vagus Nerve / physiopathology*
  • Vagus Nerve / surgery

Substances

  • Adrenergic alpha-Agonists
  • Anti-Arrhythmia Agents
  • Quaternary Ammonium Compounds
  • Angiotensin II
  • Carbon Dioxide
  • Phenylephrine
  • clofilium
  • Potassium
  • Oxygen