Document Detail


Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model.
MedLine Citation:
PMID:  18587444     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
A Farkas; J Dempster; S J Coker
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-04-21
Journal Detail:
Title:  British journal of pharmacology     Volume:  154     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-30     Completed Date:  2008-10-02     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  958-70     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, UK.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials
Adrenergic alpha-Agonists / toxicity*
Angiotensin II / toxicity
Animals
Anti-Arrhythmia Agents / toxicity
Blood Pressure
Bradycardia / complications*,  metabolism,  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*,  metabolism,  physiopathology
Vagotomy
Vagus Nerve / physiopathology*,  surgery
Grant Support
ID/Acronym/Agency:
PG96/100//British Heart Foundation
Chemical
Reg. No./Substance:
0/Adrenergic alpha-Agonists; 0/Anti-Arrhythmia Agents; 0/Quaternary Ammonium Compounds; 11128-99-7/Angiotensin II; 124-38-9/Carbon Dioxide; 59-42-7/Phenylephrine; 68379-02-2/clofilium; 7440-09-7/Potassium; 7782-44-7/Oxygen
Comments/Corrections

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