Relevance of anaesthesia for dofetilide-induced torsades de pointes in alpha1-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 alpha-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in alpha(1)-adrenoceptor-stimulated rabbits.

EXPERIMENTAL APPROACH:

Rabbits anaesthetized intravenously with pentobarbital, propofol or alpha-chloralose were infused simultaneously with the alpha(1)-adrenoceptor agonist phenylephrine (15 microg 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 alpha-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 alpha-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the alpha-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.

• Authors: D Vincze, A S Farkas, L Rudas, P Makra, N Csík, I Leprán, T Forster, M Csanády, J G Papp, A Varró, A Farkas
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 153 Issue 1 Pg. 75-89 (Jan 2008) ISSN: 0007-1188 [Print] England
• PMID: 17965737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics
• Anti-Inflammatory Agents
• Phenethylamines
• Receptors, Adrenergic, alpha-1
• Sulfonamides
• Chloralose
• Pentobarbital
• dofetilide
• Propofol

Topics

• Anesthesia
• Anesthetics (pharmacology)
• Animals
• Anti-Inflammatory Agents (toxicity)
• Baroreflex (drug effects)
• Blood Pressure (drug effects)
• Chloralose (pharmacology)
• Female
• Heart Rate (drug effects)
• Pentobarbital (pharmacology)
• Phenethylamines (toxicity)
• Propofol (pharmacology)
• Rabbits
• Receptors, Adrenergic, alpha-1 (physiology)
• Sulfonamides (toxicity)
• Sympathetic Nervous System (drug effects)
• Torsades de Pointes (chemically induced)
• Vagus Nerve (drug effects)