Relevance of anaesthesia for dofetilide‐induced torsades de pointes in α1‐adrenoceptor‐stimulated rabbits (Englisch)

in British Journal of Pharmacology ; 153 , 1 ; 75-89
British Journal of Pharmacology

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 α1‐adrenoceptor‐stimulated rabbits.

Rabbits anaesthetized intravenously with pentobarbital, propofol or α‐chloralose were infused simultaneously with the α1‐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 peakT 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.

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.

In rabbits, anaesthetics may affect drug‐induced TdP genesis differently, which must be considered when results of different studies are compared.

British Journal of Pharmacology (2008) 153, 75–89; doi:10.1038/sj.bjp.0707536; published online 29 October 2007

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