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.

Figure 1

Drug administration protocol. (a) The anaesthetic agent is α-chloralose, or propofol, or pentobarbital. Phenylephrine is administered at increasing rates (3, 6, 9, 12 and 15 μg kg⁻¹ min⁻¹). Dofetilide is infused at a rate of 0.04 mg kg⁻¹ min⁻¹. (b) Drug administration protocol in the ‘double dofetilide' group. The anaesthetic agent is pentobarbital. Phenylephrine is administered at increasing rates (3, 6, 9, 12 and 15 μg kg⁻¹ min⁻¹). Dofetilide is infused at a rate of 0.08 mg kg⁻¹ min⁻¹. (c) Drug administration protocol in the ‘triple phenylephrine' group. The anaesthetic agent is pentobarbital. Phenylephrine is administered at increasing rates (3, 6, 9, 12, 15 and 45 μg kg⁻¹ min⁻¹). Dofetilide is infused at a rate of 0.04 mg kg⁻¹ min⁻¹.

Figure 2

An example of dofetilide-induced torsades de pointes ventricular tachycardia (TdP). ECG I–III, electrocardiogram Leads I–III; BP, arterial blood pressure; Block, intraventricular conduction block; VT, polymorphic ventricular tachycardia different from torsades de pointes.

Figure 3

The spectral power of the systolic arterial pressure and the RR interval calculated in the mid-frequency range (0.15–0.5 Hz) in anaesthetized rabbits. (a and b) The spectral power of the systolic arterial blood pressure at baseline and during phenylephrine infusion, respectively. (c and d) The spectral power of the RR interval at baseline and during phenylephrine infusion, respectively. Chlor, group of animals anaesthetized with α-chloralose (‘chloralose' group); Prop, group of animals anaesthetized with propofol; Pento, group of animals anaesthetized with pentobarbital (‘pentobarbital' group); Dof2x, group of animals anaesthetized with pentobarbital, and dofetilide is infused at a rate of 0.08 mg kg⁻¹ min⁻¹ (‘double dofetilide' group; see Figure 1 for protocol); Phe3x, group of animals anaesthetized with pentobarbital and the maximum phenylephrine infusion rate is 45 μg kg⁻¹ min⁻¹ (‘triple phenylephrine' group); Baseline, values measured before drug administration; Phenylephrine, values measured during phenylephrine infusion at a rate of 9 μg kg⁻¹ min⁻¹; SAP MF, the spectral power of the systolic arterial pressure integrated in the mid-frequency band; RRI MF, the spectral power of the RR interval integrated in the mid-frequency band; n, number of animals. ^*P<0.05 vs ‘chloralose' and ‘propofol' groups.