Relevance of anaesthesia for dofetilide‐induced torsades de pointes in α₁‐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 a-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in a 1 -adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or a-chloralose were infused simultaneously with the a 1 -adrenoceptor agonist phenylephrine (15 mg kg À1 min À1 , i.v.) and dofetilide (0.04 mg kg À1 min À1 , 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 dofetilideinduced torsades de pointes (TdP) as compared with the results with a-chloralose (40% (P ¼ 0.011) and 70% (P ¼ 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 a-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the a-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. (2008) 153, 75-89; doi:10.1038/sj.bjp.0707536; published online 29 October 2007 Keywords: intravenous anaesthesia; pentobarbital; propofol; a-chloralose; torsades de pointes; pro-arrhythmia; dofetilide; a 1 -adrenoceptor stimulation; phenylephrine; rabbit Abbreviations: ECG, electrocardiogram; PNN8, percentage of successive QT intervals that differ by more than 8 ms; RMSSD, root mean square of the successive differences in the RR or QT intervals; SAP MF, spectral power of the systolic arterial pressure in the mid-frequency range British Journal of Pharmacology

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

“…19,20 Although both AZD1305 and dofetilide infusions were accompanied by a significant increase in the QTend-QTpeak interval, the increase by dofetilide was significantly larger indicating a more marked increase in TDR in the dofetilide-administered rabbits. This observation is in line with previous findings by Wu and colleagues but in contrast to those by Vincze et al 9,28 When interpreting these contradictory observations one should keep in mind that the TDR data stem from limb Lead II recordings. It has been suggested that the TDR calculated from such limb leads more likely reflect global dispersion than transmural dispersion of repolarisation and our results should thus be interpreted with caution.…”

“…Our findings contrast the conclusion by Vincze and coworkers that beat-by-beat QT interval variability did not predict dofetilide-induced TdP in phenylephrine-sensitized rabbits, a discrepancy that may be related to the different means of a-adrenoceptor stimulation in the two studies. 10,28 In contrast to dofetilide, AZD1305 did not alter the QT interval variability as compared to the variability seen before drug infusion commenced. Furthermore, in the rabbits experiencing dofetilide-induced TdP and in which intervention with AZD1305 promptly restored sinus rhythm and abbreviated the QT interval, the dofetilide-induced beat-by-beat QT variability was pushed back to the magnitude of variability seen under dofetilide-free conditions or during the infusion of AZD1305 solely.…”

Drug-Induced Long QT Syndrome

“…An increase in QT beat-to-beat variability was noted before development of TdP in one study (Lengyel et al, 2007), but this has not been noted in other studies (Carlsson, 2008). The peak to the end of the QT interval has been noted to increase with dofetilide in methoxamine-sensitized rabbits but did not correlate with TdP (Carlsson, 2008) and did not prolong with dofetilide in phenylephrine-sensitized rabbits (Vincze et al, 2008). These measurements were performed in a single ECG lead (lead II) and are more reflective of global, not transmural dispersion of repolarization.…”

Deep Anesthesia Suppresses Ventricular Tachyarrhythmias in Rabbit Model of the Acquired Long QT Syndrome

“…However, no earlier study has confirmed this view. 22 Also, because blood pressure and heart rate in the 2 groups with different depth of anesthesia were similar in Study 1, differences in autonomic state does not seem to be responsible for the decrease in the incidence of VT in rabbits with deep anesthesia.…”

“…In an earlier study by Vincze et al, 22 pentobarbital has shown marked effect on VT in the rabbit model of acquired LQTS. In contrast, neither propofol or α-chloralose failed to show appreciable antiarrhythmic action.…”