Hyperventilation assists proarrhythmia development during delayed repolarization in clofilium-treated, anaesthetized, mechanically ventilated rabbits.

Hyperventilation reduces partial pressure of CO2 (PCO2) in the blood, which results in hypokalaemia. Hypokalaemia helps the development of the life-threatening torsades de pointes type ventricular arrhythmia (TdP) evoked by repolarization delaying drugs. This implies that hyperventilation may assist the development of proarrhythmic events. Therefore, this study experimentally investigated the effect of hyperventilation on proarrhythmia development during delayed repolarization. Phenylephrine (an α1-adrenoceptor agonist) and clofilium (as a representative repolarization delaying agent inhibiting the rapid component of the delayed rectifier potassium current, IKr) were administered intravenously to pentobarbital-anaesthetized, mechanically ventilated, open chest rabbits. ECG was recorded, and the onset times and incidences of the arrhythmias were determined. Serum K+, pH and PCO2 were measured in arterial blood samples. Clofilium prolonged the rate corrected QT interval. TdP occurred in 15 animals (TdP+ group), and did not occur in 14 animals (TdP- group). We found a strong, positive, linear correlation between serum K+ and PCO2. There was no relationship between the occurrence of TdP and the baseline K+ and PCO2 values. However, a positive, linear correlation was found between the onset time of the first arrhythmias and the K+ and PCO2 values. The regression lines describing the relationship between PCO2 and onset time of first arrhythmias were parallel in the TdP+ and TdP- groups, but the same PCO2 resulted in earlier arrhythmia onset in the TdP+ group than in the TdP- group. We conclude that hyperventilation and hypocapnia with the resultant hypokalaemia assist the multifactorial process of proarrhythmia development during delayed repolarization. This implies that PCO2 and serum K+ should be controlled tightly during mechanical ventilation in experimental investigations and clinical settings when repolarization-delaying drugs are applied.

Relevance of anaesthesia for dofetilide-induced torsades de pointes in alpha1-adrenoceptor-stimulated rabbits.

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.