AV-block and conduction slowing prevail over TdP arrhythmias in the methoxamine-sensitized pro-arrhythmic rabbit model
Varkevisser, Rosanne; Vos, Marc A; Beekman, Jet; Tieland, Ralph G; Van Der Heyden, Marcel A
(2015) Journal of Cardiovascular Electrophysiology, volume 26, issue 1, pp. 82 - 9
(Article)
Abstract
INTRODUCTION: The methoxamine-sensitized rabbit model is widely used to screen drugs for proarrhythmic properties, especially repolarization-dependent TdP arrhythmias. With the change of anesthesia and/or sensitizing agent, conduction disturbances have been reported as well. Therefore, we compared currently available in-house anesthetics in order to preserve arrhythmia sensitivity and preclude conduction disturbances.
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METHODS AND RESULTS: Rabbits were randomly assigned to 3 groups: (1) 35 mg/kg ketamine + 5 mg/kg xylazine; (2) 0.5 mL/kg hypnorm + 3 mg/kg midazolam; (3) 35 mg/kg ketamine + 20 mg/kg propofol. Anesthesia was maintained by 1.5% isoflurane. Concomitant infusion of methoxamine (17 μg/kg/min for 40 minutes) and dofetilide (10 μg/kg/min for 30 minutes) was used to induce arrhythmias. Sole methoxamine infusion exclusively decreased HR in groups 1 and 3. Dofetilide lengthened repolarization, followed in time by PQ/QRS prolongation, second-degree AV block, and subsequently TdP arrhythmias. TdP was seen in 80%, 0%, and 33% of the rabbits in groups 1, 2, and 3, respectively. Decreasing the dose of dofetilide to 5 μg/kg/min in ketamine/xylazine anesthetized rabbits resulted in a drop in TdP incidence (25%) while conduction disturbances persisted. Flunarizine (n = 6) suppressed all TdP arrhythmias while conduction disturbances remained present. CONCLUSION: TdP incidence in the methoxamine-sensitized rabbit could be dramatically influenced by anesthesia, drug dose, and flunarizine, while conduction slowing remained present. Thus, conduction slowing seems to be the integral outcome in this model.
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Keywords: Action Potentials, Anesthetics, Animals, Anti-Arrhythmia Agents, Atrioventricular Block, Disease Models, Animal, Electrophysiologic Techniques, Cardiac, Flunarizine, Heart Conduction System, Heart Rate, Methoxamine, Phenethylamines, Rabbits, Sulfonamides, Time Factors, Torsades de Pointes, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 1045-3873
Publisher: Wiley-Blackwell
Note: © 2014 Wiley Periodicals, Inc.
(Peer reviewed)