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AV‐Block and Conduction Slowing Prevail Over TdP Arrhythmias in the Methoxamine‐Sensitized Pro‐Arrhythmic Rabbit Model
Author(s) -
VARKEVISSER ROSANNE,
VOS MARC A.,
BEEKMAN JET D.,
TIELAND RALPH G.,
VAN DER HEYDEN MARCEL A.
Publication year - 2015
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/jce.12533
Subject(s) - methoxamine , dofetilide , medicine , anesthesia , ketamine , xylazine , repolarization , cardiology , qt interval , agonist , electrophysiology , receptor
Anesthesia in the Methoxamine‐Sensitized Rabbit 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. 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.