title: AV-block and conduction slowing prevail over TdP arrhythmias in the methoxamine-sensitized pro-arrhythmic rabbit model.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Physiology, Division Heart & Lungs University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Varkevisser
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Jet D
authors.initials: JD
authors.lastname: Beekman
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Tieland
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Van Der Heyden
mesh_terms: D000200:Action Potentials; D000777:Anesthetics / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D054537:Atrioventricular Block / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005444:Flunarizine / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D008729:Methoxamine; D010627:Phenethylamines; D011817:Rabbits; D013449:Sulfonamides; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000777:Anesthetics; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D008729:Methoxamine; C063533:dofetilide; D005444:Flunarizine
keywords: Torsade de Pointes; anesthesia; conduction block; dofetilide; drug safety; methoxamine rabbit model