The influence of specific and nonspecific potassium current blockade on the defibrillation energy requirement of biphasic shock.
Block of delayed rectifier potassium current (IK) is known to decrease defibrillation energy requirements (DERs). We tested the hypothesis that there would be no difference in DER reduction with a nonspecific IK (IKr + IKs) blocker, ambasilide, and a specific IKr blocker, dofetilide.


METHODS
An anesthetized canine model (n = 30) of internal transvenous defibrillation with biphasic shocks was used. Ambasilide (n = 9; dose: 4.8 mg/kg, then 9.6 mg/kg/hour), dofetilide (n = 10; dose: 10 (micrograms/kg, then 3.6 (micrograms/kg/hour), or matched placebo (n = 11) were administered. DERs (J) were determined in triplicate using an increment-decrement protocol at baseline and during each treatment. ECG intervals were measured at baseline and during each treatment. ANOVA with post-hoc Bonferroni test was used for statistical analysis.


RESULTS
Ambasilide resulted in a +23.5 +/- 4.06% prolongation of the QTc interval, while dofetilide resulted in a +20.5% +/- 3.76% prolongation of the QTc interval. Thus, the two drugs resulted in comparable prolongation of the QTc interval (P < 0.05 compared to placebo). Both drugs significantly reduced the DER (-17.7% +/- 5.33% reduction by ambasilide, and -21.9% +/- 5.21% reduction by dofetilide, P < 0.05 compared to placebo). There was no difference in the magnitude of DER reduction between the two treatments.


CONCLUSIONS
Administration of equipotent doses (as indicated by QTc changes) of ambasilide or dofetilide had comparable effects on DERs. Selectivity of IK blockade has no significant effect on the magnitude of reduction in DERs.
Mehdirad
A A
AA
Department of Internal Medicine, College of Pharmacy, Ohio State University, Columbus, USA.
Carnes
C A
CA
Nelson
S D
SD
D000200:Action Potentials / Q000187:drug effects; D062365:Aminobenzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D017147:Defibrillators, Implantable; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004554:Electric Countershock; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate; D007262:Infusions, Intravenous; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage / Q000627:therapeutic use*; D010865:Pilot Projects; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*