Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction.
BACKGROUND
Azimilide blocks the slow (I(Ks)) and fast (I(Kr)) components of the delayed rectifier potassium channel. It also has blocking effects on sodium (I(Na)) and calcium currents (I(CaL)). Its effects on reentrant circuits in infarct border zones causing ventricular tachyarrhythmias are unknown.


RESULTS
Activation in reentrant circuits causing sustained ventricular tachycardia (SVT) and the initial polymorphic tachycardia that leads to ventricular fibrillation (VF) was mapped in the epicardial border zone (EBZ) of 4-day-old canine infarcts. Azimilide prolonged the effective refractory period (ERP) in both normal myocardium and EBZ, but reverse use-dependence in EBZ was prominent. Azimilide abolished SVT initiation by programmed electrical stimulation by prolonging the ERP at the site of stimulation either in normal or EBZ, preventing the occurrence of early premature impulses and the formation of lines of block in the EBZ necessary for formation of reentrant circuits. Azimilide prevented VF initiation by programmed electrical stimulation by causing conduction block of reentrant impulses in the EBZ during the initial beats of rapid polymorphic ventricular tachycardia, despite the reverse use-dependent effects on ERP.


CONCLUSIONS
Azimilide has antiarrhythmic effects to prevent reentry causing SVT and VF in a canine infarct model.
Schmitt
H
H
Department of Pharmacology, Center of Molecular Therapeutics, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Cabo
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Coromilas
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JC
Wit
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006827:Hydantoins; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D010879:Piperazines / Q000627:therapeutic use*; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide