Comparison of the in vivo electrophysiological and proarrhythmic effects of amiodarone with those of a selective class III drug, sematilide, using a canine chronic atrioventricular block model.
Amiodarone effectively blocks both the sodium and calcium channels and beta-adrenoceptors, in addition to blocking several potassium currents including IKr, IKs, Ito, IK1, IKACh and IKNa. The incidence of clinical torsade de pointes (TdP) associated with amiodarone has been reported to be low and the present study compared the proarrhythmic potential of amiodarone with that of a selective IKr channel blocker, sematilide, using a canine chronic atrioventrucular block model. Amiodarone or sematilide (3 and 30 mg/kg; n=4 for each group) was administered orally without anesthesia under continuous ECG monitoring. Both drugs prolonged the QT interval, although the onset was faster for sematilide. The high dose of sematilide induced TdP in 3 of 4 animals, which caused their death, but neither the low dose of sematilide nor the 2 dosages of amiodarone induced lethal ventricular arrhythmias. These results suggest that IKr channel inhibition by amiodarone with its additional ion channel blocking action may contribute to the prevention of TdP.
Department of Pharmacology, Yamanashi Medical University, Nakakoma-gun, Japan.
Hiroshi
H
Yoshida
Atsushi
A
Sugiyama
Yoshioki
Y
Satoh
Yuko
Y
Ishida
Masahiko
M
Yoneyama
Kiyotaka
K
Kugiyama
Keitaro
K
Hashimoto
D000638:Amiodarone / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002908:Chronic Disease; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006327:Heart Block / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011342:Procainamide / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000401:mortality
D000889:Anti-Arrhythmia Agents; C062818:sematilide; D011342:Procainamide; D000638:Amiodarone