Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence.
1. Tedisamil is a bradycardiac agent that prolongs the QT interval of the ECG and prevents cardiac arrhythmias. Given this profile, tedisamil might be expected to have proarrhythmic actions similar to Class III antiarrhythmic drugs. To address this question, the actions of dofetilide and tedisamil were examined in rabbit isolated hearts in which bradycardia was induced by AV ablation. 2. The QT interval was prolonged in a reverse rate-dependent fashion by dofetilide (3 and 30 nM) and tedisamil (0.3 and 3 microM). 3. Torsades de pointes was observed in 1/7 hearts treated with 3 nM dofetilide and 0/7 hearts treated with 0.3 microM tedisamil. The incidence of torsades de pointes was increased to 5/7 in hearts treated with 30 nM dofetilide and to 7/7 in hearts treated with 3 microM tedisamil (both P < 0.05 vs control). 4. The actions of 30 nM dofetilide and 3 microM tedisamil were also examined in hearts paced at 50, 100, 200 and 50 beats min(-1) successively. Both drugs caused torsades de pointes in 5/5 hearts paced at 50 beats min(-1); however, the incidence was reduced to 0/5 during pacing at 200 beats min(-1). Thus, drug-induced proarrhythmia was bradycardia-dependent. 5. Drug-induced prolongation of the interval between the peak and end of the T-wave (QTa-e) was reverse rate-dependent and was associated with the occurrence of torsades de pointes (r = 0.91, P < 0.01). 6. The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, MI 48019-0632, USA.
T D
TD
Barrett
J K
JK
Hennan
P S
PS
Fischbach
B P
BP
O'Neill
E M
EM
Driscoll
B R
BR
Lucchesi
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D011188:Potassium / Q000097:blood / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D010627:Phenethylamines; D013449:Sulfonamides; C059921:tedisamil; C063533:dofetilide; D011188:Potassium