Tedisamil and dofetilide‐induced torsades de pointes, rate and potassium dependence (English)

In: British Journal of Pharmacology ;  132 ,  7 ;  1493-1500 ;  2001

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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.

The QT interval was prolonged in a reverse rate‐dependent fashion by dofetilide (3 and 30 nM) and tedisamil (0.3 and 3 μM).

Torsades de pointes was observed in 1/7 hearts treated with 3 nM dofetilide and 0/7 hearts treated with 0.3 μM 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 μM tedisamil (both P<0.05 vs control).

The actions of 30 nM dofetilide and 3 μM 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.

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).

The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.

British Journal of Pharmacology (2001) 132, 1493–1500; doi:10.1038/sj.bjp.0703967

Table of contents – Volume 132, Issue 7

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1359
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Minyan, Wang / Dunn, W R / Blaylock, N A / Chan, S L F / Wilson, V G | 2001
1365
Chronic vascular toxicity of doxorubicin in an organ‐cultured artery
Murata, Takahisa / Yamawaki, Hideyuki / Hori, Masatoshi / Sato, Koichi / Ozaki, Hiroshi / Karaki, Hideaki | 2001
1374
Effects of anti‐oestrogens and β‐estradiol on calcium uptake by cardiac sarcoplasmic reticulum
Dodds, Marnie L / Kargacin, Margaret E / Kargacin, Gary J | 2001
1383
Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5‐hydroxytryptamine by KB‐R7943, a Na+/Ca2+ exchange inhibitor
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1396
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1411
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1417
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1423
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1493
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1501
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1509
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1524
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Chang, C‐P / Pan, S‐P / Lin, M‐T | 2001
1531
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1542
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1549
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1558
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1565
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1574
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1581
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1590
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1597
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1606
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1615
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