Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes.
Br J Pharmacol
; 151(7): 941-51, 2007 Aug.
Article
em En
| MEDLINE
| ID: mdl-17533421
ABSTRACT
BACKGROUND AND PURPOSE:
Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I(Ks) and I(Kr) block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. EXPERIMENTALAPPROACH:
ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I(Kr) blocker dofetilide (DOF), the I(Ks) blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. KEYRESULTS:
DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits. CONCLUSION AND IMPLICATIONS STV(QT) was markedly increased by combined pharmacological block of I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome do QT Longo
/
Torsades de Pointes
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Canais de Potássio de Abertura Dependente da Tensão da Membrana
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Canais de Potássio de Retificação Tardia
Limite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Hungria
País de publicação:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
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UK
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UNITED KINGDOM