Slow delayed rectifier potassium current blockade contributes importantly to drug-induced long QT syndrome.
Circ Arrhythm Electrophysiol
; 6(5): 1002-9, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23995305
ABSTRACT
BACKGROUND:
Drug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (IKr). Effects on the slow delayed rectifier potassium current (IKs) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the IKs channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on IKs. METHODS ANDRESULTS:
ECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on IKs and IKr demonstrated significant action potential prolongation, to which IKs block contributed importantly. Although the effects of the mutation per se were small, additional IKs blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced IKs blockade on QTc prolongation.CONCLUSIONS:
IKs blockade contributes importantly to drug-induced long QT syndrome, especially when repolarization reserve is reduced. Drug safety tests might have to include screening for IKs blockade.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome do QT Longo
/
Fluoxetina
/
Inibidores Seletivos de Recaptação de Serotonina
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Canais de Potássio de Abertura Dependente da Tensão da Membrana
/
Canal de Potássio KCNQ1
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
/
Middle aged
Idioma:
En
Revista:
Circ Arrhythm Electrophysiol
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Holanda