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1.
Cardiovasc Res ; 116(8): 1434-1445, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628797

RESUMO

AIMS: Current treatment for congenital long QT syndrome Type 2 (cLQTS2), an electrical disorder that increases the risk of life-threatening cardiac arrhythmias, is aimed at reducing the incidence of arrhythmia triggers (beta-blockers) or terminating the arrhythmia after onset (implantable cardioverter-defibrillator). An alternative strategy is to target the underlying disease mechanism, which is reduced rapid delayed rectifier current (IKr) passed by Kv11.1 channels. Small molecule activators of Kv11.1 have been identified but the extent to which these can restore normal cardiac signalling in cLQTS2 backgrounds remains unclear. Here, we examined the ability of ICA-105574, an activator of Kv11.1 that impairs transition to the inactivated state, to restore function to heterozygous Kv11.1 channels containing either inactivation enhanced (T618S, N633S) or expression deficient (A422T) mutations. METHODS AND RESULTS: ICA-105574 effectively restored Kv11.1 current from heterozygous inactivation enhanced or expression defective mutant channels in heterologous expression systems. In a human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of cLQTS2 containing the expression defective Kv11.1 mutant A422T, cardiac repolarization, estimated from the duration of calcium transients in isolated cells and the rate corrected field potential duration (FPDc) in culture monolayers of cells, was significantly prolonged. The Kv11.1 activator ICA-105574 was able to reverse the prolonged repolarization in a concentration-dependent manner. However, at higher doses, ICA-105574 produced a shortening of the FPDc compared to controls. In vitro and in silico analysis suggests that this overcorrection occurs as a result of a temporal redistribution of the peak IKr to much earlier in the plateau phase of the action potential, which results in early repolarization. CONCLUSION: Kv11.1 activators, which target the primary disease mechanism, provide a possible treatment option for cLQTS2, with the caveat that there may be a risk of overcorrection that could itself be pro-arrhythmic.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Benzamidas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Canal de Potássio Kv1.1/agonistas , Síndrome do QT Longo/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antiarrítmicos/toxicidade , Benzamidas/toxicidade , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Canal de Potássio ERG1/genética , Canal de Potássio ERG1/metabolismo , Células HEK293 , Humanos , Canal de Potássio Kv1.1/genética , Canal de Potássio Kv1.1/metabolismo , Síndrome do QT Longo/genética , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Mutação , Miócitos Cardíacos/metabolismo , Fatores de Tempo
2.
CNS Neurosci Ther ; 25(4): 442-451, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30242974

RESUMO

AIMS: Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvß1 subunit resulting in rapid inactivating A-type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvß1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity. METHODS: We applied high-throughput screening to identify ligands able to modulate the Kv1.1-T1 domain/Kvß1 protein complex. We then selected a compound that was characterized on recombinant Kv1.1/Kvß1 channels by electrophysiology and further evaluated on sustained neuronal firing and on in vitro epileptiform activity using a high K+ -low Ca2+ model in hippocampal slices. RESULTS: We identified a novel compound able to modulate the interaction of the Kv1.1/Kvß1 complex and that produced a functional inhibition of Kv1.1/Kvß1 channel inactivation. We demonstrated that this compound reduced the sustained repetitive firing in hippocampal neurons and was able to abolish the development of in vitro epileptiform activity. CONCLUSIONS: This study describes a rational drug discovery approach for the identification of novel ligands that inhibit Kv1.1 channel inactivation and provides pharmacological evidence that such a mechanism translates into physiological effects by reducing in vitro epileptiform activity.


Assuntos
Potenciais de Ação/fisiologia , Descoberta de Drogas/métodos , Hipocampo/fisiologia , Canal de Potássio Kv1.1/fisiologia , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Hipocampo/efeitos dos fármacos , Humanos , Canal de Potássio Kv1.1/agonistas , Canal de Potássio Kv1.1/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Bloqueadores dos Canais de Potássio/farmacologia , Estrutura Secundária de Proteína , Ratos , Xenopus laevis
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