Augmentation of Ouabain-Induced Increase in Heart Muscle Contractility by Akt Inhibitor MK-2206.
J Cardiovasc Pharmacol Ther
; 24(1): 78-89, 2019 01.
Article
em En
| MEDLINE
| ID: mdl-30033751
Cardiac steroids (CSs), such as ouabain and digoxin, increase the force of contraction of heart muscle and are used for the treatment of congestive heart failure (CHF). However, their small therapeutic window limits their use. It is well established that Na+, K+-ATPase inhibition mediates CS-induced increase in heart contractility. Recently, the involvement of intracellular signal transduction was implicated in this effect. The aim of the present study was to test the hypothesis that combined treatment with ouabain and Akt inhibitor (MK-2206) augments ouabain-induced inotropy in mammalian models. We demonstrate that the combined treatment led to an ouabain-induced increase in contractility at concentrations at which ouabain alone was ineffective. This was shown in 3 experimental systems: neonatal primary rat cardiomyocytes, a Langendorff preparation, and an in vivo myocardial infarction induced by left anterior descending coronary artery (LAD) ligation. Furthermore, cell viability experiments revealed that this treatment protected primary cardiomyocytes from MK-2206 toxicity and in vivo reduced the size of scar tissue 10 days post-LAD ligation. We propose that Akt activity imposes a constant inhibitory force on muscle contraction, which is attenuated by low concentrations of MK-2206, resulting in potentiation of the ouabain effect. This demonstration of the increase in the CS effect advocates the development of the combined treatment in CHF.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ouabaína
/
Cardiotônicos
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Função Ventricular Esquerda
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Miócitos Cardíacos
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Inibidores de Proteínas Quinases
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Proteínas Proto-Oncogênicas c-akt
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Compostos Heterocíclicos com 3 Anéis
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Contração Miocárdica
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Infarto do Miocárdio
Limite:
Animals
Idioma:
En
Revista:
J Cardiovasc Pharmacol Ther
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Israel
País de publicação:
Estados Unidos