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The citrus flavanone hesperetin preferentially inhibits slow-inactivating currents of a long QT syndrome type 3 syndrome Na+ channel mutation.

ABSTRACT: BACKGROUND AND PURPOSE:The citrus flavanone hesperetin has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain largely unexplored. Here, we evaluated the effect of hesperetin on cardiac electrical and contractile activities, on aortic contraction, on the wild-type voltage-gated NaV 1.5 channel, and on a channel mutant (R1623Q) associated with lethal ventricular arrhythmias in the long QT syndrome type 3 (LQT3). EXPERIMENTAL APPROACH:We used cardiac surface ECG and contraction force recordings to evaluate the effects of hesperetin in rat isolated hearts and aortic rings. Whole-cell patch clamp was used to record NaV 1.5 currents (INa ) in rat ventricular cardiomyocytes and in HEK293T cells expressing hNaV 1.5 wild-type or mutant channels. KEY RESULTS:Hesperetin increased the QRS interval and heart rate and decreased the corrected QT interval and the cardiac and aortic contraction forces at concentrations equal or higher than 30 ?mol·L-1 . Hesperetin blocked rat and human NaV 1.5 channels with an effective inhibitory concentration of ?100 ?mol·L-1 . This inhibition was enhanced at depolarized holding potentials and higher stimulation frequency and was reduced by the disruption of the binding site for local anaesthetics. Hesperetin increased the rate of inactivation and preferentially inhibited INa during the slow inactivation phase, these effects being more pronounced in the R1623Q mutant. CONCLUSIONS AND IMPLICATIONS:Hesperetin preferentially inhibits the slow inactivation phase of INa , more markedly in the mutant R1623Q. Hesperetin could be used as a template to develop drugs against lethal cardiac arrhythmias in LQT3.

SUBMITTER: Alvarez-Collazo J

PROVIDER: S-EPMC6451064 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The citrus flavanone hesperetin preferentially inhibits slow-inactivating currents of a long QT syndrome type 3 syndrome Na<sup>+</sup> channel mutation.

Alvarez-Collazo Julio J López-Requena Alejandro A Galán Loipa L Talavera Ariel A Alvarez Julio L JL Talavera Karel K

British journal of pharmacology 20190327 8

<h4>Background and purpose</h4>The citrus flavanone hesperetin has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain largely unexplored. Here, we evaluated the effect of hesperetin on cardiac electrical and contractile activities, on aortic contraction, on the wild-type voltage-gated Na<sub>V</sub> 1.5 channel, and on a channel mutant (R1623Q) associated with lethal ventricular arrhythmias in the long QT syndrome type 3 (LQT3).<h4>Experimental ap ...[more]

PMID: 30650182

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Project description:Oligodendrocytes (oligodendroglial cells) are glial cells that wrap neuronal axons with their differentiated plasma membranes called myelin membranes. In the pathogenesis of inflammatory cytokine-related oligodendroglial cell and myelin diseases such as multiple sclerosis (MS), typical inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) are thought to contribute to the degeneration and/or progression of the degeneration of oligodendroglial cells and, in turn, the degeneration of naked neuronal cells in the central nervous system (CNS) tissues. Despite the known involvement of these inflammatory cytokines in disease progression, it has remained unclear whether and how TNFα or IL-6 affects the oligodendroglial cells themselves or indirectly. Here we show that TNFα or IL-6 directly inhibits morphological differentiation in FBD-102b cells, which are differentiation models of oligodendroglial cells. Their phenotype changes were supported by the decreased expression levels of oligodendroglial cell differentiation and myelin marker proteins. In addition, TNFα or IL-6 decreased phosphorylation levels of Akt kinase, whose upregulation has been associated with promoting oligodendroglial cell differentiation. Hesperetin, a flavonoid mainly contained in citrus fruit, is known to have neuroprotective effects. Hesperetin might also be able to resolve pre-illness conditions, including the irregulated secretion of cytokines, through diet. Notably, the addition of hesperetin into cells recovered TNFα- or IL-6-induced inhibition of differentiation, as supported by increased levels of marker protein expression and phosphorylation of Akt kinase. These results suggest that TNFα or IL-6 itself contributes to the inhibitory effects on the morphological differentiation of oligodendroglial cells, possibly providing information not only on their underlying pathological effects but also on flavonoids with potential therapeutic effects at the molecular and cellular levels.

Dataset Information

The citrus flavanone hesperetin preferentially inhibits slow-inactivating currents of a long QT syndrome type 3 syndrome Na+ channel mutation.

Publications

The citrus flavanone hesperetin preferentially inhibits slow-inactivating currents of a long QT syndrome type 3 syndrome Na<sup>+</sup> channel mutation.

Similar Datasets

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