Abstract
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). 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. 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 30μmol·L-1 . Hesperetin blocked rat and human NaV 1.5 channels with an effective inhibitory concentration of ≈100μmol·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. 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.
Highlights
Rapid heart rhythms, such as torsades de pointes (TdP) culminating in ventricular fibrillation, are still some of leading causes of morbidity and Abbreviations: hNaV1.5, human voltage‐gated sodium 1.5 channel; INa, sodium current; INa‐10 ms, sodium current at 10 ms after depolarization; INa‐500 ms, sodium current at 500 ms after depolarization; LQT3, long QT syndrome type 3; TdP, torsades de pointes mortality including sudden cardiac death (Janse & Rosen, 2006)
In order to determine the actions of hesperetin in a more pathologically relevant condition, we studied its effects on the LQT3 mutant channel R1623Q
The results show that hesperetin was significantly more potent on INa at 50 and 500 ms than on peak INa and more potent on these currents in R1623Q channels (Figure 4c,d; n = 12, P < 0.05, two‐way ANOVA with Tukey's post hoc test)
Summary
All LQT3 phenotypes show an increased net influx of Na+ that lengthens the action potential duration and could give rise to early afterdepolarizations and triggered activity inducing TdP and ventricular fibrillation in LQT3 (Veerman, Wilde, & Lodder, 2015) Targeting these mechanistic features in LQT3 mutations could be an effective strategy to reduce the Na+ overload, suggesting a novel therapeutic approach to treat LQT3 patients (Remme & Wilde, 2014). We aimed at determining the effects of hesperetin on the human cardiac NaV1.5 channel and on its mutant R1623Q, which features a slower INa inactivation that is associated with a severe LQT3 arrhythmic phenotype (Kambouris et al, 1998). The development of new compounds that would target the slow inactivation responsible for arrhythmias in this LQT3 mutation
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