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

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 NaV1.5 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 NaV1.5 currents (INa) in rat ventricular cardiomyocytes and in HEK293T cells expressing hNaV1.5 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 μmol·L−1. Hesperetin blocked rat and human NaV1.5 channels with an effective inhibitory concentration of ≈100 μmol·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.