The citrus flavanone hesperetin preferentially inhibits slow-inactivating currents of an LQT3 syndrome Na + channel mutation.

BACKGROUND AND PURPOSE: The citrus flavanone hesperetin (HSP) has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain largely unexplored. Here we evaluated HSP effects on cardiac electrical and contractile activities, on aortic contraction, on the wild type voltage-gated Na+ channel NaV 1.5 and on a channel mutant (R1623Q) associated with lethal ventricular arrhythmias in the Long QT syndrome subtype 3 (LQT3).

EXPERIMENTAL APPROACH: We used cardiac surface electrocardiogram and contraction force recordings to evaluate HSP effects in isolated rat 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 (WT) or mutant channels.

KEY RESULTS: HSP 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 . HSP blocked the rat and human NaV 1.5 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 of local anaesthetics. HSP increased the rate of inactivation and preferentially inhibited INa during the slow inactivation phase, being these effects more pronounced in the R1623Q mutant.

CONCLUSIONS AND IMPLICATIONS: HSP preferentially inhibits the slow inactivation phase of INa , more markedly in the mutant R1623Q. HSP could be used as a template to develop drugs against lethal cardiac arrhythmias in LQT3.