Hesperetin preferentially inhibits slow-activating currents of an LQT3 syndrome Na+ channel mutation




Julio Alvarez-Collazo, Alejandro López-Requena, Loipa Galán, Ariel Talavera, Julio L. Alvarez and Karel Talavera



The citrus flavanone hesperetin (HSP) has been proposed for the treatment of several human pathologies, but its cardiovascular actions remain unexplored. Here we studied the effects of HSP on the human cardiac voltage-gated Na+ channel (hNaV1.5) and compared it to its effects on a recombinant hNaV1.5 channel baring a mutation (R1623Q) associated with lethal ventricular arrhythmias in the Long QT syndrome type 3 (LQT3).

METHODS: Whole-cell patch clamp experiments were used to record Na+-currents (INa) in HEK293T cells expressing hNaV1.5 wild type (WT) or mutant channels.

RESULTS: HSP blocked thehNaV1.5 channels in voltage-dependent manner with an IC50 ≈ 100 μM. Its inhibition was decreased by disruption of the F1760 residue. HSP preferentially accelerated the inactivation phase of INa and decreased the Na+ net influx into the cell. The effects of HSP on the inactivation phase and voltage-dependent inhibition of INa were more marked in the LQT3 mutant.

CONCLUSIONS: HSP could be used as a template to develop drugs against cardiac arrhythmias in LQT3.

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