Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, LATE SODIUM CURRENT, SCN5A, ION, RANOLAZINE, BLOCKADE, UPDATE, CELLS, HERG, Animals, Aorta, Abdominal, Cardiac Conduction System Disease, Cardiotonic Agents, Citrus, HEK293 Cells, Heart, Hesperidin, Humans, Long QT Syndrome, Male, Models, Molecular, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Rats, Wistar, Vasodilator Agents, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

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 μmol·L-1 . Hesperetin blocked 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 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.