title: Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes.
abstract: (-)-Epicatechin-3-gallate (ECG), a polyphenol extracted from green tea, has been proposed as an effective compound for improving cardiac contractility. However, the therapeutic potential of ECG on the treatment of arrhythmia remains unknown. We investigated the direct actions of ECG on the modulation of ion currents and cardiac cell excitability in the primary culture of neonatal rat ventricular myocyte (NRVM), which is considered a hypertrophic model for analysis of myocardial arrhythmias. By using the whole-cell patch-clamp configurations, we found ECG enhanced the slowly inactivating component of voltage-gated Na(+) currents (I(Na)) in a concentration-dependent manner (0.1-100 μM) with an EC(50) value of 3.8 μM. ECG not only shifted the current-voltage relationship of peak I(Na) to the hyperpolarizing direction but also accelerated I(Na) recovery kinetics. Working at a concentration level of I(Na) enhancement, ECG has no notable effect on voltage-gated K(+) currents and L-type Ca(2+) currents. With culture time increment, the firing rate of spontaneous action potential (sAP) in NRVMs was gradually decreased until spontaneous early after-depolarization (EAD) was observed after about one week culture. ECG increased the firing rate of normal sAP about two-fold without waveform alteration. Interestingly, the bradycardia-dependent EAD could be significantly restored by ECG in fast firing rate to normal sAP waveform. The expression of dominant cardiac sodium channel subunit, Nav1.5, was consistently detected throughout the culture periods. Our results reveal how ECG, the novel I(Na) agonist, may act as a promising candidate in clinical applications on cardiac arrhythmias.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Adonis Zhi-Yang
authors.initials: AZ
authors.lastname: Wu
authors.forename: Shih-Hurng
authors.initials: SH
authors.lastname: Loh
authors.forename: Tzu-Hurng
authors.initials: TH
authors.lastname: Cheng
authors.forename: Hsin-Hsiang
authors.initials: HH
authors.lastname: Lu
authors.forename: Cheng-I
authors.initials: CI
authors.lastname: Lin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D062687:Sodium Channel Agonists / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568322:Scn5a protein, rat; D062687:Sodium Channel Agonists; D002392:Catechin; C062669:epicatechin gallate