Characterization of a Novel Multifunctional Resveratrol Derivative for the Treatment of Atrial Fibrillation

Br J Pharmacol. 2014 Jan;171(1):92-106. doi: 10.1111/bph.12409.

Abstract

Background and purpose: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk for stroke, heart failure and cardiovascular-related mortality. Candidate targets for anti-AF drugs include a potassium channel K(v)1.5, and the ionic currents I(KACh) and late I(Na), along with increased oxidative stress and activation of NFAT-mediated gene transcription. As pharmacological management of AF is currently suboptimal, we have designed and characterized a multifunctional small molecule, compound 1 (C1), to target these ion channels and pathways.

Experimental approach: We made whole-cell patch-clamp recordings of recombinant ion channels, human atrial I(Kur), rat atrial I(KACh), cellular recordings of contractility and calcium transient measurements in tsA201 cells, human atrial samples and rat myocytes. We also used a model of inducible AF in dogs.

Key results: C1 inhibited human peak and late K(v)1.5 currents, frequency-dependently, with IC₅₀ of 0.36 and 0.11 μmol·L(-1) respectively. C1 inhibited I(KACh)(IC₅₀ of 1.9 μmol·L(-1)) and the Na(v)1.5 sodium channel current (IC₅₀s of 3 and 1 μmol·L(-1) for peak and late components respectively). C1 (1 μmol·L(-1)) significantly delayed contractile and calcium dysfunction in rat ventricular myocytes treated with 3 nmol·L(-1) sea anemone toxin (ATX-II). C1 weakly inhibited the hERG channel and maintained antioxidant and NFAT-inhibitory properties comparable to the parent molecule, resveratrol. In a model of inducible AF in conscious dogs, C1 (1 mg·kg(-1)) reduced the average and total AF duration.

Conclusion and implications: C1 behaved as a promising multifunctional small molecule targeting a number of key pathways involved in AF.

Keywords: Kv1.5; atrial fibrillation; electrophysiology; ion channels; pharmacology; resveratrol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Adult
  • Aged
  • Animals
  • Animals, Newborn
  • Anti-Arrhythmia Agents / pharmacology*
  • Antioxidants / pharmacology
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / physiopathology
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Excitation Contraction Coupling / drug effects
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / antagonists & inhibitors
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • HEK293 Cells
  • Humans
  • Kv1.5 Potassium Channel / antagonists & inhibitors
  • Kv1.5 Potassium Channel / genetics
  • Kv1.5 Potassium Channel / metabolism
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel / drug effects
  • NAV1.5 Voltage-Gated Sodium Channel / genetics
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • NFATC Transcription Factors / antagonists & inhibitors
  • NFATC Transcription Factors / metabolism
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Resveratrol
  • Sodium Channel Blockers / pharmacology
  • Stilbenes / pharmacology*
  • Transfection

Substances

  • Anti-Arrhythmia Agents
  • Antioxidants
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNA5 protein, human
  • KCNH2 protein, human
  • Kv1.5 Potassium Channel
  • NAV1.5 Voltage-Gated Sodium Channel
  • NFATC Transcription Factors
  • Potassium Channel Blockers
  • SCN5A protein, human
  • Sodium Channel Blockers
  • Stilbenes
  • Resveratrol