Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation

I. Baczkó, David Liknes, Wei Yang, Kevin C. Hamming, Gavin Searle, Kristian Jaeger, Zoltan Husti, Viktor Juhasz, Gergely Klausz, Robert Pap, Laszlo Saghy, A. Varró, Vernon Dolinsky, Shaohua Wang, Vivek Rauniyar, Dennis Hall, Jason R B Dyck, Peter E. Light

Research output: Contribution to journalArticle

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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 Kv1.5, and the ionic currents I KACh and late INa, 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 IKur, 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 Kv1.5 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 Nav1.5 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.

Original languageEnglish
Pages (from-to)92-106
Number of pages15
JournalBritish Journal of Pharmacology
Volume171
Issue number1
DOIs
Publication statusPublished - Jan 2014

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Atrial Fibrillation
Ion Channels
Kv1.5 Potassium Channel
Muscle Cells
Inhibitory Concentration 50
Dogs
Calcium
Sodium Channels
resveratrol
Cardiac Arrhythmias
Oxidative Stress
Heart Failure
Antioxidants
Stroke
Pharmacology
Mortality
Pharmaceutical Preparations
Genes

Keywords

  • atrial fibrillation
  • electrophysiology
  • ion channels
  • K1.5
  • pharmacology
  • resveratrol

ASJC Scopus subject areas

  • Pharmacology

Cite this

Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation. / Baczkó, I.; Liknes, David; Yang, Wei; Hamming, Kevin C.; Searle, Gavin; Jaeger, Kristian; Husti, Zoltan; Juhasz, Viktor; Klausz, Gergely; Pap, Robert; Saghy, Laszlo; Varró, A.; Dolinsky, Vernon; Wang, Shaohua; Rauniyar, Vivek; Hall, Dennis; Dyck, Jason R B; Light, Peter E.

In: British Journal of Pharmacology, Vol. 171, No. 1, 01.2014, p. 92-106.

Research output: Contribution to journalArticle

Baczkó, I, Liknes, D, Yang, W, Hamming, KC, Searle, G, Jaeger, K, Husti, Z, Juhasz, V, Klausz, G, Pap, R, Saghy, L, Varró, A, Dolinsky, V, Wang, S, Rauniyar, V, Hall, D, Dyck, JRB & Light, PE 2014, 'Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation', British Journal of Pharmacology, vol. 171, no. 1, pp. 92-106. https://doi.org/10.1111/bph.12409
Baczkó, I. ; Liknes, David ; Yang, Wei ; Hamming, Kevin C. ; Searle, Gavin ; Jaeger, Kristian ; Husti, Zoltan ; Juhasz, Viktor ; Klausz, Gergely ; Pap, Robert ; Saghy, Laszlo ; Varró, A. ; Dolinsky, Vernon ; Wang, Shaohua ; Rauniyar, Vivek ; Hall, Dennis ; Dyck, Jason R B ; Light, Peter E. / Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 1. pp. 92-106.
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AU - Jaeger, Kristian

AU - Husti, Zoltan

AU - Juhasz, Viktor

AU - Klausz, Gergely

AU - Pap, Robert

AU - Saghy, Laszlo

AU - Varró, A.

AU - Dolinsky, Vernon

AU - Wang, Shaohua

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