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

Authors

  • Istvan Baczko,

    1. Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
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    • These two authors contributed equally to the work.
  • David Liknes,

    1. Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, Edmonton, AB, Canada
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    • These two authors contributed equally to the work.
  • Wei Yang,

    1. Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, Edmonton, AB, Canada
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  • Kevin C Hamming,

    1. Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, Edmonton, AB, Canada
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  • Gavin Searle,

    1. Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, Edmonton, AB, Canada
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  • Kristian Jaeger,

    1. Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, Edmonton, AB, Canada
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  • Zoltan Husti,

    1. Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
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  • Viktor Juhasz,

    1. Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
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  • Gergely Klausz,

    1. 2nd Department of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary
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  • Robert Pap,

    1. 2nd Department of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary
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  • Laszlo Saghy,

    1. 2nd Department of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary
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  • Andras Varro,

    1. Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
    2. Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
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  • Vernon Dolinsky,

    1. Department of Pharmacology and Therapeutics, Manitoba Institute of Child Health, University of Manitoba, Winnipeg, MB, Canada
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  • Shaohua Wang,

    1. Division of Cardiac Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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  • Vivek Rauniyar,

    1. Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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  • Dennis Hall,

    1. Department of Chemistry, University of Alberta, Edmonton, AB, Canada
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  • Jason RB Dyck,

    1. Department of Pediatrics, Cardiovascular Research Centre and the Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
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  • Peter E Light

    Corresponding author
    1. Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, Edmonton, AB, Canada
    • Correspondence

      Peter E Light, Department of Pharmacology, Cardiovascular Research Centre and the Alberta Diabetes Institute, Li Ka Shing Research Centre, University of Alberta, i-OCS Liha Shing Research Centre, Edmonton, AB, Canada T6G 2E1. E-mail: peter.light@ualberta.ca

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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 IKACh 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 IKACh, 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 IKACh (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.

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