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

Istvan Baczko, David Liknes, Wei Yang, Kevin C Hamming, Gavin Searle, Kristian Jaeger, Zoltan Husti, Viktor Juhasz, Gergely Klausz, Robert Pap, Laszlo Saghy, Andras Varro, Vernon Dolinsky, Shaohua Wang, Vivek Rauniyar, Dennis Hall, Jason Rb Dyck, Peter E Light
British Journal of Pharmacology 2014, 171 (1): 92-106

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.

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