These two authors contributed equally to the work.
Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation
Article first published online: 10 DEC 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 1, pages 92–106, January 2014
How to Cite
Baczko, I., Liknes, D., Yang, W., Hamming, K. C., Searle, G., Jaeger, K., Husti, Z., Juhasz, V., Klausz, G., Pap, R., Saghy, L., Varro, A., Dolinsky, V., Wang, S., Rauniyar, V., Hall, D., Dyck, J. R. and Light, P. E. (2014), Characterization of a novel multifunctional resveratrol derivative for the treatment of atrial fibrillation. British Journal of Pharmacology, 171: 92–106. doi: 10.1111/bph.12409
- Issue published online: 10 DEC 2013
- Article first published online: 10 DEC 2013
- Accepted manuscript online: 17 SEP 2013 11:10PM EST
- Manuscript Accepted: 7 SEP 2013
- Manuscript Revised: 28 AUG 2013
- Manuscript Received: 25 FEB 2013
- Canadian Institutes of Health Research and Technology Entrepreneurs and Companies (TEC) Edmonton
- Hungarian National Office for Research and Technology, Ányos Jedlik Programs. Grant Number: NKFP_07_01-RYT07_AF
- European Regional Fund. Grant Number: TÁMOP-4.2.2/B-10/1-2010-0012
- Hungarian Academy of Sciences and the Hungarian Scientific Research Fund. Grant Number: OTKA NK-104331
- atrial fibrillation;
- ion channels
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.
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.
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.