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.
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