RESUMO
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.