Characterization of hERG K+ channel inhibition by the new class III antiarrhythmic drug cavutilide

Cavutilide (niferidil, refralon) is a new class III antiarrhythmic drug which effectively terminates persistent atrial fibrillation (AF; 84.6% of patients, mean AF duration 3 months) and demonstrates low risk of torsade de pointes (1.7%). ERG channels of rapid delayed rectifier current(I-Kr) are the primary target of cavutilide, but the particular reasons of higher effectiveness and lower proarrhythmic risk in comparison with other class III I-Kr blockers are unclear. The inhibition of hERG channels expressed in CHO-K1 cells by cavutilide was studied using whole-cell patch-clamp. The present study demonstrates high sensitivity of I-hERG expressed in CHO-K1 cells to cavutilide (IC50 = 12.8 nM). Similarly to methanesulfonanilide class III agents, but unlike amiodarone and related drugs, cavutilide does not bind to hERG channels in their resting state. However, in contrast to dofetilide, cavutilide binds not only to opened, but also to inactivated channels. Moreover, at positive constantly set membrane potential (+ 60 mV) inhibition of I-hERG by 100 nM cavutilide develops faster than at 0 mV and, especially, - 30 mV (tau of inhibition was 78.8, 103, and 153 ms, respectively). Thereby, cavutilide produces I-hERG inhibition only when the cell is depolarized. During the same period of time, cavutilide produces greater block of I-hERG when the cell is depolarized with 2 Hz frequency, if compared to 0.2 Hz. We suggest that, during the limited time after injection, cavutilide produces stronger inhibition of I-Kr in fibrillating atrium than in non-fibrillating ventricle. This leads to beneficial combination of antiarrhythmic effectiveness and low proarrhythmicity of cavutilide.