Objective: Atrial-selective drug therapy represents a novel therapeutic approach for atrial fibrillation management. The aim of the present study was to investigate the mechanism of hKv1.5 channel inhibition by the atrial-selective compound AVE1231.
Methods: Ionic currents were recorded from CHO cells transfected with KCNA5 cDNA with whole-cell patch-clamp technique. The effect of AVE1231 on human atrial cell action potentials was explored with a computer model.
Results: KCNA5 expression resulted in typical K currents that activated and inactivated voltage dependently. Ascending concentrations of AVE1231 (0.1-100 microM) led to concentration- and voltage-dependent current inhibition (IC50 at +40 mV: 2.0 +/- 0.5 microM, Hill coefficient 0.69 +/- 0.12). Acceleration of hKv1.5 current inactivation occurred with increasing AVE1231 concentrations, indicating channel inhibition in the open state (eg, taufast at +40 mV: 318 +/- 92 milliseconds under control; 14 +/- 1 milliseconds with 3 microM, P < 0.05). Using 1/taufast as an approximation of the time course of drug-channel interaction, association rate (K+1) and dissociation rate (K-1) constants were 8.18 x 10 M/s and 45.95 seconds, respectively (KD = 5.62 microM). The onset of current inhibition occurred more rapidly with higher concentrations along with a prominent tail current crossover phenomenon after AVE1231 application. Drug inhibition remained effective through a range of stimulation frequencies. Computer modeling suggested more pronounced prolongation of action potential duration under conditions of atrial remodeling.
Conclusion: AVE1231 is an inhibitor of hKv1.5 currents with predominant action on channels in their open state; thus, it may be suitable for the treatment of AF.