Effect of dronedarone on Na+, Ca2+ and HCN channels

Previous studies showed that amiodarone causes state-dependent inhibition of Na+ channels thereby mediating an atrial-selective drug effect. The aim of the present study was to investigate the impact of the new antiarrhythmic compound dronedarone on Na+, Ca2+ and hyperpolarization-activated cyclic nucleotide-gated ion channels. Monophasic action potentials (MAP) and effective refractory period (ERP) were studied in arterially perfused left atria and ventricular wedge preparations of the pig. Fast Na+ and Ca2+ currents in isolated guinea pig ventricular myocytes as well as human HCN4 channels expressed in Chinese hamster ovary (CHO) cells were investigated with the patch-clamp technique. In left atrial epicardial tissue, dronedarone (3 mu M) had no effect on the MAP duration, but the drug caused a significant prolongation of the ERP from 1.45+/-9 to 184+/-17 ms (n=6; p<0.05). In guinea pig ventricular myocytes, dronedarone exhibited a state-dependent inhibition of the fast Na+ channel current with an IC50 of 0.7+/-0.1 mu M, when the holding potential (V-hold) was -80 mV. The maximal block at the highest concentration used was 77+/-8%. In contrast, when V-hold was -100 mV, inhibition with 10 mu M dronedarone was only 9=3% (n=7). Dronedarone blocked Ca2+ currents elicited by rectangular pulses at V-hold=-40 mV with an IC50 value of 0.4+/-0.1 mu M (maximal block by 10 mu M dronedarone, 80+/-6%), whereas at V-hold=-80 mV, 10 mu M dronedarone blocked only 20+/-6% (n=4) of the current. Applying an action potential clamp (V-hold=-80 mV) yielded an IC50 of 0.4+/-0.3 mu M. Human HCN4 channels expressed in CHO cells were blocked by dronedarone with an IC50 of 1.0+/-0.1 mu M. Inhibition of fast Na+ and Ca2+ channels by dronedarone depends on the cell's resting membrane potential (state-dependent block) favouring an atrial-selective mode of action. Besides fast Na+ and Ca2+ channels, dronedarone also inhibits HCN4 currents. This might contribute to the clinically observed reduction in heart rate seen in patients in sinus rhythm after dronedarone treatment.