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

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Abstract

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 μM) had no effect on the MAP duration, but the drug caused a significant prolongation of the ERP from 145 ± 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 μM, 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 μM 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 μM (maximal block by 10 μM dronedarone, 80 ± 6%), whereas at V hold = −80 mV, 10 μM 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 μM. Human HCN4 channels expressed in CHO cells were blocked by dronedarone with an IC50 of 1.0 ± 0.1 μM. 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.

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Acknowledgements

We acknowledge the skillful assistance of Ms. Karin Kopp and Mr. Roland Klein in performing the experiments.

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All authors are employees of Sanofi-Aventis Germany GmbH.

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Correspondence to Heinz Goegelein.

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Bogdan, R., Goegelein, H. & Ruetten, H. Effect of dronedarone on Na+, Ca2+ and HCN channels. Naunyn-Schmied Arch Pharmacol 383, 347–356 (2011). https://doi.org/10.1007/s00210-011-0599-9

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