Clin Res Cardiol 108, Suppl 2, October 2019
Pharmacological profile of doxapram at atrial potassium channels
M. Kraft1, F. Wiedmann1, A. Ratte1, D. Thomas1, W. E. Haefeli2, H. A. Katus1, C. Schmidt1
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinische Pharmakologie u. Pharmaepidemiologie, Universitätsklinikum Heidelberg, Heidelberg;

Background ­­­­

Atrial potassium channels play an important role in arrhythmias. In recent years, several members of this group could be identified as important pharmacological targets. One of them, the TASK-1 (hK2P3.1) two-pore-domain potassium channel, is a strong regulator of atrial action potential duration. Because TASK-1 is upregulated in patients suffering from atrial fibrillation (AF) and exhibits an atrial-specific expression pattern, it represents a promising target for AF therapy. Furthermore, preclinical testing of high affinity TASK-1 inhibitors could successfully restore sinus rhythm in a porcine model of persistent AF. Doxapram is an FDA-approved drug known to inhibit the TASK-1 channel.

Aims

In the present study we aimed to characterize the pharmacological profile of doxapram and its active metabolite at atrial potassium channels.

Methods

Atrial-specific potassium channels were cloned and heterologously expressed in Xenopus laevis oocytes. Ion channel functions were studied by two-electrode voltage clamp measurements before and after application of doxapram and its metabolite.

Results/Conclusion

Doxapram and its metabolite were both potent blockers of atrial TASK channels. The inhibitory effects of doxapram on human TASK-1 were significantly higher when compared with other atrial potassium channels. Doxapram showed a lower half maximal inhibitory concentration (IC50) than its metabolite (0.5 µM vs. 1.25 µM). However, the metabolite caused a higher maximal inhibition (71 % vs. 95 %). Collectively, both compounds showed high selectivity for the TASK-1 channel and had almost no effect on Kv1.4, Kv1.5, Kv2.1, Kv4.3, and Kir3.1/3.4. Finally, experimental results were validated using in-silico modeling and pharmacodynamic simulations. In conclusion, doxapram and its metabolite were identified as efficient and highly selective inhibitors of TASK-1. Due to the atrial-specific expression of TASK-1, no side effects on ventricular potassium channels are expected. Our results point towards a potential role of doxapram and its metabolite in the pharmacotherapy of AF.
https://www.abstractserver.com/dgk2019/ht/abstracts//BS279.htm