Background: In recent years, the two-pore-domain potassium channel TASK-1 (K2P3.1) has been established as a promising target in antiarrhythmic therapy. TASK-1 is significantly upregulated in atrial fibrillation (AF) patients, eminently contributing to the shortening of the atrial action potential, which is typical for AF. Due to its almost atrium-specific expression pattern within the heart, TASK-1 is an ideal target for AF therapy. In a porcine model of persistent AF, application of the TASK-1 inhibitor doxapram led to a successful restoration of sinus rhythm (SR). Ketodoxapram, a main metabolite of doxapram, has long been described in the literature as an active metabolite but without much supporting data. Therefore, the exact effect of ketodoxapram still needs to be investigated.

Aims: The aim of the present study was to compare doxapram and its metabolite ketodoxapram at the electrophysiological and pharmacological levels. Furthermore, a possible use of the pharmacological TASK-1 inhibitor ketodoxapram in the therapy of AF was assessed.

Methods: Ion channels were heterologously expressed in Xenopus leavis oocytes and the two-electrode voltage-clamp technique was used to quantify the influence of ketodoxapram on ion channel function. Whole-cell patch-clamp measurements were performed on isolated human cardiomyocytes. Pharmacokinetics of intravenously administered doxapram and ketodoxapram were determined in pigs using an ultra-performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS) assay. Furthermore, a porcine animal model of AF was utilised to assess the use of ketodoxapram in the restoration of SR.

Results: Ketodoxapram shows similar effects on the studied ion channels as doxapram. However, while both are strong inhibitors of TASK-1 and TASK-3, ketodoxapram is more effective (higher maximal inhibition) and more potent (lower IC50). While doxapram concentrations in the brain and its brain-to-plasma ratio were high, ketodoxapram availability in porcine brain was low, indicating reduced permeability of the blood-brain barrier (BBB) for ketodoxapram. Furthermore, ketodoxapram half-life was longer than that of doxapram. In the porcine AF model, pigs treated with ketodoxapram twice daily had a significantly reduced AF burden.

Conclusion: The stronger inhibitory effect of ketodoxapram in in vitro experiments, together with the reduced crossing of the BBB, and the longer half-life all imply a superiority of ketodoxapram compared to doxapram in the treatment of AF. The data of this large animal model further advocate a possible use of ketodoxapram in AF therapy.