Background/Objective:

Recently, the atrial-selectively expressed potassium channel K_2P3.1 alias TASK-1 (TWIK-related acid sensitive potassium channel 1) was identified as a potential antiarrhythmic target in atrial fibrillation. TASK-1 upregulation in chronic AF contributes to action potential duration (APD) shortening and sustenance of arrhythmias. Interestingly, the respiratory stimulant doxapram possesses high potency and specificity for TASK-1 inhibition and has previously demonstrated anti-arrhythmic properties in animal models of AF. However, effectivity in human and multicellular models requires further investigation.

Purpose:

In this study, we tested the anti-arrhythmic properties of doxapram in multicellular isolated human atrial trabeculae.

Methods and Results:

We analyzed atrial appendage biopsies from 25 patients undergoing coronary artery bypass grafting. Premature atrial contractions (PACs) as surrogate for atrial arrhythmias were measured in isolated atrial trabeculae. Regular contractions were elicited by electrical field stimulation at 1 Hz (5 V for 50 ms, 37°C). PAC severity was classified by a severity-score (ARS) from 0 points (no arrhythmias) to 5 points (salve). To facilitate arrhythmias, trabeculae were exposed to isoprenaline (ISO, 100 nM) and increased Ca_o (3.5 mM). Interestingly, the ARS severity was significantly reduced by doxapram (5 µM) from 2.07±0.44 to 0.43±0.21 (p<0.001, n=21, figure 1A). Moreover, the 90% relaxation time (RT₉₀) was significantly prolonged by doxapram from 146.8±5.8 ms in control (CTRL) to 152.4±6.3 ms (p=0.004, figure 1B). Contractility was analyzed in a separate protocol without increased Ca_o+ISO, and importantly, doxapram did not exert any negative inotropic effect (0.78±0.04 CTRL vs. 0.76±0.04 doxapram, normalized developed tension, n=4, p=n.s., figure 1C). Additionally, preliminary analysis in left atrial trabeculae (n=4 patients) also revealed a reduction in arrhythmia severity upon doxapram by non-significant trend (1.25±1.25 CTRL vs. 0±0 doxapram, not shown).

Conclusion:

In isolated human atrial trabeculae, doxapram demonstrated anti-arrhythmic effects without impairing developed force. This study further underlines the potential for use of doxapram as an anti-arrhythmic agent for atrial fibrillation, which may have clinical implications.