Background: Etripamil, a short-acting phenylalkylamine L-type calcium channel blocker, has been developed for intranasal application and is currently undergoing phase-III testing for the self-managed cardioversion of paroxysmal supraventricular tachycardia (PSVT). Further, the drug is being tested for rate control in atrial fibrillation and is also being considered for other indications, such as angina pectoris. In contrast, there are only few data on the full pharmacological profile of etripamil, particularly with respect to its affinity for other cardiac ion channels beyond L-type calcium channels. The structural similarity to the long-acting phenylalkylamine verapamil, with a broad range of known ion channel targets, suggests that etripamil may also act as a multichannel inhibitor. Precise knowledge of etripamil's ion channel inhibition profile is essential if it is about to play a future role in patient-specific pharmacotherapy of atrial arrhythmopathy.

Purpose/Goal: To characterize the effects of etripamil on the human atrial action potential and to determine its molecular interactions with the individual ion channel components.

Methods: Two-electrode voltage clamp (TEVC) measurements were used to study the effects of etripamil on cardiac ion channels, heterologously expressed in Xenopus laevis oocytes. The patch-clamp technique was applied to determine the effects of etripamil on action potential (AP) formation in human atrial cardiomyocytes isolated from the right atrial tissue samples derived from of patients undergoing cardiac surgery.

Results: A comprehensive screening in Xenopus laevis oocytes showed that etripamil (100 µM) inhibited the atrial expressed ion channels K_V1.5 (74% current inhibition), TASK-1 (67%) and TASK-3 (73%), hERG (82%), the heteromeric channels K_ir3. 1/K_ir3.4 (59%) and KCNQ1/KCNE1 (71%), and the Na_V1.5 channel (59%) more strongly than the Ca_V1.2 channel (55%), which was previously considered  its primary target. For comparison, verapamil (100 µM) was also applied in the same set-up, which yielded 48% inhibition of Ca_V1.2 channels. While K_ir2.1 (-3%) and K_V1.4 (-2%) channels showed no significant current inhibition at the screening concentration of 100 µM, K_V2.1 (48%), K_V4.3 (38%), TREK‑1 (26%) and MaxiK (34%) channels displayed lower inhibition than Ca_V1.2. Given the importance of TASK-1 in the pathophysiology of atrial arrhythmopathy, this channel was subjected to an in-depth analysis. Etripamil inhibited TASK-1 with an IC₅₀ of 18.8 µM in our TEVC set-up. Similar IC₅₀-values were obtained for the equine and porcine orthologues of the channel. In patch-clamp experiments, performed on isolated human atrial cardiomyocytes, administration of etripamil 12.5 µM led to a significant increase in APD₅₀ by 21% and APD₉₀ by 47%. Furthermore, as typical for a calcium channel blocker, a reduction of the upstroke velocity by 10.3% could be described.