https://doi.org/10.1007/s00392-024-02526-y
1University Hospital Heidelberg Cardiology Heidelberg, Deutschland; 2Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland
Background: As a first-generation antihistamine, antazoline is primary used for treatment of nasal congestion and allergic conjunctivitis. However, an implication of this agent as an antiarrhythmic drug has been suggested due to its successful termination of atrial fibrillation in over 70 % of the patients according to recent studies. Upon intravenous antazoline treatment, significant prolongation of the P-wave, the QRS complex and the QT-interval was observed, as well as significant lengthening of the action potential duration and the post-repolarization refractoriness on atrial and ventricular level. The exact mechanism of antazoline’s antiarrhythmic properties remains, unknown - yet effects on multiple cardiac ion channels are anticipated.
Aims: This study aimed to assess antazoline’s interaction profile with several cardiac potassium channels.
Methods: The addressed ion channels were heterologously expressed in Xenopus laevis oocytes and electrophysiological measurements were performed using the two-electrode voltage clamp technique.
Results: Critical representatives of the K2P-family (hTASK-1, -2 and -3, hTREK-1 and -2, hTWIK-1 and -2, hTRAAK, hTHIK-1, hTALK-1 and -2, hTRESK), important KV-channels (hERG, hKV1.4, hKV1.5, hKV2.1, hKV4.3), as well as hKir2.1 and hNaV1.5 were screened for their sensitivity to 100 µM antazoline. Among them, significant inhibition was revealed for hTREK-1 (23.8 ±5.3 %; n = 9; p = 0.031), hTRESK (35.8 ± 3.4 %; n = 6; p = 0.0024), hERG (53.0 ± 8.5 %; n = 8; p = 0.0079) and the late hNaV1.5 current component (19. 6 ± 3.6 %; n = 6; p = 0.035). Due to the strong inhibition of hERG channels by antazoline and their prominent expression in the cardiac tissue, we further explored this channel’s modulation, obtaining a half maximal inhibitory concentration (IC50) of 167 µM (n = 4–10). Assessment of the molecular determinants of the drug channel interaction via mutated aromatic residues of hERG’s pore region (Y652A and F656A) revealed a significantly attenuated inhibition of the F656A variant (F656A, 100 µM antazoline: 11.24 ± 2.3 %; n = 15; p<0.0001). Furthermore, experiments applying pulse protocols with 0.1 Hz or 1 Hz stimulation indicated significant frequency dependence of hERG channel inhibition (0.1 Hz, 100 µM antazoline: 31.1 ± 3.8 %; n = 7; 1 Hz + 100 µM antazoline: 48.2 ± 3.0 %; n = 5; p = 0.0049).
Conclusion:. The identified significant blockade not only of hERG channels, but also of several other cardiac ion channels thus provides a possible explanation for antazoline’s antiarrhythmic properties, supporting the assumed multi-channel inhibition.