title: Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²⁺ channel.
abstract: Azelastine is a second generation histamine H₁-receptor antagonist used as an anti-asthmatic and anti-allergic drug that can induce QT prolongation and torsades de pointes. We investigated the acute effects of azelastine on human ether-a-go-go-related gene (hERG) channels, action potential duration (APD), and L-type (I(Ca,L)) and T-type Ca²⁺ current (I(Ca,T)) to determine the electrophysiological basis for its proarrhythmic potential. Azelastine increased the APD at 90% of repolarization concentration dependently, with an IC₅₀ of 1.08 nM in guinea-pig ventricular myocytes. We examined the effects of azelastine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Azelastine induced a concentration-dependent decrease of the hERG current amplitude at the end of the voltage steps and tail currents. The IC₅₀ for the azelastine-induced block of the hERG currents expressed in HEK293 cells was 11.43 nM, while the drug inhibited I(Ca,L) and I(Ca,T) with IC₅₀ values of 7.60 and 26.21 μM, respectively. The S6 domain mutations, Y652A partially attenuated and F656A abolished hERG current block. These results suggest that azelastine is a potent blocker of hERG channels rather than I(Ca,L) or I(Ca,T), providing molecular mechanisms for the arrhythmogenic side effects during the clinical administration of azelastine.
authors.affiliation: Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Korea.
authors.forename: Mi-Hyeong
authors.initials: MH
authors.lastname: Park
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Chu
authors.forename: Kwang Hee
authors.initials: KH
authors.lastname: Won
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology; D006634:Histamine H1 Antagonists / Q000009:adverse effects* / Q000494:pharmacology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010793:Phthalazines / Q000009:adverse effects* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014982:Xenopus laevis
chemical_list: D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C000606913:KCNH2 protein, human; D010793:Phthalazines; C020976:azelastine