Artikel ; Online: Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²⁺ channel.
Journal of pharmacological sciences
2013 Band 123, Heft 1, Seite(n) 67–77
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 ... ...
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. |
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Mesh-Begriff(e) | Action Potentials/drug effects ; Animals ; Arrhythmias, Cardiac/chemically induced ; Calcium Channels, L-Type/metabolism ; Calcium Channels, T-Type/metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; ERG1 Potassium Channel ; Electrophysiological Phenomena/drug effects ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/chemistry ; Ether-A-Go-Go Potassium Channels/metabolism ; Guinea Pigs ; HEK293 Cells ; Heart Ventricles/cytology ; Histamine H1 Antagonists/adverse effects ; Histamine H1 Antagonists/pharmacology ; Humans ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/physiology ; Oocytes ; Patch-Clamp Techniques ; Phthalazines/adverse effects ; Phthalazines/pharmacology ; Protein Structure, Tertiary ; Xenopus laevis |
Chemische Substanzen | Calcium Channels, L-Type ; Calcium Channels, T-Type ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; Histamine H1 Antagonists ; KCNH2 protein, human ; Phthalazines ; azelastine (ZQI909440X) |
Sprache | Englisch |
Erscheinungsdatum | 2013-09-03 |
Erscheinungsland | Japan |
Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2104264-0 |
ISSN | 1347-8648 ; 1347-8613 |
ISSN (online) | 1347-8648 |
ISSN | 1347-8613 |
DOI | 10.1254/jphs.12239fp |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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