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Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²⁺ channel.
J Pharmacol Sci. 2013 Sep 20; 123(1):67-77.JP

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+Show Affiliations

Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24005046

Citation

Park, Mi-Hyeong, et al. "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, vol. 123, no. 1, 2013, pp. 67-77.
Park MH, Lee SH, Chu DH, et al. Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²⁺ channel. J Pharmacol Sci. 2013;123(1):67-77.
Park, M. H., Lee, S. H., Chu, D. H., Won, K. H., Choi, B. H., Choe, H., & Jo, S. H. (2013). 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, 123(1), 67-77.
Park MH, et al. Effect of Azelastine On Cardiac Repolarization of Guinea-pig Cardiomyocytes, hERG K⁺ Channel, and Human L-type and T-type Ca²⁺ Channel. J Pharmacol Sci. 2013 Sep 20;123(1):67-77. PubMed PMID: 24005046.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of azelastine on cardiac repolarization of guinea-pig cardiomyocytes, hERG K⁺ channel, and human L-type and T-type Ca²⁺ channel. AU - Park,Mi-Hyeong, AU - Lee,Seung Ho, AU - Chu,Dae Hyun, AU - Won,Kwang Hee, AU - Choi,Bok Hee, AU - Choe,Han, AU - Jo,Su-Hyun, Y1 - 2013/09/03/ PY - 2013/9/6/entrez PY - 2013/9/6/pubmed PY - 2014/4/3/medline SP - 67 EP - 77 JF - Journal of pharmacological sciences JO - J Pharmacol Sci VL - 123 IS - 1 N2 - 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. SN - 1347-8648 UR - https://www.unboundmedicine.com/medline/citation/24005046/Effect_of_azelastine_on_cardiac_repolarization_of_guinea_pig_cardiomyocytes_hERG_K⁺_channel_and_human_L_type_and_T_type_Ca²⁺_channel_ L2 - https://linkinghub.elsevier.com/retrieve/pii/DN/JST.JSTAGE/jphs/12239FP DB - PRIME DP - Unbound Medicine ER -