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Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac action potential duration.
Acta Pharmacol Sin. 2011 Sep; 32(9):1128-37.AP

Abstract

AIM

To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects.

METHODS

hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp.

RESULTS

Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD(90)) in both concentration- and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC(50) for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold.

CONCLUSION

The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.

Authors+Show Affiliations

Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University School of Medicine, Chuncheon 200-701, 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

21892192

Citation

Lee, Byung Hoon, et al. "Effects of the Histamine H(1) Receptor Antagonist Hydroxyzine On hERG K(+) Channels and Cardiac Action Potential Duration." Acta Pharmacologica Sinica, vol. 32, no. 9, 2011, pp. 1128-37.
Lee BH, Lee SH, Chu D, et al. Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac action potential duration. Acta Pharmacol Sin. 2011;32(9):1128-37.
Lee, B. H., Lee, S. H., Chu, D., Hyun, J. W., Choe, H., Choi, B. H., & Jo, S. H. (2011). Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac action potential duration. Acta Pharmacologica Sinica, 32(9), 1128-37. https://doi.org/10.1038/aps.2011.66
Lee BH, et al. Effects of the Histamine H(1) Receptor Antagonist Hydroxyzine On hERG K(+) Channels and Cardiac Action Potential Duration. Acta Pharmacol Sin. 2011;32(9):1128-37. PubMed PMID: 21892192.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac action potential duration. AU - Lee,Byung Hoon, AU - Lee,Seung Ho, AU - Chu,Daehyun, AU - Hyun,Jin Won, AU - Choe,Han, AU - Choi,Bok Hee, AU - Jo,Su-Hyun, PY - 2011/9/6/entrez PY - 2011/9/6/pubmed PY - 2012/1/6/medline SP - 1128 EP - 37 JF - Acta pharmacologica Sinica JO - Acta Pharmacol Sin VL - 32 IS - 9 N2 - AIM: To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects. METHODS: hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. RESULTS: Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD(90)) in both concentration- and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC(50) for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold. CONCLUSION: The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine. SN - 1745-7254 UR - https://www.unboundmedicine.com/medline/citation/21892192/Effects_of_the_histamine_H_1__receptor_antagonist_hydroxyzine_on_hERG_K_+__channels_and_cardiac_action_potential_duration_ L2 - https://doi.org/10.1038/aps.2011.66 DB - PRIME DP - Unbound Medicine ER -