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 (APD90) 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 IC50 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.
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Acknowledgements
This study was supported by a grant (08172KFDA465) from the Korea Food & Drug Administration and a grant (A100096) of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea.
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Lee, B., Lee, S., Chu, D. et al. Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration. Acta Pharmacol Sin 32, 1128–1137 (2011). https://doi.org/10.1038/aps.2011.66
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DOI: https://doi.org/10.1038/aps.2011.66
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