Effects of the histamine H ₁ receptor antagonist hydroxyzine on h ERG K ⁺ channels and cardiac action potential duration

Aim:To investigate the effects of hydroxyzine on human ether-a-go-go- related gene (h ERG) channels to determine the electrolphysiological basis for its proarrhythmic effects.Methods:h ERG 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 mol/L) significantly increased the action potential duration at 90% repolarization (APD 90) in both concentration- and time-dependent manners. Hydroxyzine (0.03-3 mol/L) blocked both the steady-state and tail h ERG currents. The block was voltage-dependent, and the values of IC 50 for blocking the steady-state and tail currents at +20 m V was 0.180.02 mol/L and 0.160.01 mol/L, respectively, in HEK293 cells. Hydroxyzine (5 mol/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 h ERG current by 6-fold.Conclusion:The results suggest that hydroxyzine could block h ERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.