Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac action potential duration.

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. 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. 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. 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.