Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines

In the current study, the potential blocking ability of K+ channels encoded by the human ether-a-go-go related gene (HERG) by the piperazine H-1 receptor antagonist cetirizine has been examined and compared with that of other second-generation antihistamines (astemizole, terfenadine, and loratadine). Cetirizine was completely devoid of any inhibitory action on HERG K+ channels heterologously expressed in Xenopus laevis oocytes in concentrations up to 30 mu M On the other hand, terfenadine and astemizole effectively blocked HERG KC channels with nanomolar affinities (the estimated lc,, values were 330 and 480 nM, respectively), whereas loratadine was similar to 300-fold less potent (IC50 approximate to 100 mu M). In addition, in contrast to terfenadine, cetirizine did not show use-dependent blockade. In SH-SY5Y cells, a human neuroblastoma clone that constitutively expresses K+ currents carried by HERG channels (I-HERG), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with 3 mu M cetirizine did not exert any inhibitory action on I-HERG. Astemizole (3 mu M), on the other hand, was highly effective. Terfenadine (3 mu M) caused a marked (approximate to 80%) inhibition of I-HERG in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 mu M) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did not affect I-HERG, whereas the same intracellular concentration of astemizole caused a complete block. The results of the current study suggest that second-generation antihistamines display marked differences in their ability to block HERG K+ channels. Cetirizine in particular, which possesses more polar and smaller substituent groups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use.