Molecular Basis for the Lack of HERG K+ Channel Block-Related Cardiotoxicity by the H1 Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines

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Vol. 54, Issue 1, 113-121, July 1998

Molecular Basis for the Lack of HERG K⁺ Channel Block-Related Cardiotoxicity by the H₁ Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines

Maurizio Taglialatela, Anna Pannaccione, Pasqualina Castaldo, Giovanna Giorgio, Zhengfeng Zhou, Craig T. January, Arturo Genovese, Gianni Marone, and Lucio Annunziato

Section of Pharmacology, Department of Neuroscience (M.T., A.P., P.C., G.G., L.A.), and Section of Clinical Immunology, Department of Internal Medicine (A.G., G.M.), School of Medicine, University of Naples Federico II, 80131 Naples, Italy, and Section of Cardiology (Z.Z., C.T.J.), University of Wisconsin, Madison, Wisconsin 53792-3240

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 H₁ receptor antagonist cetirizine has been examinedand compared with that of other second-generation antihistamines(astemizole, terfenadine, and loratadine). Cetirizine was completelydevoid of any inhibitory action on HERG K⁺ channels heterologously expressed in Xenopus laevis oocytes inconcentrations up to 30 µM. On the other hand, terfenadine andastemizole effectively blocked HERG K⁺ channels with nanomolar affinities (the estimated IC₅₀ valueswere 330 and 480 nM, respectively), whereas loratadine was ~300-foldless potent (IC₅₀ $approx$ 100 µM). 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 humanembryonic kidney 293 cells stably transfected with HERG cDNA,extracellular perfusion with 3 µM cetirizine did not exert anyinhibitory action on I_HERG. Astemizole (3 µM), on the other hand,was highly effective. Terfenadine (3 µM) caused a marked ( $approx$ 80%)inhibition of I_HERG in SH-SY5Y cells, whereas loratadine, at thesame concentration, caused a 40% blockade. Furthermore, the applicationof cetirizine (3 µM) on the intracellular side of the membraneof HERG-transfected human embryonic kidney 293 cells did not affectI_HERG, whereas the same intracellular concentration of astemizolecaused a complete block. The results of the current study suggestthat second-generation antihistamines display marked differencesin their ability to block HERG K⁺ channels. Cetirizine in particular, which possesses more polarand smaller substituent groups attached to the tertiary aminecompared with other antihistamines, lacks HERG-blocking properties,possibly explaining the absence of torsade de pointes ventriculararrhythmias associated with its therapeutical use.

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