Inhibition of HERG1 K + channels by the novel second-generation antihistamine mizolastine

1. Ventricular arrhythmias are rare but life-threatening side effects of therapy with the second-generation H ₁ receptor antagonists terfenadine and astemizole. Blockade of the K ⁺ channels encoded by the Human Ether-a-go-go-Related Gene 1 (HERG1) K ⁺ channels, which is the molecular basis of the cardiac repolarizing current I(Kr), by prolonging cardiac repolarization, has been recognized as the mechanism underlying the cardiac toxicity of these compounds. 2. In the present study, the potential blocking ability of the novel second-generation H ₁ receptor antagonist mizolastine of the HERG1 K ⁺ channels heterologously expressed in Xenopus oocytes and in HEK 293 cells or constitutively present in SH-SY5Y human neuroblastoma cells has been examined and compared to that of astemizole. 3. Mizolastine blocked HERG1 K ⁺ channels expressed in Xenopus oocytes with an estimated IC ₅₀ of 3.4 μM. Mizolastine blockade was characterized by a fast dissociation rate when compared to that of astemizole; when fitted to a monoexponential function, the time constants for drug dissociation from the K ⁺ channel were 72.4 ± 11.9 s for 3 μM mizolastine, and 1361 ± 306 s for 1 μM astemizole. 4. In human embryonic kidney 293 cells (HEK 293 cells) stably transfected with HERG1 cDNA, extracellular application of mizolastine exerted a dose-related inhibitory action on I(HERG1), with an IC ₅₀ of 350 ± 76 nM. Furthermore, mizolastine dose-dependently inhibited HERG1 K ⁺ channels constitutively expressed in SH-SY5Y human neuroblastoma clonal cells. 5. The results of the present study suggest that the novel second-generation H ₁ receptor antagonist mizolastine, in concentrations higher than those achieved in vivo during standard therapy, is able to block in some degree both constitutively and heterologously expressed HERG1 K ⁺ channels, and confirm the heterogeneity of molecules belonging to this therapeutical class with respect to their HERG1-inhibitory action.