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 H1 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 IC50 of 3.4 muM. 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 a for 3 muM mizolastine, and 1361+/-306 s for 1 muM 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 ICS,, 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.