1 Ventricular arrhythmias are rare but life-threatening side effects of the
rapy with the second-generation H-1 receptor antagonists terfenadine and as
temizole. Blockade of the K+ channels encoded by the Human Ether-a-go-go-Re
lated Gene 1 (HERG1) K+ channels, which is the molecular basis of the cardi
ac repolarizing current I-Kr, by prolonging cardiac repolarization, has bee
n recognized as the mechanism underlying the cardiac toxicity of these comp
2 In the present study, the potential blocking ability of the novel second-
generation H1 receptor antagonist mizolastine of the HERG1 K+ channels hete
rologously expressed in Xenopus oocytes and in HEK 293 cells or constitutiv
ely present in SH-SY5Y human neuroblastoma cells has been examined and comp
ared to that of astemizole.
3 Mizolastine blocked HERG1 K+ channels expressed in Xenopus oocytes with a
n estimated IC50 of 3.4 muM. Mizolastine blockade was characterized by a fa
st 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 wi
th HERG1 cDNA, extracellular application of mizolastine exerted a dose-rela
ted inhibitory action on I-HERG1, with an ICS,, of 350+/-76 nM. Furthermore
, mizolastine dose-dependently inhibited HERG1 K+ channels constitutively e
xpressed 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 a
chieved in vivo during standard therapy, is able to block in some degree bo
th constitutively and heterologously expressed HERG1 K+ channels, and confi
rm the heterogeneity of molecules belonging to this therapeutical class wit
h respect to their HERG1-inhibitory action.