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

Citation
M. Taglialatela et al., Inhibition of HERG1 K+ channels by the novel second-generation antihistamine mizolastine, BR J PHARM, 131(6), 2000, pp. 1081-1088
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
0007-1188 → ACNP
Volume
131
Issue
6
Year of publication
2000
Pages
1081 - 1088
Database
ISI
SICI code
0007-1188(200011)131:6<1081:IOHKCB>2.0.ZU;2-R
Abstract
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 ounds. 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.