title: Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters.
abstract: Our in vitro characterization showed that physiological concentrations of estrogen partially suppressed the I(Kr) channel current in guinea pig ventricular myocytes and the human ether-a-go-go-related gene (hERG) channel currents in CHO-K1 cells regardless of estrogen receptor signaling and revealed that the partially suppressed hERG currents enhanced the sensitivity to the hERG blocker E-4031. To obtain in vivo proof-of-concept data to support the effects of estrogen on cardiac electrophysiology, we here employed an aromatase knockout mouse as an in vivo estrogen-null model and compared the acute effects of E-4031 on cardiac electrophysiological parameters with those in wild-type mice (C57/BL6J) by recording surface electrocardiogram (ECG). The ablation of circulating estrogens blunted the effects of E-4031 on heart rate and QT interval in mice under a denervation condition. Our result provides in vivo proof of principle and demonstrates that endogenous estrogens increase the sensitivity of E-4031 to cardiac electrophysiology.
authors.affiliation: Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical Dental University.
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sasano
authors.forename: Masami
authors.initials: M
authors.lastname: Kodama
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ebana
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Harada
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Honda
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000502:physiology; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D004967:Estrogens / Q000502:physiology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology
chemical_list: D000072237:ERG1 Potassium Channel; D004967:Estrogens; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D001141:Aromatase