title: Raloxifene inhibits transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes.
abstract: The selective estrogen receptor modulator raloxifene is widely used in the treatment of postmenopausal osteoporosis, and has cardioprotective properties. However, effects of raloxifene on cardiac ion channels are unclear. The present study was designed to investigate the effects of raloxifene and beta-estradiol on transient outward and ultra-rapid delayed rectifier potassium currents (Ito1 and IKur) in human atrial myocytes with a whole cell patch-clamp technique. Ito1 was inhibited by raloxifene in a concentration-dependent manner with an IC50 of 0.9 microM. Raloxifene at 1 microM decreased Ito1 by 40.2+/-1.9% (at +50 mV, n=14, P<0.01 vs control). Time-dependent recovery from inactivation was slowed, and time to peak and time-dependent inactivation of Ito1 were significantly accelerated, while steady-state voltage dependent activation and inactivation of Ito1 were not affected by raloxifene. In addition, raloxifene remarkably suppressed IKur (IC50=0.7 microM). Raloxifene at 1 microM decreased IKur by 57.3+/-3.3% (at +50 mV, n=10, P<0.01 vs control). However, beta-estradiol inhibited Ito1 (IC50=10.3 microM) without affecting IKur. The inhibitory effects of raloxifene and beta-estradiol on Ito1 and/or IKur were unaffected by the estrogen receptor antagonist ICI 182,780. Our results indicate that raloxifene directly inhibits the human atrial repolarization potassium currents Ito1 and IKur. Whether raloxifene is beneficial for supraventricular arrhythmias remains to be studied.
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Man-Wen
authors.initials: MW
authors.lastname: Jin
authors.forename: Ji-Zhou
authors.initials: JZ
authors.lastname: Xiang
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Sun
authors.forename: Shui-Wha
authors.initials: SW
authors.lastname: Chiu
authors.forename: Chu-Pak
authors.initials: CP
authors.lastname: Lau
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D051668:Delayed Rectifier Potassium Channels; D004965:Estrogen Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D020845:Selective Estrogen Receptor Modulators; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D011188:Potassium