Raloxifene inhibits transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes.
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.
Liu
Hui
H
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Jin
Man-Wen
MW
Xiang
Ji-Zhou
JZ
Huang
Yu
Y
Sun
Hai-Ying
HY
Chiu
Shui-Wha
SW
Lau
Chu-Pak
CP
Li
Gui-Rong
GR
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
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