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 β-estradiol on transient outward and ultra-rapid delayed rectifier potassium currents (I_to1 and I_Kur) in human atrial myocytes with a whole cell patch-clamp technique. I_to1 was inhibited by raloxifene in a concentration-dependent manner with an IC₅₀ of 0.9 μM. Raloxifene at 1 μM decreased I_to1 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 I_to1 were significantly accelerated, while steady-state voltage dependent activation and inactivation of I_to1 were not affected by raloxifene. In addition, raloxifene remarkably suppressed I_Kur (IC₅₀ = 0.7 μM). Raloxifene at 1 μM decreased I_Kur by 57.3 ± 3.3% (at + 50 mV, n = 10, P < 0.01 vs control). However, β-estradiol inhibited I_to1 (IC₅₀ = 10.3 μM) without affecting I_Kur. The inhibitory effects of raloxifene and β-estradiol on I_to1 and/or I_Kur were unaffected by the estrogen receptor antagonist ICI 182,780. Our results indicate that raloxifene directly inhibits the human atrial repolarization potassium currents I_to1 and I_Kur. Whether raloxifene is beneficial for supraventricular arrhythmias remains to be studied. © 2007 Elsevier B.V. All rights reserved.