Upregulation of ventricular potassium channels by chronic tamoxifen treatment.
OBJECTIVE
Tamoxifen is a selective oestrogen receptor modulator widely used in the prevention and treatment of breast cancer. Women receiving long-term tamoxifen therapy do not experience cardiac arrhythmias although acute perfusion of tamoxifen has been shown to inhibit cardiac K(+) currents. This observation suggests that chronic tamoxifen treatment does not negatively modulate cardiac K(+) currents. Therefore, we investigated the chronic effects of tamoxifen on K(+) currents and channels in mouse and guinea pig ventricles.


RESULTS
Female mice and guinea pigs were treated with placebo or tamoxifen pellets for 60 days. Voltage-clamp experiments showed that the density of the Ca²(+)-independent transient outward (I(to)), the ultrarapid delayed rectifier (I(Kur)), the steady-state (I(ss)), and the inward rectifier (I(K1)) K(+) currents were increased in tamoxifen-treated mice ventricle. Western blot analysis revealed that protein expression of the underlying K(+) channels Kv4.3 (I(to)), Kv1.5 (I(Kur)), Kv2.1 (I(ss)), and Kir2.1 (I(K1)) were significantly higher in the ventricle of tamoxifen-treated mice. Protein expression of the K(+) channel subunits encoding I(Kr) and I(Ks) (ERG1, KCNQ1, and KCNE1) was also increased in tamoxifen-treated guinea pig ventricle.


CONCLUSIONS
Conditions with high oestrogen levels are associated with reduced K(+) currents. Thus, conceivably, tamoxifen might prevent the inhibitory effects of oestrogen on K(+) channels by blocking the oestrogen receptors, which would explain the reported increase in K(+) currents. These findings could contribute to explain the absence of cardiac arrhythmia with long-term tamoxifen therapy.
Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T 1C8.
Gracia
G
El Gebeily
Céline
C
Fiset
D000200:Action Potentials; D000818:Animals; D015153:Blotting, Western; D004343:Drug Implants; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D013629:Tamoxifen / Q000008:administration & dosage*; D015854:Up-Regulation
D004343:Drug Implants; D015221:Potassium Channels; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D011188:Potassium