AIMS: 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. METHODS AND 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. CONCLUSION: 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.
AIMS: 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. METHODS AND 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. CONCLUSION: 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.