4-Hydroxytamoxifen inhibits K(+) currents in mouse ventricular myocytes.
Tamoxifen is a widely used chemotherapeutic agent, which has been associated with prolongation of the QT interval. Other studies have reported that acute exposure to tamoxifen can reduce cardiac K(+) currents. However, in vivo tamoxifen is largely metabolized and most of its activity is attributable to its major metabolite, 4-hydroxytamoxifen (4OH-tamoxifen). Accordingly, in the present study, we performed voltage-clamp experiments to directly investigate the effects of 4OH-tamoxifen on the repolarizing K(+) currents in adult mouse ventricular myocytes in order to determine whether the effects of tamoxifen on repolarization could be ascribed to 4OH-tamoxifen. K(+) currents were recorded before and after acute exposure to 4OH-tamoxifen (0.5, 1 and 10microM). 4OH-tamoxifen reduced the density of the Ca(2+)-independent transient outward (I(to)), the ultrarapid delayed rectifier (I(Kur)) and the inward rectifier (I(K1)) K(+) currents (by up to 43%, 41% and 26%, respectively) but had no significant effect on the steady-state outward K(+) current (I(ss)). Voltage dependence of steady-state inactivation and reactivation time of I(to) and I(Kur) were not affected by 4OH-tamoxifen. Experiments using the pure estrogen receptor antagonist, ICI 182,780 and the inhibitor of gene transcription, actinomycin D, were undertaken to assess the involvement of estrogen receptor. Administered alone these compounds did not affect the density of K(+) currents. Moreover, pretreatment of the cells with ICI 182,780 or actinomycin D did not prevent the inhibitory response to 4OH-tamoxifen. Overall, 4OH-tamoxifen reduced K(+) currents in mouse ventricle and this effect is unrelated to gene transcription and does not involve interaction of the drug with estrogen receptor.
El Gebeily
Gracia
G
Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec, Canada H1T 1C8.
Fiset
Céline
C
D000818:Animals; D003609:Dactinomycin / Q000494:pharmacology; D004553:Electric Conductivity; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006352:Heart Ventricles / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D003609:Dactinomycin; D000077267:Fulvestrant; D004958:Estradiol; D011188:Potassium