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The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes.
J Pharmacol Exp Ther. 1998 Dec; 287(3):877-83.JP

Abstract

Tamoxifen is an antiestrogen drug commonly used to treat breast cancer and has been shown to cause prolongation of the electrocardiographic QT interval in humans. Because QT prolongation could influence cardiac arrhythmias, we sought to determine the electrophysiologic mechanism(s) underlying the tamoxifen action. The whole-cell patch-clamp technique was used to study the effect of tamoxifen on the delayed rectifier (IKr), the inward rectifier (IK1), the transient outward current (Ito), and the inward L-type calcium current (ICa) in rabbit ventricular myocytes. By switching to the current-clamp mode, the effect of tamoxifen on action potential duration (APD) was also studied. Tamoxifen blocked IKr in a time-, concentration- and voltage-dependent fashion. IKr tail currents were completely blocked by 10 micromol/l tamoxifen with no recovery after 15 min of washout. At +50 mV, tamoxifen 1 and 3.3 micromol/l blocked IKr by 39.5 +/- 1.7% (P <.01) and 84.8 +/- 1.3% (P <.01) respectively, while no significant block of IK1 or Ito was observed. Significant block of ICa by tamoxifen was also observed at concentrations greater than 1 micromol/l, with almost complete inhibition at 10 micromol/l. Tamoxifen showed no significant effect on APD at concentrations up to 3.3 micromol/l. We conclude that tamoxifen potently blocks both IKr and ICa at clinically relevant concentrations. The observed QT prolongation by tamoxifen in humans may be a result of its predominant effect on IKr. Inhibition of IKr, in conjunction with other QT-prolonging factors in patients could increase their risk of developing torsades de pointes-type cardiac arrhythmias.

Authors+Show Affiliations

Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9864267

Citation

Liu, X K., et al. "The Antiestrogen Tamoxifen Blocks the Delayed Rectifier Potassium Current, IKr, in Rabbit Ventricular Myocytes." The Journal of Pharmacology and Experimental Therapeutics, vol. 287, no. 3, 1998, pp. 877-83.
Liu XK, Katchman A, Ebert SN, et al. The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes. J Pharmacol Exp Ther. 1998;287(3):877-83.
Liu, X. K., Katchman, A., Ebert, S. N., & Woosley, R. L. (1998). The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes. The Journal of Pharmacology and Experimental Therapeutics, 287(3), 877-83.
Liu XK, et al. The Antiestrogen Tamoxifen Blocks the Delayed Rectifier Potassium Current, IKr, in Rabbit Ventricular Myocytes. J Pharmacol Exp Ther. 1998;287(3):877-83. PubMed PMID: 9864267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes. AU - Liu,X K, AU - Katchman,A, AU - Ebert,S N, AU - Woosley,R L, PY - 1998/12/24/pubmed PY - 1998/12/24/medline PY - 1998/12/24/entrez SP - 877 EP - 83 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 287 IS - 3 N2 - Tamoxifen is an antiestrogen drug commonly used to treat breast cancer and has been shown to cause prolongation of the electrocardiographic QT interval in humans. Because QT prolongation could influence cardiac arrhythmias, we sought to determine the electrophysiologic mechanism(s) underlying the tamoxifen action. The whole-cell patch-clamp technique was used to study the effect of tamoxifen on the delayed rectifier (IKr), the inward rectifier (IK1), the transient outward current (Ito), and the inward L-type calcium current (ICa) in rabbit ventricular myocytes. By switching to the current-clamp mode, the effect of tamoxifen on action potential duration (APD) was also studied. Tamoxifen blocked IKr in a time-, concentration- and voltage-dependent fashion. IKr tail currents were completely blocked by 10 micromol/l tamoxifen with no recovery after 15 min of washout. At +50 mV, tamoxifen 1 and 3.3 micromol/l blocked IKr by 39.5 +/- 1.7% (P <.01) and 84.8 +/- 1.3% (P <.01) respectively, while no significant block of IK1 or Ito was observed. Significant block of ICa by tamoxifen was also observed at concentrations greater than 1 micromol/l, with almost complete inhibition at 10 micromol/l. Tamoxifen showed no significant effect on APD at concentrations up to 3.3 micromol/l. We conclude that tamoxifen potently blocks both IKr and ICa at clinically relevant concentrations. The observed QT prolongation by tamoxifen in humans may be a result of its predominant effect on IKr. Inhibition of IKr, in conjunction with other QT-prolonging factors in patients could increase their risk of developing torsades de pointes-type cardiac arrhythmias. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9864267/The_antiestrogen_tamoxifen_blocks_the_delayed_rectifier_potassium_current_IKr_in_rabbit_ventricular_myocytes_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=9864267 DB - PRIME DP - Unbound Medicine ER -