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Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline.
Br J Pharmacol. 2000 Apr; 129(7):1474-80.BJ

Abstract

1. Amitriptyline has been known to induce QT prolongation and torsades de pointes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the rapidly activating delayed rectifier K(+) current (I(Kr)) in rat atrial myocytes. 2. The amplitudes of steady-state currents and tail currents of HERG were decreased by amitriptyline dose-dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by amitriptyline is voltage dependent. IC(50) for amitriptyline block of HERG current was progressively decreased according to depolarization: IC(50) values at -30, -10, +10 and +30 mV were 23.0, 8.71, 5.96 and 4.66 microM, respectively. 3. Block of HERG by amitriptyline was use dependent: exhibiting a much faster block at higher activation frequency. Subsequent decrease in frequency after high activation frequency resulted in a partial relief of HERG blockade. 4. Steady-state block by amitriptyline was obtained while depolarization to +20 mV for 0.5 s was applied at 0.5 Hz: IC(50) was 3.26 microM in 2 mM [K(+)](o). It was increased to 4. 78 microM in 4 mM [K(+)](o), suggesting that the affinity of amitriptyline on HERG was decreased by external K(+). 5. In rat atrial myocytes bathed in 35 degrees C, 5 microM amitriptyline blocked I(Kr) by 55%. However, transient outward K(+) current (I(to)) was not significantly affected. 6. In summary, the data suggest that the block of HERG currents may contribute to arrhythmogenic side effects of amitriptyline.

Authors+Show Affiliations

Department of Life Science, Pohang University of Science and Technology, Pohang 790 - 784, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10742304

Citation

Jo, S H., et al. "Blockade of the HERG Human Cardiac K(+) Channel By the Antidepressant Drug Amitriptyline." British Journal of Pharmacology, vol. 129, no. 7, 2000, pp. 1474-80.
Jo SH, Youm JB, Lee CO, et al. Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol. 2000;129(7):1474-80.
Jo, S. H., Youm, J. B., Lee, C. O., Earm, Y. E., & Ho, W. K. (2000). Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. British Journal of Pharmacology, 129(7), 1474-80.
Jo SH, et al. Blockade of the HERG Human Cardiac K(+) Channel By the Antidepressant Drug Amitriptyline. Br J Pharmacol. 2000;129(7):1474-80. PubMed PMID: 10742304.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. AU - Jo,S H, AU - Youm,J B, AU - Lee,C O, AU - Earm,Y E, AU - Ho,W K, PY - 2000/4/1/pubmed PY - 2000/6/8/medline PY - 2000/4/1/entrez SP - 1474 EP - 80 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 129 IS - 7 N2 - 1. Amitriptyline has been known to induce QT prolongation and torsades de pointes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the rapidly activating delayed rectifier K(+) current (I(Kr)) in rat atrial myocytes. 2. The amplitudes of steady-state currents and tail currents of HERG were decreased by amitriptyline dose-dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by amitriptyline is voltage dependent. IC(50) for amitriptyline block of HERG current was progressively decreased according to depolarization: IC(50) values at -30, -10, +10 and +30 mV were 23.0, 8.71, 5.96 and 4.66 microM, respectively. 3. Block of HERG by amitriptyline was use dependent: exhibiting a much faster block at higher activation frequency. Subsequent decrease in frequency after high activation frequency resulted in a partial relief of HERG blockade. 4. Steady-state block by amitriptyline was obtained while depolarization to +20 mV for 0.5 s was applied at 0.5 Hz: IC(50) was 3.26 microM in 2 mM [K(+)](o). It was increased to 4. 78 microM in 4 mM [K(+)](o), suggesting that the affinity of amitriptyline on HERG was decreased by external K(+). 5. In rat atrial myocytes bathed in 35 degrees C, 5 microM amitriptyline blocked I(Kr) by 55%. However, transient outward K(+) current (I(to)) was not significantly affected. 6. In summary, the data suggest that the block of HERG currents may contribute to arrhythmogenic side effects of amitriptyline. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/10742304/Blockade_of_the_HERG_human_cardiac_K_+__channel_by_the_antidepressant_drug_amitriptyline_ L2 - https://doi.org/10.1038/sj.bjp.0703222 DB - PRIME DP - Unbound Medicine ER -