Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K                         
                        v
                                                 11.1

Kirstine Calloe; Salomé Rognant; Søren Friis; Catherine Shaughnessy; Dan A. Klaerke; Dagmar Trachsel

doi:10.1016/j.rvsc.2019.01.009

Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K _v 11.1

Kirstine Calloe, Salomé Rognant, Søren Friis, Catherine Shaughnessy, Dan A. Klaerke^*, Dagmar Trachsel

^*Corresponding author for this work

2 Citations (Scopus)

Abstract

Background: The voltage-gated K ⁺ -channel K _v 11.1 has a central role in cardiac repolarization. Blockage of K _v 11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). K _v 11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of K _v 11.1. This suggests that equine K _v 11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. Aim: To screen a series of commonly used drugs in equine medicine for interaction with K _v 11.1. Methods: High-throughput screening of selected compounds on human K _v 11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine K _v 11.1 expressed in CHO-K1 cells by manual patch clamp. Results: Acepromazine maleat (IC ₅₀ = 0.5 μM) trimethoprim (IC ₅₀ = 100 μM), diphenhydramine hydrochloride (IC ₅₀ = 2 μM) and cyproheptadine hydrochloride (IC ₅₀ = 1.84 μM) inhibited equine K _v 11.1 current at clinically relevant drug concentrations. Conclusion: The results suggest that drug interaction with K _v 11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.

Original language	English
Journal	Research in Veterinary Science
Volume	123
Pages (from-to)	239-246
Number of pages	8
ISSN	0034-5288
DOIs	https://doi.org/10.1016/j.rvsc.2019.01.009
Publication status	Published - 2019

Keywords

Acquired long QT syndrome (aLQTS)
Cardiac electrophysiology
Kv11.1
Rapid delayed rectifier current (IKr,)
Safety pharmacology
Sudden cardiac death (SCD)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.rvsc.2019.01.009

Cite this

Calloe, K., Rognant, S., Friis, S., Shaughnessy, C., Klaerke, D. A., & Trachsel, D. (2019). Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K _v 11.1. Research in Veterinary Science, 123, 239-246. https://doi.org/10.1016/j.rvsc.2019.01.009

Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K _v 11.1. / Calloe, Kirstine ; Rognant, Salomé; Friis, Søren et al.
In: Research in Veterinary Science, Vol. 123, 2019, p. 239-246.

Research output: Contribution to journal › Journal article › Research › peer-review

Calloe, K , Rognant, S, Friis, S, Shaughnessy, C, Klaerke, DA & Trachsel, D 2019, 'Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K _v 11.1', Research in Veterinary Science, vol. 123, pp. 239-246. https://doi.org/10.1016/j.rvsc.2019.01.009

@article{785512933a284aa087f1b86b45ec4bea,

title = "Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K v 11.1",

abstract = " Background: The voltage-gated K + -channel K v 11.1 has a central role in cardiac repolarization. Blockage of K v 11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). K v 11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of K v 11.1. This suggests that equine K v 11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. Aim: To screen a series of commonly used drugs in equine medicine for interaction with K v 11.1. Methods: High-throughput screening of selected compounds on human K v 11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine K v 11.1 expressed in CHO-K1 cells by manual patch clamp. Results: Acepromazine maleat (IC 50 = 0.5 μM) trimethoprim (IC 50 = 100 μM), diphenhydramine hydrochloride (IC 50 = 2 μM) and cyproheptadine hydrochloride (IC 50 = 1.84 μM) inhibited equine K v 11.1 current at clinically relevant drug concentrations. Conclusion: The results suggest that drug interaction with K v 11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses. ",

keywords = "Acquired long QT syndrome (aLQTS), Cardiac electrophysiology, Kv11.1, Rapid delayed rectifier current (IKr,), Safety pharmacology, Sudden cardiac death (SCD)",

author = "Kirstine Calloe and Salom{\'e} Rognant and S{\o}ren Friis and Catherine Shaughnessy and Klaerke, {Dan A.} and Dagmar Trachsel",

year = "2019",

doi = "10.1016/j.rvsc.2019.01.009",

language = "English",

volume = "123",

pages = "239--246",

journal = "Research in Veterinary Science",

issn = "0034-5288",

publisher = "Elsevier",

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TY - JOUR

T1 - Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel K v 11.1

AU - Calloe, Kirstine

AU - Rognant, Salomé

AU - Friis, Søren

AU - Shaughnessy, Catherine

AU - Klaerke, Dan A.

AU - Trachsel, Dagmar

PY - 2019

Y1 - 2019

N2 - Background: The voltage-gated K + -channel K v 11.1 has a central role in cardiac repolarization. Blockage of K v 11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). K v 11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of K v 11.1. This suggests that equine K v 11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. Aim: To screen a series of commonly used drugs in equine medicine for interaction with K v 11.1. Methods: High-throughput screening of selected compounds on human K v 11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine K v 11.1 expressed in CHO-K1 cells by manual patch clamp. Results: Acepromazine maleat (IC 50 = 0.5 μM) trimethoprim (IC 50 = 100 μM), diphenhydramine hydrochloride (IC 50 = 2 μM) and cyproheptadine hydrochloride (IC 50 = 1.84 μM) inhibited equine K v 11.1 current at clinically relevant drug concentrations. Conclusion: The results suggest that drug interaction with K v 11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.

AB - Background: The voltage-gated K + -channel K v 11.1 has a central role in cardiac repolarization. Blockage of K v 11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). K v 11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of K v 11.1. This suggests that equine K v 11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. Aim: To screen a series of commonly used drugs in equine medicine for interaction with K v 11.1. Methods: High-throughput screening of selected compounds on human K v 11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine K v 11.1 expressed in CHO-K1 cells by manual patch clamp. Results: Acepromazine maleat (IC 50 = 0.5 μM) trimethoprim (IC 50 = 100 μM), diphenhydramine hydrochloride (IC 50 = 2 μM) and cyproheptadine hydrochloride (IC 50 = 1.84 μM) inhibited equine K v 11.1 current at clinically relevant drug concentrations. Conclusion: The results suggest that drug interaction with K v 11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.

KW - Acquired long QT syndrome (aLQTS)

KW - Cardiac electrophysiology

KW - Kv11.1

KW - Rapid delayed rectifier current (IKr,)

KW - Safety pharmacology

KW - Sudden cardiac death (SCD)

U2 - 10.1016/j.rvsc.2019.01.009

DO - 10.1016/j.rvsc.2019.01.009

M3 - Journal article

C2 - 30685649

AN - SCOPUS:85060341618

SN - 0034-5288

VL - 123

SP - 239

EP - 246

JO - Research in Veterinary Science

JF - Research in Veterinary Science

ER -