Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel Kv11.1.
Abstract: The voltage-gated K-channel K11.1 has a central role in cardiac repolarization. Blockage of K11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). K11.1 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 K11.1. This suggests that equine K11.1 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. Objective: To screen a series of commonly used drugs in equine medicine for interaction with K11.1. Methods: High-throughput screening of selected compounds on human K11.1 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 K11.1 expressed in CHO-K1 cells by manual patch clamp. Results: Acepromazine maleat (IC = 0.5 μM) trimethoprim (IC = 100 μM), diphenhydramine hydrochloride (IC = 2 μM) and cyproheptadine hydrochloride (IC = 1.84 μM) inhibited equine K11.1 current at clinically relevant drug concentrations. Conclusions: The results suggest that drug interaction with K11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.
Copyright © 2019. Published by Elsevier Ltd.
Publication Date: 2019-01-08 PubMed ID: 30685649DOI: 10.1016/j.rvsc.2019.01.009Google Scholar: Lookup
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- Journal Article
Summary
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This research focuses on the implications of the use of certain commonly used equine drugs on cardiovascular health, particularly in relation to the function of the K11.1 voltage-gated potassium channel, which is crucial for cardiac repolarization.
Role of Voltage-gated K-channel K11.1 in Cardiac Repolarization
- The K11.1 potassium channel plays a critical role in the process of cardiac repolarization, a period where the heart’s cells repolarize to conduct again.
- Any interference or blockage to K11.1 can have severe implications including acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia, and sudden cardiac death (SCD).
- K11.1 is prone to non-specific drug interactions because of two aromatic amino acids located within the pore’s inner vestibule. These residues are also present in horses’ K11.1, indicating that horses may also experience critical cardiac-related side effects and SCD if exposed to different chemical compounds.
Objective of the Research
- This study aimed to analyze the interaction of a series of drugs commonly used in equine medicine with K11.1.
Research Methodology
- The research team carried out a high-throughput screening of select compounds on human K11.1, expressed in a specific mammalian cell line, using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany).
- The results were then validated on equine K11.1, which was expressed in a CHO-K1 cell line via manual patch clamp measures.
Results of the Study
- The study revealed that Acepromazine maleat (IC = 0.5 μM), trimethoprim (IC = 100 μM), diphenhydramine hydrochloride (IC = 2 μM) and cyproheptadine hydrochloride (IC = 1.84 μM) could inhibit the current of the equine K11.1 channel at clinically relevant drug concentrations.
Conclusion
- The findings from this research suggest that drug interaction on the K11.1 channel can occur in horses, and that these drugs may potentially lead to repolarization disorders in horses.
Cite This Article
APA
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 Kv11.1.
Res Vet Sci, 123, 239-246.
https://doi.org/10.1016/j.rvsc.2019.01.009 Publication
Researcher Affiliations
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark; Nanion Technologies GmbH, Munich, Germany.
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark. Electronic address: dk@sund.ku.dk.
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
MeSH Terms
- Animals
- CHO Cells
- Cricetinae
- Cricetulus
- ERG1 Potassium Channel / antagonists & inhibitors
- High-Throughput Screening Assays
- Horses
- Humans
- Pharmaceutical Preparations / classification
Citations
This article has been cited 2 times.- Trachsel DS, Stage HJ, Rausch S, Trappe S, Söllig K, Sponder G, Merle R, Aschenbach JR, Gehlen H. Comparison of Sources and Methods for the Isolation of Equine Adipose Tissue-Derived Stromal/Stem Cells and Preliminary Results on Their Reaction to Incubation with 5-Azacytidine.. Animals (Basel) 2022 Aug 11;12(16).
- Braun N, Friis S, Ihling C, Sinz A, Andersen J, Pless SA. High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology.. PLoS Biol 2021 Sep;19(9):e3001321.
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