Effects of trimethoprim-sulfadiazine and detomidine on the function of equine Kv 11.1 channels in a two-electrode voltage-clamp (TEVC) oocyte model.
Abstract: The long QT syndrome (LQTS) is a channelopathy that can lead to severe arrhythmia and sudden cardiac death. Pharmacologically induced LQTS is caused by interaction between drugs and potassium channels, especially the K 11.1 channel. Due to such interactions, numerous drugs have been withdrawn from the market or are administered with precautions in human medicine. However, some compounds, such as trimethoprim-sulfonamide combinations are still widely used in veterinarian medicine. Therefore, we investigate the effect of trimethoprim-sulfadiazine (TMS), trimethoprim, sulfadiazine, and detomidine on equine-specific K 11.1 channels. K 11.1 channels cloned from equine hearts were heterologously expressed in Xenopus laevis oocytes, and whole cell currents were measured by two-electrode voltage-clamp before and after drug application. TMS blocked equine K 11.1 current with an IC of 3.74 mm (95% CI: 2.95-4.73 mm) and affected the kinetics of activation and inactivation. Similar was found for trimethoprim but not for sulfadiazine, suggesting the effect is due to trimethoprim. Detomidine did not affect equine K 11.1 current. Thus, equine K 11.1 channels are also susceptible to pharmacological block, indicating that some drugs may have the potential to affect repolarization in horse. However, in vivo studies are needed to assess the potential risk of these drugs to induce equine LQTS.
© 2018 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.
Publication Date: 2018-03-22 PubMed ID: 29566261DOI: 10.1111/jvp.12502Google Scholar: Lookup
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Summary
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The research article investigates how certain veterinary drugs including trimethoprim-sulfadiazine and detomidine interact with the K 11.1 potassium channels of horses, influencing their heart function, and potentially leading to Long QT Syndrome (LQTS), a severe heart condition.
Overview of Long QT Syndrome (LQTS)
- LQTS is a heart condition that can cause severe arrhythmia and sudden cardiac death. It is a channelopathy, meaning it is linked to issues with the ion channels that assist electric activity in the heart.
- LQTS can be induced pharmacologically when certain drugs interact with potassium channels, especially the K 11.1 channel.
- In human medicine, drugs that interact with K 11.1 have been withdrawn from the market or require precautions. However, some of these drugs are still widely used in veterinary medicine. Therefore, the research study investigates the effects of these drugs on horses.
The Test on Equine K 11.1 Channels
- The study tests the effects of the compounds trimethoprim-sulfadiazine (TMS), trimethoprim, sulfadiazine, and detomidine on equine-specific K 11.1 channels.
- K 11.1 channels were recreated from horse heart material in the Xenopus laevis oocyte (frog eggs), a scientific model for cellular study.
- The researchers measure the heart electrical currents before and after drug application using a technique known as two-electrode voltage-clamp.
Findings from the Experiment
- The study found that TMS blocked the flow of the K 11.1 current with an IC (half maximal inhibitory concentration) of 3.74 mm, implying it has an impact on the activation and inactivation kinetics of the channels.
- Similar results were found when testing for trimethoprim, but not for sulfadiazine, suggesting trimethoprim is the responsible agent.
- Detomidine appeared to have no effect on the equine K 11.1 current.
- This shows that some drugs can affect the function of the K 11.1 channels in horses, potentially causing LQTS.
- However, the study suggests further in vivo testing is needed to fully understand the actual risk these drugs might pose in real-life applications.
Cite This Article
APA
Trachsel DS, Tejada MA, Groesfjeld Christensen V, Pedersen PJ, Kanters JK, Buhl R, Calloe K, Klaerke DA.
(2018).
Effects of trimethoprim-sulfadiazine and detomidine on the function of equine Kv 11.1 channels in a two-electrode voltage-clamp (TEVC) oocyte model.
J Vet Pharmacol Ther, 41(4), 536-545.
https://doi.org/10.1111/jvp.12502 Publication
Researcher Affiliations
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
- Laboratory of Experimental Cardiology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
- Department of Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
MeSH Terms
- Animals
- Drug Combinations
- ERG1 Potassium Channel / drug effects
- Electrodes
- Electrophysiology
- Horses
- Imidazoles / adverse effects
- Imidazoles / pharmacology
- Oocytes / drug effects
- Oocytes / physiology
- Patch-Clamp Techniques / veterinary
- Sulfadoxine / adverse effects
- Sulfadoxine / pharmacology
- Trimethoprim / adverse effects
- Trimethoprim / pharmacology
- Xenopus laevis
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).
- Liu Z, Zhang X, Wang P, Hong M, Yan X, Qi X, Zhao Q, Chen Z, Nie H, Li H, Li Z, Zhang L, Qi J, He C, Van Truong N, Le MD, Nadler T, Imai H, Roos C, Li M. Living on the Rocks: Genomic Analysis of Limestone Langurs Provides Novel Insights into the Adaptive Evolution in Extreme Karst Environments. Genomics Proteomics Bioinformatics 2025 May 10;23(1).
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