Calloe Kirstine, Rognant Salomé, Friis Søren, Shaughnessy Catherine, Klaerke Dan A, Trachsel Dagmar
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.
Res Vet Sci. 2019 Apr;123:239-246. doi: 10.1016/j.rvsc.2019.01.009. Epub 2019 Jan 8.
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.
To screen a series of commonly used drugs in equine medicine for interaction with K11.1.
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.
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.
The results suggest that drug interaction with K11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.
电压门控钾通道K11.1在心脏复极化过程中起核心作用。K11.1的阻断与严重的心血管副作用有关，如获得性长QT综合征（aLQTS）、尖端扭转型室性心律失常和心源性猝死（SCD）。由于孔道内部前庭存在两个芳香族氨基酸，K11.1易发生非特异性药物相互作用。这些芳香族残基在K11.1的马同源物中也存在。这表明马K11.1可能也容易受到一系列不同化学实体的高亲和力阻断，这可能会在马身上引起严重的心脏副作用和SCD。
筛选一系列马医学中常用药物与K11.1的相互作用。
使用自动膜片钳系统SyncroPatch 384PE（德国慕尼黑Nanion Technologies公司）对在哺乳动物细胞系中表达的人K11.1进行所选化合物的高通量筛选。结果通过手动膜片钳在CHO-K1细胞中表达的马K11.1上进行验证。
马来酸乙酰丙嗪（IC = 0.5 μM）、甲氧苄啶（IC = 100 μM）、盐酸苯海拉明（IC = 2 μM）和盐酸赛庚啶（IC = 1.84 μM）在临床相关药物浓度下抑制马K11.1电流。
结果表明马体内可能发生药物与K11.1的相互作用，且某些药物可能会在马体内诱发复极障碍。
