2019 - Compounds commonly used in equine medicine inhibits the voltage-gated potassium channel Kv11.1
SyncroPatch 384PE publication in Research in Veterinary Science (2019)
Calloe K., Rognant, S., Friis S., Shaughnessy C., Klaerke D.A., Trachsel D.
Research in Veterinary Science (2019) 123: 239-246
- Kv11.1 is important for repolarization of the ventricular action potential in equine hearts
- In humans, decreased Kv11.1 current is associated with an increased risk of sudden cardiac death
- Acepromazine maleate, cyproheptadine, diphenhydramine and trimethoprim inhibit Kv11.1 in the therapeutic range
- Drug interaction with Kv11.1 can occur in horses and may induce repolarization disorders
- There is a potential unmet need for veterinary safety pharmacology programs
The voltage-gated K+-channel Kv11.1 has a central role in cardiac repolarization. Blockage of Kv11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). Kv11.1 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 Kv11.1. This suggests that equine Kv11.1 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 Kv11.1.
High-throughput screening of selected compounds on human Kv11.1 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 Kv11.1 expressed in CHO-K1 cells by manual patch clamp.
Acepromazine maleat (IC50 = 0.5 μM) trimethoprim (IC50 = 100 μM), diphenhydramine hydrochloride (IC50 = 2 μM) and cyproheptadine hydrochloride (IC50 = 1.84 μM) inhibited equine Kv11.1 current at clinically relevant drug concentrations.
The results suggest that drug interaction with Kv11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.