Effects of trimethoprim–sulfadiazine and detomidine on the function of equine Kv11.1 channels in a two-electrode voltage-clamp (TEVC) oocyte model
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Effects of trimethoprim–sulfadiazine and detomidine on the function of equine Kv11.1 channels in a two-electrode voltage-clamp (TEVC) oocyte model. / Trachsel, D. S.; Tejada, M. A.; Groesfjeld Christensen, V.; Pedersen, P. J.; Kanters, J. K.; Buhl, R.; Calloe, K.; Klaerke, D. A.
In: Journal of Veterinary Pharmacology and Therapeutics, Vol. 41, No. 4, 2018, p. 536-545.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Effects of trimethoprim–sulfadiazine and detomidine on the function of equine Kv11.1 channels in a two-electrode voltage-clamp (TEVC) oocyte model
AU - Trachsel, D. S.
AU - Tejada, M. A.
AU - Groesfjeld Christensen, V.
AU - Pedersen, P. J.
AU - Kanters, J. K.
AU - Buhl, R.
AU - Calloe, K.
AU - Klaerke, D. A.
PY - 2018
Y1 - 2018
N2 - 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 Kv11.1 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 Due to such interactions, numerous drugs have been withdrawn from the market or are administered with precautions in human medicine.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 Kv11.1 channels. Kv11.1 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 Kv11.1 current with an IC50 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 Kv11.1 current. Thus, equine Kv11.1 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.
AB - 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 Kv11.1 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 Kv11.1 channels. Kv11.1 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 Kv11.1 current with an IC50 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 Kv11.1 current. Thus, equine Kv11.1 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.
KW - acquired LQTS
KW - heart
KW - hERG
KW - potassium channels
KW - Repolarization
U2 - 10.1111/jvp.12502
DO - 10.1111/jvp.12502
M3 - Journal article
C2 - 29566261
AN - SCOPUS:85044239745
VL - 41
SP - 536
EP - 545
JO - Journal of Veterinary Pharmacology and Therapeutics
JF - Journal of Veterinary Pharmacology and Therapeutics
SN - 0140-7783
IS - 4
ER -
ID: 203052513