Blockade of the human ether-a-go-go-related gene potassium channel by ketamine

Zhang, Peihua; Xing, Junlian; Luo, Antao; Feng, Juan; Liu, Zhi-Pei; Gao, Chenghao; Ma, Jing

doi:10.1111/jphp.12095

Cited by 9 publications

(6 citation statements)

References 29 publications

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“…Furthermore, the IC 50 for these drugs (Kamiya et al., ) were much lower than the IC 50 for TMS established in our experiments. Ketamine, a partially reversible, open‐state voltage‐dependent K v 11.1 blocker showed also blocking activity at lower concentrations (Zhang et al., ) than those found for TMS or TRIM in our study. Therefore, TRIM and TMS might be considered moderate K v 11.1 blockers with fast recovery, suggesting binding to the closed state.…”

Section: Discussionsupporting

confidence: 49%

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine K_v11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Trachsel

Tejada

Christensen

et al. 2018

Vet Pharm & Therapeutics

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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 Due to such interactions, numerous drugs have been withdrawn from the market or are administered with precautions in human medicine.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.

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Section: Discussionsupporting

confidence: 49%

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine K_v11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Trachsel

Tejada

Christensen

et al. 2018

Vet Pharm & Therapeutics

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“…Ketamine has been reported to inhibit various ionic currents [29][30][31][32][33][34][35][36][37][38] . Hara et al reported that ketamine (30, 100, 300 μmol/L) dose-dependently blocked peak I Na in guinea pig ventricular myocytes [32] .…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that ketamine may have cardioprotective effects, but the underlying mechanisms are still unknown. Ketamine has been reported to inhibit various ionic currents, including the L-type Ca 2+ current (I CaL ) [29][30][31][32][33][34] , peak sodium current (I Na ) [32] , inward rectifier K + current (I K1 ) [30,35] , delayed rectifier K + current (I K ) [30] , ATP-sensitive K + current (I KATP ) [36,37] , and human ether-a-go-go-related gene (hERG) channel [38] . However, there is no study regarding the effects of ketamine on I NaL .…”

Section: Introductionmentioning

confidence: 99%

Ketamine attenuates the Na+-dependent Ca2+ overload in rabbit ventricular myocytes in vitro by inhibiting late Na+ and L-type Ca2+ currents

Luo

Cao

et al. 2015

Acta Pharmacol Sin

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] i transients were measured simultaneously using a video-based edge detection and dual excitation fluorescence photomultiplier system. Results: Ketamine (20, 40, 80 μmol/L) inhibited I NaL in a concentration-dependent manner. In the presence of sea anemone toxin II (ATX, 30 nmol/L), I NaL was augmented by more than 3-fold, while ketamine concentration-dependently suppressed the ATX-augmented I NaL . Ketamine (40 μmol/L) also significantly suppressed hypoxia or H 2 O 2 -induced enhancement of I NaL . Furthermore, ketamine concentration-dependently attenuated ATX-induced enhancement of reverse-mode I NCX . In addition, ketamine (40 μmol/L) inhibited I CaL by 33.4%. In the presence of ATX (3 nmol/L), the rate and amplitude of cell shortening and relaxation, the diastolic [Ca 2+ ] i , and the rate and amplitude of [Ca 2+ ] i rise and decay were significantly increased, which were reverted to control levels by tetrodotoxin (TTX, 2 μmol/L) or by ketamine (40 μmol/L). Conclusion: Ketamine protects isolated rabbit ventricular myocytes against [Ca 2+ ] i overload by inhibiting I NaL and I CaL .

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“… 9 The inhibitory effects on cardiac hERG channels have already been observed for other anesthetics, eg, ketamine (IC 50 =12.05±1.38 μM) and articaine (IC 50 =224±6 μM). 36 – 38 However, the inhibitory effects of midazolam on heterologously expressed hERG channels have not previously been described.…”

Section: Discussionmentioning

confidence: 99%

Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action

Vonderlin¹,

Fischer²,

Zitron³

et al. 2015

DDDT

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Midazolam is a short-acting benzodiazepine that is in wide clinical use as an anxiolytic, sedative, hypnotic, and anticonvulsant. Midazolam has been shown to inhibit ion channels, including calcium and potassium channels. So far, the effects of midazolam on cardiac human ether-à-go-go-related gene (hERG) channels have not been analyzed. The inhibitory effects of midazolam on heterologously expressed hERG channels were analyzed in Xenopus oocytes using the double-electrode voltage clamp technique. We found that midazolam inhibits hERG channels in a concentration-dependent manner, yielding an IC50 of 170 μM in Xenopus oocytes. When analyzed in a HEK 293 cell line using the patch-clamp technique, the IC50 was 13.6 μM. Midazolam resulted in a small negative shift of the activation curve of hERG channels. However, steady-state inactivation was not significantly affected. We further show that inhibition is state-dependent, occurring within the open and inactivated but not in the closed state. There was no frequency dependence of block. Using the hERG pore mutants F656A and Y652A we provide evidence that midazolam uses a classical binding site within the channel pore. Analyzing the subacute effects of midazolam on hERG channel trafficking, we further found that midazolam does not affect channel surface expression. Taken together, we show that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression. These data add to the current understanding of the pharmacological profile of the anesthetic midazolam.

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Blockade of the human ether-a-go-go-related gene potassium channel by ketamine

Abstract: Ketamine blocks WT IhERG expressed in Xenopus oocytes in a concentration-dependent manner and predominantly interacts with the open hERG channels. The interaction of ketamine with hERG channel may involve the aromatic residues Tyr652 and Phe656.

Cited by 9 publications

References 29 publications

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine K_v11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine K_v11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Ketamine attenuates the Na+-dependent Ca2+ overload in rabbit ventricular myocytes in vitro by inhibiting late Na+ and L-type Ca2+ currents

Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action

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Blockade of the human ether-a-go-go-related gene potassium channel by ketamine

Abstract: Ketamine blocks WT IhERG expressed in Xenopus oocytes in a concentration-dependent manner and predominantly interacts with the open hERG channels. The interaction of ketamine with hERG channel may involve the aromatic residues Tyr652 and Phe656.

Cited by 9 publications

References 29 publications

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine Kv11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine Kv11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Ketamine attenuates the Na+-dependent Ca2+ overload in rabbit ventricular myocytes in vitro by inhibiting late Na+ and L-type Ca2+ currents

Anesthetic drug midazolam inhibits cardiac human ether-&agrave;-go-go-related gene&nbsp;channels: mode&nbsp;of&nbsp;action

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Effects of trimethoprim–sulfadiazine and detomidine on the function of equine K_v11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Effects of trimethoprim–sulfadiazine and detomidine on the function of equine K_v11.1 channels in a two‐electrode voltage‐clamp (TEVC) oocyte model

Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action