Effects of donepezil on hERG potassium channels

Chae, Yun Ju; Lee, Hong Joon; Jeon, Ji Hyun; Kim, In‐Beom; Choi, Jin-Sung; Sung, Ki-Wug; Hahn, Sang June

doi:10.1016/j.brainres.2014.11.057

Cited by 19 publications

(16 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, studies indicate that donepezil blocks the IK (A) and IK (DR) in rat dissociated hippocampal neurons 13 14 . Moreover, donepezil-induced inhibition is detected in heterologously expressed hERG 15 and Kv2.1 5 channels in HEK293 cells. Noticeably, the prolonged QT interval and Torsade de Pointes arrhythmias are adverse side effects after treatment with donepezil 16 17 .…”

mentioning

confidence: 97%

“…Noticeably, the prolonged QT interval and Torsade de Pointes arrhythmias are adverse side effects after treatment with donepezil 16 17 . The blocking effects of donepezil in human cardiac IK (DR) carried by hERG channels 18 could contribute to side effects 15 . Rapid activating Kv1.5 channels are widely expressed in a variety of tissues and carry ultra-rapid delayed rectifier K + current (IKur) which contributes to repolarization in human atrial cells 19 20 21 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

Neng

2017

Sci Rep

View full text Add to dashboard Cite

Kv1.5 channels carry ultra-rapid delayed rectifier K+ currents in excitable cells, including neurons and cardiac myocytes. In the current study, the effects of cholinesterase inhibitor donepezil on cloned Kv1.5 channels expressed in HEK29 cells were explored using whole-cell recording technique. Exposure to donepezil resulted in a rapid and reversible block of Kv1.5 currents, with an IC50 value of 72.5 μM. The mutant R476V significantly reduced the binding affinity of donepezil to Kv1.5 channels, showing the target site in the outer mouth region. Donepezil produced a significant delay in the duration of activation and deactivation, and mutant R476V potentiated these effects without altering activation curves. In response to slowed deactivation time course, a typical crossover of Kv1.5 tail currents was clearly evident after bath application of donepezil. In addition, both this chemical and mutant R476V accelerated current decay during channel inactivation in a voltage-dependent way, but barely changed the inactivation and recovery curves. The presence of donepezil exhibited the use-dependent block of Kv1.5 currents in response to a series of depolarizing pulses. Our data indicate that donepezil can directly block Kv1.5 channels in its open and closed states.

show abstract

mentioning

confidence: 97%

mentioning

confidence: 99%

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

Neng

2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“… 69 This study showed that the acute inhibitory action of donepezil on I hERG shows gating dependence, with interactions between the drug and both activated and inactivated channels. 69 Furthermore, the same study showed that the donepezil metabolites 6-O-desmethyl donepezil and 5-O-desmethyl donepezil inhibited I hERG with similar potency to the parent compound. Moreover, in addition to its acute inhibitory effect on I hERG donepezil was found to inhibit hERG channel trafficking and expression in the plasma membrane.…”

Section: Discussionmentioning

confidence: 86%

“…Donepezil has been found to inhibit hERG channel ionic current (I hERG ) recorded from hERG channels in a mammalian expression system, with a half maximal inhibitory concentration (IC 50 ) of 1.30 μM. 69 This study showed that the acute inhibitory action of donepezil on I hERG shows gating dependence, with interactions between the drug and both activated and inactivated channels. 69 Furthermore, the same study showed that the donepezil metabolites 6-O-desmethyl donepezil and 5-O-desmethyl donepezil inhibited I hERG with similar potency to the parent compound.…”

Section: Discussionmentioning

confidence: 92%

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

Malone

Hancox

2020

Therapeutic Advances in Drug Safety

View full text Add to dashboard Cite

Background: Acetylcholinesterase inhibitors (AChEis) including donepezil, galantamine and rivastigmine are used to treat Alzheimer’s disease (AD). This study aimed to evaluate evidence from the case report literature for an association between these agents and risk of QT interval prolongation and Torsades de Pointes (TdP) arrhythmia. Methods: Published literature was mined with predetermined MeSH terms for each of donepezil, galantamine and rivastigmine, to identify cases of QT interval prolongation and TdP. Case reports were analysed using causality scales and a QT interval nomogram. Results: A total of 13 case reports were found (10 for donepezil, 2 for galantamine and 1 for rivastigmine) with rate corrected QT interval (QTc) prolongation. Five cases with donepezil exhibited TdP. TdP was not reported in the cases with galantamine and rivastigmine. The use of a QT heart rate nomogram highlighted risk with donepezil compared with the other two drugs and the application of the Naranjo causality scale suggested probable or possible causation for all donepezil cases. All patients had at least two other risk factors for TdP, including modifiable risk factors such as electrolyte disturbances, bradycardia, co-administration of QT prolonging drugs. A number of recent cases involved recent changes in medication. Conclusion: Our evaluation of the case report literature suggests that there is evidence for a causal association between donepezil and QTc/TdP risk. Attention to risk factors for QTc prolongation/TdP should be exercised when prescribing donepezil and modifiable risk factors corrected. Owing to the low number of cases with galantamine and rivastigmine, further work is needed to establish whether these drugs may be more suitable than donepezil for patients with other risk factors for TdP.

show abstract

“…Human ether-a-go-go-related gene (hERG) potassium channels are crucial for cardiac action potential repolarization, conducting rapid delayed rectifier K + current (I kr ) [1][2][3]. hERG mutations that reduce conductance or expression cause result in congenital long QT syndrome (LQTS) and inhibition of hERG channels by structurally diverse drugs, either antiarrhythmic or non-antiarrhythmic, may cause acquired LQTS or other arrhythmias [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

α<sub>1</sub>-adrenergic Receptor Attenuates β<sub>1</sub>-adrenergic Modulation of IKr by Protein Kinase C-dependent Suppression of Adenylyl Cyclase in Ventricular Myocytes

Wang¹

2019

IJCEMS

View full text Add to dashboard Cite

The rapid delayed rectifier K + current (I kr) is critical for repolarization of the cardiac action potential. Previous studies have shown activated α 1-adrenergic receptor (AR) attenuates β 1-adrenergic regulation of I kr while the mechanisms involved are poorly understood. To evalutate how α 1-adrenergic receptor affect β 1-adrenergic modulation of I kr , whole-cell patch-clamp recordings were peformed in isolated guinea-pig ventricular myocytes. Application of xamoterol, a selective β 1-AR agonist, induced a negative shift in the activation curve and I kr current reduction by 40.50±6.66% at the test pulse of +40 mV. Forskolin and 8-Br-cAMP also resulted in I kr reduction by 38.17±1.50% and 24.65±3.37%, respectively. Phenylephrine, a selective α 1-AR agonist, prevented the activation shift and I kr current reduction induced by xamoterol and forskolin, but not by 8-Br-cAMP. The effect of xamoterol or forskolin on I kr was also prevented by pretreatment with PDBu, a protein kinase C (PKC) activator, while the effect of cAMP on I kr can not, which was similar to pretreatment with phenylephrine. When cells were pretreated with chelerythrine, a specific PKC inhibitor, phenylephrine failed to prevent I kr reduction induced by xamoterol. Our data suggests that α 1-adrenergic stimulation attenuates β 1-adrenergic regulation of I kr , through PKC-dependent downregulation of adenylyl cyclase/cyclic AMP pathway.

show abstract

Effects of donepezil on hERG potassium channels

Cited by 19 publications

References 36 publications

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

α<sub>1</sub>-adrenergic Receptor Attenuates β<sub>1</sub>-adrenergic Modulation of IKr by Protein Kinase C-dependent Suppression of Adenylyl Cyclase in Ventricular Myocytes

Contact Info

Product

Resources

About

Effects of donepezil on hERG potassium channels

Cited by 19 publications

References 36 publications

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

α&lt;sub&gt;1&lt;/sub&gt;-adrenergic Receptor Attenuates β&lt;sub&gt;1&lt;/sub&gt;-adrenergic Modulation of IKr by Protein Kinase C-dependent Suppression of Adenylyl Cyclase in Ventricular Myocytes

Contact Info

Product

Resources

About

α<sub>1</sub>-adrenergic Receptor Attenuates β<sub>1</sub>-adrenergic Modulation of IKr by Protein Kinase C-dependent Suppression of Adenylyl Cyclase in Ventricular Myocytes