Klasse-I-Antiarrhythmika

Pott, Christian; Dechering, Dirk G.; Muszyński, A; Zellerhoff, Stephan; Bittner, Alex; Wasmer, Kristina; Mönnig, Gerold; Eckardt, Lars

doi:10.1007/s00399-010-0090-1

Cited by 3 publications

(1 citation statement)

References 44 publications

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“…They block the sodium current to decrease the action potential's amplitude and slow conduction velocity, thus interrupting or preventing reentrant arrhythmias. (Pott et al, 2010) Considering that Na v 1.5 interacting proteins can regulate the channel function, it is highly possible that certain Na v 1.5 regulatory proteins could affect the channel's response to AADs, thus influencing the AAD's outcome or side effects. However, there are limited studies that have investigated how the different Na v 1.5 regulatory proteins influence the action of AADs on Na v 1.5.…”

Section: Introductionmentioning

confidence: 99%

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Na_v1.5 to Antiarrhythmic Drugs

Zheng¹,

Deschênes

2022

J Pharmacol Exp Ther

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The cardiac sodium channel Na v 1.5 is a key contributor to the cardiac action potential and dysregulations in Na v 1.5 can lead to cardiac arrhythmias. Na v 1.5 is a target of numerous antiarrhythmic drugs (AADs). Previous studies identified the protein 14-3-3 as a regulator of Na v 1.5 biophysical coupling. Inhibition of 14-3-3 can remove the Na v 1.5 functional coupling and has been shown to inhibit the dominant-negative effect of Brugada Syndrome mutations. However, it is unknown whether the coupling regulation is involved with AADs' modulation of Na v 1.5. Indeed, AADs could reveal important structural and functional information about Na v 1.5 coupling. Here we investigated the modulation of Na v 1.5 by four classical AADs, quinidine, lidocaine, mexiletine, and flecainide, in presence of 14-3-3 inhibition. The experiments were carried out by high-throughput patch-clamp experiments in an HEK293 Na v 1.5 stable cell line.We found that 14-3-3 inhibition can enhance acute block by quinidine, while the block by other drugs was not affected. We also saw changes in the use-and dose-dependency of quinidine, lidocaine, and mexiletine when inhibiting 14-3-3. Inhibiting 14-3-3 also shifted the channel activation toward hyperpolarized voltages in presence of the four drugs studied and slowed the recovery of inactivation in presence of quinidine. Our results demonstrated that the protein 14-3-3 and Na v 1.5 coupling could impact the effects of AADs. Therefore, 14-3-3 and Na v 1.5 coupling are new mechanisms to consider in the development of drugs targeting Na v 1.5.

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Section: Introductionmentioning

confidence: 99%

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Na_v1.5 to Antiarrhythmic Drugs

Zheng¹,

Deschênes

2022

J Pharmacol Exp Ther

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Analysis of Electrophysiological Mechanisms of N-Deacetyllapaconitine Monochlorhydrate, the Main Metabolite of Lappaconitine Hydrobromide

et al. 2022

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Isoliensinine Eliminates Afterdepolarizations Through Inhibiting Late Sodium Current and L-Type Calcium Current

Liu

Zhang

et al. 2020

Cardiovasc Toxicol

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Isoliensinine (IL) extracted from lotus seed has a good therapeutic effect on cardiovascular diseases. However, its effect on ion channels of ventricular myocytes is still unclear. We used whole-cell patch-clamp techniques to detect the effects of IL on transmembrane ion currents and action potential (AP) in isolated rabbit left ventricular myocytes. IL inhibited the transient sodium current (I NaT ), late sodium current (I NaL ) enlarged by sea anemone toxin (ATX II) and L-type calcium current (I CaL ) in a concentration-dependent manner without affecting inward rectifier potassium current (I K1 ) and delayed rectifier potassium current (I K ). These inhibitory effects are mainly manifested as reduced the AP amplitude (APA) and maximum depolarization velocity (V max ) and shortened the action potential duration (APD), but had no significant effect on the resting membrane potential (RMP). Moreover, IL significantly eliminated ATX II-induced early afterdepolarizations (EADs) and high extracellular calcium-induced delayed afterdepolarizations (DADs). These results revealed that IL effectively eliminated EADs and DADs through inhibiting I NaL and I CaL in ventricular myocytes, which indicates it has potential antiarrhythmic action.

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Klasse-I-Antiarrhythmika

Cited by 3 publications

References 44 publications

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Na_v1.5 to Antiarrhythmic Drugs

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Na_v1.5 to Antiarrhythmic Drugs

Analysis of Electrophysiological Mechanisms of N-Deacetyllapaconitine Monochlorhydrate, the Main Metabolite of Lappaconitine Hydrobromide

Isoliensinine Eliminates Afterdepolarizations Through Inhibiting Late Sodium Current and L-Type Calcium Current

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Klasse-I-Antiarrhythmika

Cited by 3 publications

References 44 publications

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Nav1.5 to Antiarrhythmic Drugs

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Nav1.5 to Antiarrhythmic Drugs

Analysis of Electrophysiological Mechanisms of N-Deacetyllapaconitine Monochlorhydrate, the Main Metabolite of Lappaconitine Hydrobromide

Isoliensinine Eliminates Afterdepolarizations Through Inhibiting Late Sodium Current and L-Type Calcium Current

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Product

Resources

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Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Na_v1.5 to Antiarrhythmic Drugs

Protein 14-3-3 Influences the Response of the Cardiac Sodium Channel Na_v1.5 to Antiarrhythmic Drugs