Class I Antiarrhythmic Drugs: Na+ Channel Blockers

Shenasa, Mohammad; Shenasa, Mohammad-Ali; Smith, Mariah

doi:10.1007/978-3-030-34893-9_2

Cited by 3 publications

(1 citation statement)

References 257 publications

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“…This is consistent with previous findings and with the knowledge that class Ib AADs have relatively fast dissociation kinetics, thus being less affected by use-dependent block at low frequency. (Wang et al, 2015;Shenasa et al, 2020) Here in our study, the 14-3-3 inhibition had the tendency to increase the use-dependent block induced by lidocaine and mexiletine at 1Hz. However, 14-3-3 impacted the use-dependent block of these two drugs at 5 and 10 Hz impairing the use-dependent block (Figure 9).…”

Section: Regulation Of Use-dependent Block By 14-3-3supporting

confidence: 51%

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: Regulation Of Use-dependent Block By 14-3-3supporting

confidence: 51%

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 antiarrhythmic activity of amino acid-containing derivatives of 1,4-naphthoquinone

Napalkova,

Buyuklinskaya

2024

Pharmacy Formulas

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In recent times, the issue of cardiac arrhythmia disturbances has garnered increasing attention from researchers. Pharmacotherapy continues to be the primary method for treating rhythm disturbances; however, its effectiveness is often limited due to the common side effects associated with many antiarrhythmic drugs, among which negative inotropic action plays a significant role. One direction in the development of antiarrhythmic agents involves the targeted search for new drugs among agents with metabolic effects. The aim of this study was to investigate the antiarrhythmic activity using models of occlusion and reperfusion arrhythmias in cats, aconitine arrhythmias in rats, and calcium chloride ventricular fibrillation in rats of five original amino acid-containing derivatives of 1,4-naphthoquinone, synthesized at the Lviv Polytechnic Institute under the guidance of Ph.D. A.P. Kartoflitska. The conducted research indicated that the studied compounds exhibit antiarrhythmic effects. The enhancement of the antiarrhythmic activity occurred primarily in those arrhythmia models where metabolic disorders play a significant role in the pathogenesis.

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Antiarrhythmic Activity of Amino Acids Containing Nibentan Derivatives in Case of Symptoms of Occlusive and Reperfusion Arrhythmias

Napalkova,

Buyuclinskaya

2023

Razrabotka i registraciâ lekarstvennyh sredstv

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Introduction. Pharmacotherapy of cardiac arrhythmias is one of the urgent problems of modern medicine. The presence of serious side effects, in particular proarrhythmic action, limits the use of known antiarrhythmics in clinical practice. One way to reduce the toxicity of pharmacological agents is to use them as complex compounds with amino acids.Aim. Studying the effect of nibentan derivatives containing magnesium salt of L-aspartic acid and glycine as anions on the course of early occlusive and reperfusion arrhythmias.Materials and methods. Aminоacid derivatives of nibentan have been studied in models of occlusive and reperfusion arrhythmias in rats. The activity of the drugs was assessed by the incidence of ventricular extrasystoles (VEC), ventricular tachycardia (VT), ventricular fibrillation (VF), by the latent period and duration of arrhythmias, the average duration of VT, and by the number of VEC per 1 animal.Results and discussion. Nibentan derivatives in models of early occlusive and reperfusion arrhythmias were not inferior in antiarrhythmic activity to lidocaine and nibentan in their ability to prevent cardiac arrhythmias. The nibentan derivative containing the magnesium salt of L-aspartic acid (compound LHT-53-91) in the model of occlusive arrhythmias at a dose of 2 % LD50 completely prevented cardiac arrhythmias in experimental animals. A nibentan derivative containing glycine (compound LHT-20-92) at a dose of 1 % LD50 significantly reduced the number of cases of PVCs, prevented the occurrence of ventricular tachycardia and ventricular fibrillation in 100 % of cases. In the model of reperfusion arrhythmias, LHT-53-91 at a dose of 1 % LD50 prevented the development of ventricular fibrillation and paroxysms of ventricular tachycardia and reduced the risk of developing ventricular extrasystole (p < 0.05). Increasing the dose to 2 % LD50 led to an increase in the activity of the substance, which was expressed in the prevention of cardiac arrhythmias in 100 % of the animals. LHT-20-92 at a dose of 1 % LD50 in this model of cardiac arrhythmias statistically significantly reduced the occurrence of VES and VT paroxysms and completely prevented the occurrence of VF (p < 0.05).Conclusion. The inclusion of nibenthan amino acids in the structure, which shielded genotic grouping and reduced potential teratogenicity and mutagenicity, had not led to a reduction in the antiarrhythmic and antifibril-torn activity on the studied models of rhythm disorders.

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Class I Antiarrhythmic Drugs: Na+ Channel Blockers

Cited by 3 publications

References 257 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

The antiarrhythmic activity of amino acid-containing derivatives of 1,4-naphthoquinone

Antiarrhythmic Activity of Amino Acids Containing Nibentan Derivatives in Case of Symptoms of Occlusive and Reperfusion Arrhythmias

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Class I Antiarrhythmic Drugs: Na+ Channel Blockers

Cited by 3 publications

References 257 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

The antiarrhythmic activity of amino acid-containing derivatives of 1,4-naphthoquinone

Antiarrhythmic Activity of Amino Acids Containing Nibentan Derivatives in Case of Symptoms of Occlusive and Reperfusion Arrhythmias

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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