Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model

State-dependent sodium channel blockers are often prescribed to treat cardiac arrhythmias, but many sodium channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a sodium channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the sodium channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-sodium channel interaction by Moreno et al. Specifically, we find that (1) the vast majority of lidocaine bound to sodium channels is in the neutral form, i.e., the binding of charged lidocaine to sodium channels is negligible, and (2) neutral lidocaine binds almost exclusively to inactivated channels and, upon binding, immobilizes channels in the inactivated state. We then develop a novel 3-variable lidocaine-sodium channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates an extensive amount of the voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.

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Voltage Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues

Current Medicinal Chemistry ◽

10.2174/0929867327666200504080530 ◽

2020 ◽

Vol 27 ◽

Author(s):

Alessia Catalano ◽

Carlo Franchini ◽

Alessia Carocci

Keyword(s):

Sodium Channel ◽

Channel Blocker ◽

Parent Compound ◽

Channel Blockers ◽

Sodium Channel Blocker ◽

Starting Point ◽

Channel Blocking ◽

Blocking Activity ◽

Synthetic Routes ◽

Lateral Sclerosis

: Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic distrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers were widely demonstrated, with (–)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.

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Mechanism of action of sodium channel blocker insecticides (SCBIs) on insect sodium channels

Pesticide Biochemistry and Physiology ◽

10.1016/j.pestbp.2009.09.001 ◽

2010 ◽

Vol 97 (2) ◽

pp. 87-92 ◽

Cited By ~ 39

Author(s):

Kristopher S. Silver ◽

Weizhong Song ◽

Yoshiko Nomura ◽

Vincent L. Salgado ◽

Ke Dong

Keyword(s):

Sodium Channel ◽

Sodium Channels ◽

Mechanism Of Action ◽

Channel Blocker ◽

Sodium Channel Blocker

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Vanilloid Receptor Agonists Potentiate the In Vivo Local Anesthetic Activity of Percutaneously Injected Site 1 Sodium Channel Blockers

Anesthesiology ◽

10.1097/00000542-199902000-00029 ◽

1999 ◽

Vol 90 (2) ◽

pp. 524-534 ◽

Cited By ~ 23

Author(s):

Daniel S. Kohane ◽

Yu Kuang ◽

Nu T. Lu ◽

Robert Langer ◽

Gary R. Strichartz ◽

...

Keyword(s):

Sodium Channel ◽

Channel Blocker ◽

Synergistic Effects ◽

Small Diameter ◽

Channel Blockers ◽

Sodium Channel Blocker ◽

Sodium Channel Blockers ◽

Nerve Blockade ◽

Motor Strength

Background Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. Methods Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. Results Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. Conclusions Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.

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Baseline Response, Monitoring, and Cross-Resistance of Spodoptera frugiperda (Lepidoptera: Noctuidae) to Sodium Channel Blocker Insecticides in Brazil

Journal of Economic Entomology ◽

10.1093/jee/toab011 ◽

2021 ◽

Author(s):

Ingrid S Kaiser ◽

Rubens H Kanno ◽

Anderson Bolzan ◽

Fernando S A Amaral ◽

Ewerton C Lira ◽

...

Keyword(s):

Sodium Channel ◽

Spodoptera Frugiperda ◽

Channel Blocker ◽

Resistance Management ◽

Response Monitoring ◽

Cross Resistance ◽

Channel Blockers ◽

Sodium Channel Blocker ◽

Baseline Response ◽

Lepidoptera Noctuidae

Abstract Spodoptera frugiperda (J.E. Smith) is one of the key cross-crop pests in Brazilian agroecosystems. Field-evolved resistance of S. frugiperda to some conventional insecticides and Bt proteins has already been reported. Thus, the use of insecticides with new mode of action such as sodium channel blockers (indoxacarb and metaflumizone) could be an important tool in insecticide resistance management (IRM) programs. To implement a proactive IRM, we conducted baseline response and monitoring to indoxacarb and metaflumizone in 87 field populations of S. frugiperda collected from major maize-growing regions of Brazil from 2017 to 2020, estimated the frequency of resistance alleles to indoxacarb, and evaluated cross-resistance of indoxacarb and metaflumizone to some selected insecticides and Bt proteins. Low variation in susceptibility to indoxacarb (4.6-fold) and metaflumizone (2.6-fold) was detected in populations of S. frugiperda in 2017. The frequency of the resistance allele to indoxacarb was 0.0452 (0.0382–0.0527 CI 95%), by using F2 screen method. The mean survival at diagnostic concentration, based on CL99, varied from 0.2 to 12.2% for indoxacarb and from 0.0 to 12.7% for metaflumizone, confirming high susceptibility of S. frugiperda to these insecticides in Brazil. No cross-resistance was detected between sodium channel blocker insecticides and other insecticides (organophosphate, pyrethroid, benzoylurea, spinosyn, and diamide) and Bt proteins. These findings showed that sodium channel blocker insecticides are important candidates to be exploited in IRM strategies of S. frugiperda in Brazil.

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Opposite change with ischaemia in the antifibrillatory effects of class I and class IV antiarrhythmic drugs resulting from the alteration in ion transmembrane exchanges related to depolarization

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y99-129 ◽

2000 ◽

Vol 78 (3) ◽

pp. 208-216 ◽

Cited By ~ 3

Author(s):

Jean-François Aupetit ◽

Bernard Bui-Xuan ◽

Idriss Kioueh ◽

Joseph Loufoua ◽

Dominique Frassati ◽

...

Keyword(s):

Action Potential ◽

Calcium Channel ◽

Sodium Channel ◽

Sodium Channels ◽

Antiarrhythmic Drugs ◽

Channel Blocker ◽

Class I ◽

Monophasic Action Potential ◽

Channel Blockers ◽

Class Iv

It is known that class I antiarrhythmic drugs lose their antifibrillatory activity with severe ischaemia, whereas class IV antiarrhythmic drugs acquire such activity. Tachycardia, which is also a depolarizing factor, has recently been shown to give rise to an alteration of ion transmembrane exchanges which is particularly marked in the case of calcium. This leads one to wonder if the change in antifibrillatory activity of antiarrhythmic drugs caused by ischaemia depends on the same process. The change in antifibrillatory activity was studied in normal conditions ranging to those of severe ischaemia with a class I antiarrhythmic drug, flecainide (1.00 mg·kg-1 plus 0.04 mg·kg-1·min-1), a sodium channel blocker, and a class IV antiarrhythmic drug, verapamil (50 µg·kg-1 plus 2 µg·kg-1·min-1), a calcium channel blocker. The experiments were performed in anaesthetized, open-chest pigs. The resulting blockade of each of these channels was assessed at the end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (heart rate 180 beats per min). Ischaemia was induced by completely occluding the left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction time (VCT). The monophasic action potential duration (MAPD) varied with membrane polarization of the fibres. The blockade of sodium channels by flecainide, which normally raises VFT (7.0 ± 0.4 to 13.8 ± 0.8 mA, p < 0.001) and lengthens VCT (28 ± 3 to 44 ± 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the ischaemia-induced fall of VFT and decreased aggravation of the ischaemia-induced lengthening of VCT. The blockade of calcium channels, which normally does not alter VFT (between 7.2 ± 0.6 and 8.4 ± 0.7 mA, n.s.) or VCT (between 30 ± 2 and 34 ± 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibrillation. Membrane depolarization itself was opposed as the shortening of MAPD and the lengthening of VCT were also delayed. Consequently there is a progressive decrease in the role played by sodium channels during ischaemia in the rhythmic systolic depolarization of the ventricular fibres. This reduces or suppresses the ability of sodium channel blockers to act on excitability or conduction, and increases the role of calcium channel blockers in attenuating ischaemia-induced disorders.Key words: pigs, ion transmembrane exchanges, myocardial ischaemia, sodium channel, calcium channel.

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Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

10.1101/2020.12.07.414763 ◽

2020 ◽

Author(s):

Ivan Tochitsky ◽

Sooyeon Jo ◽

Nicholas Andrews ◽

Masakazu Kotoda ◽

Benjamin Doyle ◽

...

Keyword(s):

Sodium Channel ◽

Sensory Neurons ◽

Channel Blocker ◽

Allergic Inflammation ◽

Selective Inhibition ◽

Channel Blockers ◽

Common Condition ◽

Sodium Channel Blocker ◽

Large Pore ◽

Extracellular Activity

Although multiple diseases of the respiratory system cause cough, there are few effective treatments for this common condition. We previously developed a strategy to treat pain and itch via the long-lasting inhibition of nociceptor sensory neurons with QX-314, a cationic sodium channel blocker that selectively enters only into activated nociceptors by permeating through the endogenous TRPV1 and TRPA1 large pore ion channels they express. In this study we design and characterize BW-031, a novel cationic compound with ~6-fold greater potency than QX-314 for inhibiting sodium channels when introduced inside cells and with minimal extracellular activity. We show that inhalation of aerosolized BW-031 effectively inhibits citric acid-induced cough in an allergic inflammation guinea pig cough model. These data support the use of charged sodium channel blockers for the selective inhibition of airway sensory neurons with activated large pore channels as a novel targeted therapy for treating cough.

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