Inhibition of sodium currents in frog ranvier node treated with local anesthetics Role of slow sodium inactivation

Bi, Khodorov; Shishkova, L. D.; Peganov, É. M.; Revenko, S. V.

doi:10.1016/0005-2736(76)90105-x

Cited by 192 publications

(111 citation statements)

References 20 publications

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“…Alternatively, a modulated receptor hypothesis for LA binding originally proposed by HiUe (1977) and others (Khodorov, 1976;Hondeghem and Katzung, 1977) may also explain these results. The modulated receptor hypothesis states that (a) the LA receptor has a voltage-and time-dependent conformation and (b) different conformations of Na + channels bind with LA drugs with different affinities.…”

Section: Possible Explanations For the Change Of La Stereoseleaivity mentioning

confidence: 76%

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Wang

1990

The Journal of General Physiology

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Several local anesthetics (LA) have been previously shown to block muscle batrachotoxin (BTX)-activated Na § channels in planar bilayers. The mean dwell time of different LA drugs, however, varies widely, from <10 ms to longer than several seconds. In this study, we have examined the structural determinants that govern the dwell time, the binding affinity, and the stereoselectivity of LA drugs using cocaine and bupivacaine homologues, RAC compounds, and their available stereoisomers. Our results from the structure-activity experiments reveal that (a) there are two apparent hydrophobic binding domains present in the LA binding site; one interacts with the aromatic moiety of the LA drugs, and the other interacts with the alkyl group attached to the tertiary amine of the LA drugs; (b) the LA mean dwell time and the binding affinity are largely determined by the hydrophobic interactions; (c) the LA binding site is highly stereoselective, with a difference in K D values over 50-and 6-fold for (+/-) cocaine and (+/-) bupivacaine, respectively; (d) the cocaine stereoselectivity is comparable among muscle, brain, and heart BTX-activated Na + channels; and finally and most unexpectedly, (e) the stereoselectivity of LA drugs in BTX-activated Na + channels appears greatly different from that reported in normal Na + channels. Possible explanations for this difference are discussed.

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Section: Possible Explanations For the Change Of La Stereoseleaivity mentioning

confidence: 76%

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Wang

1990

The Journal of General Physiology

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“…4,31,32,33 Hille,34 in his modulated receptor hypothesis explains the shift of inactivation in presence of use-dependent block of sodium currents during repetitive pulses. 35,36,37 The hypothesis predicted that the open and inactivated states of voltage gated Na channels have higher affinities toward LA drugs than that of the resting state. The guardedreceptor model emphasizes the dependence of hydrophilic or hydrophobic path of the drug in binding and unbinding kinetics.…”

Section: Kinetics Of Drug Bindingmentioning

confidence: 99%

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

Pal

Gangopadhyay

2015

Channels

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The kinetics and nonequilibrium thermodynamics of open state and inactive state drug binding mechanisms have been studied here using different voltage protocols in sodium ion channel. We have found that for constant voltage protocol, open state block is more efficient in blocking ionic current than inactive state block. Kinetic effect comes through peak current for mexiletine as an open state blocker and in the tail part for lidocaine as an inactive state blocker. Although the inactivation of sodium channel is a free energy driven process, however, the two different kinds of drug affect the inactivation process in a different way as seen from thermodynamic analysis. In presence of open state drug block, the process initially for a long time remains entropy driven and then becomes free energy driven. However in presence of inactive state block, the process remains entirely entropy driven until the equilibrium is attained. For oscillating voltage protocol, the inactive state blocking is more efficient in damping the oscillation of ionic current. From the pulse train analysis it is found that inactive state blocking is less effective in restoring normal repolarisation and blocks peak ionic current. Pulse train protocol also shows that all the inactive states behave differently as one inactive state responds instantly to the test pulse in an opposite manner from the other two states.

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“…This phenomenon, known as 'use-dependence' (Courtney, 1975) because the level of block increases when the frequency at which channels are opened increases, has been observed with local anaesthetic block of sodium channels in nerve (Strichartz, 1973;Courtney, 1975;Khodorov et al, 1976;Cahalan, 1978) and skeletal muscle (Schwartz etal., 1977) and is of particular interest here as it could account for the marked dependence of the blocking effect on stimulation frequency that has been described for ganglionic blocking drugs (Paton & Zaimis, 1949; 1951; Kharkevich, 1967), and also occurs with agents that inhibit ACh action at the neuromuscular junction (Magazanik & Vyskocil, 1976;Burgermeister et al, 1977;Maleque et al, 1982). It was of interest to measure the degree of use-dependence seen with drugs of the methonium series, and to compare their actions in respect of this characteristic with those of ganglionic blocking drugs that do not act principally by blocking channels.…”

Section: Introductionmentioning

confidence: 99%

The channel‐blocking action of methonium compounds on rat submandibular ganglion cells

Gurney

Rang

1984

British J Pharmacology

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1 The effects of drugs of the polymethylene bis-trimethylammonium (methonium) series on the characteristics of the synaptic currents (e.s.cs) recorded from voltage-clamped rat submandibular ganglion cells have been studied. The drugs studied were from C4 to C 10 (decamethonium). 18.1 x 106M-1 S-1) for all of the compounds except C4, which had no effect on the e.s.c. decay. 3 All of the compounds produced use-dependent block when tested with short trains of stimuli at 10 Hz, or with trains of ionophoretic pulses of acetylcholine, consistent with their channel blocking property. Tubocurarine had a similar effect, but not trimetaphan or mecamylamine. 4 Recovery from use-dependent block with short chain methonium compounds, up to C8, was very slow in the absence of agonist, being incomplete even after several minutes. With C9 or C10 or tubocurarine, recovery from use-dependent block was complete within a few seconds. With C6 recovery in the absence of agonist was unaffected by membrane potential, but could be accelerated by applying acetylcholine with the cell depolarized to -40 mV. This persistent block was ascribed to the ability of the blocking molecule to become trapped by closure of the channel. With C9 and C 10 it is assumed that their presence inhibits channel closure, so they can escape without the help of agonist. 5 When use-dependent block is avoided by leaving the ganglion unstimulated during equilibration with the blocking drug, the first e.s.c. elicited shows no appreciable reduction of amplitude, though with C6, C7 or C8 subsequent responses elicited at 0

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Inhibition of sodium currents in frog ranvier node treated with local anesthetics Role of slow sodium inactivation

Cited by 192 publications

References 20 publications

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Binding affinity and stereoselectivity of local anesthetics in single batrachotoxin-activated Na+ channels.

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

The channel‐blocking action of methonium compounds on rat submandibular ganglion cells

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