The properties of Na channels of the node of Ranvier are altered by neutral, amine, and quaternary local anesthetic compounds. The kinetics of the Na currents are governed by a composite of voltage- and time-dependent gating processes with voltage- and time-dependent block of channels by drug. Conventional measurements of steady-state sodium inactivation by use of 50-ms prepulses show a large negative voltage shift of the inactivation curve with neutral benzocaine and with some ionizable amines like lidocaine and tetracaine, but no shift is seen with quaternary OX-572. However, when the experiment is done with repetitive application of a prepulse-testpulse waveform, a shift with the quaternary cations (applied internally) is seen as well. 1-min hyperpolarizations of lidocaine- or tetracaine-treated fibers restore two to four times as many channels to the conducting pool as 50-ms hyperpolarizations. Raising the external Ca++ concentration also has a strong unblocking effect. These manipulations do not relieve block in fibers treated with internal quaternary drugs. The results are interpreted in terms of a single receptor in Na channels for the different drug types. Lipid-soluble drug forms are thought to come and go from the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass via a hydrophilic region (the inner channel mouth). The hydrophilic pathway is open only when the gates of the channel are open. Any drug form in the channel increases the probability of closing the inactivation gate which, in effect, is equivalent to a negative shift of the voltage dependence of inactivation.

/pdf/local-anesthetics-hydrophilic-and-hydrophobic-pathways-for-ky21zppwgy.pdf

Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.

1. Inward currents in chromaffin cells were studied with the patch-clamp technique (Hamill, Marty, Neher, Sakmann & Sigworth, 1981). The intracellular solution contained 120 mM-Cs+ and 20 mM-tetraethylammonium (TEA+). Na+ currents were studied after blockade of Ca2+ channels with 1 mM-Co2+ applied externally. Ca2+ currents were recorded after eliminating Na+ currents with tetrodotoxin (TTX). The current recordings were obtained in cell-attached, outside-out and whole-cell recording configurations (Hamill et al. 1981).

2. Single channel measurements gave an elementary current amplitude of 1 pA at -10 mV for Na+ channels. This amplitude increased with hyperpolarization between -10 and -40 mV, but did not vary significantly between -40 and -70 mV.

3. The mean Na+ channel open time was 1 ms at -30 mV. This open time decreased both with depolarization and hyperpolarization. Its value was close to the time constant of inactivation, τh, above -20 mV.

4. Ensemble fluctuation analysis of Na+ currents gave results consistent with those of single channel measurements. Noise power spectra obtained between -35 mV and 0 mV could be fitted with a single Lorentzian. A range of Na+ channel densities of 1·5-10 channels per μm2 was calculated.

5. Cell-attached single Ca2+ channel recordings were obtained in isotonic BaCl2 solution. The single channel amplitude was 0·9 pA at -5 mV, and it became smaller for positive potential values.

6. At -5 mV, single Ba2+ currents appeared as bursts of 1·9 ms mean duration containing on the average 0·6 short gaps. The burst duration was larger at positive potentials.

7. Ensemble fluctuation analysis of Ca2+ channels was performed on whole-cell recordings in external solutions containing isotonic BaCl2 or external Ca2+ (Cao) concentrations of 1 and 5 mM. The unit amplitude calculated in the former case was similar to that obtained in single channel measurements.

8. Noise power spectra of Ca2+ or Ba2+ currents could be fitted by the sum of two, but not one, Lorentzian components.

9. Tail currents could be fitted by the sum of two exponential components. The corresponding time constants had values close to those obtained with noise analysis.

10. The rising phase of Ca2+ and Ba2+ currents was sigmoid. It could be fitted by the sum of three exponentials. The time constant of the largest amplitude component, τ1, was similar to the time constants of the slow component observed in noise and tail experiments. This time constant also corresponded to the burst duration obtained in single channel measurements.

11. The value of τ1 was larger in 5 mM-Cao and in isotonic Ba2+ than in 5 mM-Bao. Thus, the kinetic properties of Ca2+ channels depend on the nature and concentration of the permeating ion.

12. A simple kinetic scheme is proposed to model the activation pathway of Ca2+ channels.

13. Currents in 1 mM-Cao and 5 mM-Cao showed clear reversals around +53 mV and +64 mV respectively. The outward currents observed above these potentials are most probably due to Cs+ ions flowing through Ca2+ channels.

14. The instantaneous current—voltage relation was obtained from tail current data in the range -70 to +100 mV in 5 mM-Cao. The resulting curve displayed an inflexion point around the reversal potential.

15. Very little inactivation of Ca2+ currents was observed. However, a slow current decline was observed in some cells above +10 mV.

16. Conditioning prepulses to positive potentials had potentiating or depressing effects on Ca2+ currents depending on whether the test pulse lay below or above the maximal current potential. The potentiating effect may be linked to the slowest component of the current rise observed below +10 mV. The depressing effect may be related to the slow decline obtained above +10 mV.

17. Analysis of ensemble variance and of tail current amplitudes suggested that the opening probability of Ca2+ channels was at least 0·9 above +40 mV.

18. A slow rundown of Ca2+ currents was observed in whole-cell recordings. The speed of the rundown was dependent on intracellular Ca2+ concentration. The rundown was apparently due to a progressive elimination of the channels available for activation.

19. The density of Ca2+ channels (before rundown) was estimated at 5-15/μm2.

20. In cell-attached experiments, inward current channels were often seen to follow action potentials. These events did not appear to be the usual Na+ and Ca2+ currents. They were probably due to cation influx of either Na+ or Ba2+, depending on the pipette solution, through Ca2+-dependent channels. Voltage-independent single channel activity observed in whole-cell and outside-out recordings may be due to the same channels.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1982.sp014394

Sodium and calcium channels in bovine chromaffin cells

https://www.degruyter.com/view/j/crll.2004.2004.issue-572/crll.2004.048/crll.2004.048.pdf

Primary cyclotomic units and a proof of Catalans conjecture

Molecular Determinants of High Affinity Binding of α-Scorpion Toxin and Sea Anemone Toxin in the S3-S4 Extracellular Loop in Domain IV of the Na+ Channel α Subunit

Summary
Tricaine methane-sulfonate (MS-222) is one of the most widely used anaesthetics for poikilotherms worldwide. This paper outlines its anaesthetic efficacy and dosage in fish and legislation for its use, fish stress responses to MS-222 anaesthesia and its effect on fish physiology and blood properties, pharmacokinetics, genotoxicity, immune response, potential interference with fish hepatic cytochrome P450 spectra, and its impact on nerve sensitivity. Key questions arising from the available data are analysed, such as regulatory constraints on its use, the need for the standardization of buffering protocols, and interdependencies of the factors impacting the specific applicative efficacy of MS-222. Current research has provided an abundance of data on MS-222 use in fish, although the applications within these studies are often impractical at the farming level. Specific emphasis is therefore placed on highlighting application strategies on a practical basis, presenting potential future research on topics that require in-depth analysis (preparation and storage of anaesthetic solutions, pre-anaesthetic sedation and stress reduction, cortisol response in aquarium fish, toxicity of MS-222 metabolites, and possible immunodepressive properties). Additionally, both from a scientific and practical perspective, it is necessary to have a better understanding of safety margins, induction, immersion and recovery times for many (marine and freshwater, farmed and ornamental) fish species in order to achieve optimal utilization.

/pdf/tricaine-methane-sulfonate-ms-222-application-in-fish-4t14gd0gzb.pdf

Tricaine methane-sulfonate (MS-222) application in fish anaesthesia

Modification of sodium inactivation in myelinated nerve by Anemonia toxin II and iodate. Analysis of current fluctuations and current relaxations

Comparison of the effects of Anemonia toxin II on sodium and gating currents in frog myelinated nerve.

Differences between K channels in the nodal membrane of sensory and motor myelinated nerve fibres of the frog were investigated by fluctuation analysis. Spectral densities,S(f), between 3 Hz and 5 kHz were determined from K-current fluctuations measured between 145 and 460 ms after the onset of depolarizationsV between 16 and 80 mV. Fits by the sum of a 1/f component and Lorentzian spectra corresponding to Hodgkin-Huxleyn4-kinetics gave significant deviations from the measured spectra. The best fit was obtained by:

$$S(f) = {{S_1 } \mathord{\left/ {\vphantom {{S_1 } {[1 + ({f \mathord{\left/ {\vphantom {f f}} \right. \kern-\nulldelimiterspace} f}_c )^{1.5} ]}}} \right. \kern-\nulldelimiterspace} {[1 + ({f \mathord{\left/ {\vphantom {f f}} \right. \kern-\nulldelimiterspace} f}_c )^{1.5} ]}} + S_2 .$$

Differences between K channels in motor and sensory nerve fibres of the frog as revealed by fluctuation analysis.

Kinetics of the slow variation of peak sodium current in the membrane of muelinated nerve following changes of holding potential or extracellular pH

Fluctuation analysis of Na+ channels modified by batrachotoxin in myelinated nerve.

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