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A comparative study of anaesthetic agents on high voltage activated calcium channel currents in identified molluscan neurons

18 Dec 2020-bioRxiv (Cold Spring Harbor Laboratory)-

TL;DR: Using the two electrode voltage clamp configuration, a high voltage activated whole-cell Ca2+ channel current (IBa) was recorded from a cluster of neurosecretory ‘Light Yellow’ Cells (LYC) in the right parietal ganglion of the pond snail Lymnaea stagnalis, showing a reversible concentration-dependent depression of current amplitude in the presence of the volatile anaesthetics halothane, isoflurane and sevofl Lurane.

AbstractO_LIUsing the two electrode voltage clamp configuration, a high voltage activated whole-cell Ca2+ channel current (IBa) was recorded from a cluster of neurosecretory Light Yellow Cells (LYC) in the right parietal ganglion of the pond snail Lymnaea stagnalis. C_LIO_LIRecordings of IBa from LYCs show a reversible concentration-dependent depression of current amplitude in the presence of the volatile anaesthetics halothane, isoflurane and sevoflurane, or the non-volatile anaesthetic pentobarbitone at clinical concentrations. C_LIO_LIIn the presence of the anaesthetics investigated, IBa measured at the end of the depolarizing test pulse showed proportionally greater depression than that at measured peak amplitude, as well as significant decrease in the rate of activation or increase in inactivation or both. C_LIO_LIWithin the range of concentrations used, the concentration-response plots for all the anaesthetics investigated correlate strongly to straight line functions, with linear regression R2 values > 0.99 in all instances. C_LIO_LIFor volatile anaesthetics, the dose-response regression slopes for IBa increase in magnitude, in order of gradient: sevoflurane, isoflurane and halothane, a sequence which reflects their order of clinical potency in terms of MAC value. C_LI

Topics: Isoflurane (50%)

Summary (2 min read)

INTRODUCTION

  • General anaesthetics form a chemically diverse group of agents which have in common the property of inducing narcosis and analgesia to varying degrees.
  • In vertebrate tissues, calcium channels have been classified by their electrophysiological and biochemical properties.

METHODS

  • Briefly, intact central ganglia were pinned out in the perfusion chamber, ventral surface uppermost, and the sheath of connective tissue removed from the right parietal ganglion with fine ground forceps.
  • The whole cell currents measured were Ba2+ currents rather than Ca2+ currents per se.
  • CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
  • The anaesthetic-air mixture was bubbled at 1 litre per minute into a small volume (about 150 ml) of recording solution in a 250 ml flask and vented though a closed extraction system.
  • BioRxiv preprint Optimum results were achieved when the preparation was allowed to equilibrate in recording solution 4−6 minutes before inserting microelectrodes into the selected cell.

1) The properties of whole cell calcium channel currents recorded from LYCs

  • Two electrode voltage clamp recordings from LYCs in Lymnaea revealed large inward currents elicited by depolarizing the cells from a holding potential of −70 mV in the recording solution with Ba2+ as the charge carrier.
  • The copyright holder for this preprintthis version posted December 18, 2020.
  • .CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
  • The plots of IBa(max) for Itrans and Isus against holding potential fit quite well to a single sigmoidal shaped curve and there were no significant differences between the level of steady state inactivation of any of these currents at each holding potential.

2) The effect of anaesthetics on IBa

  • Calcium channel currents recorded from LYCs were reversibly depressed in the presence of all the anaesthetics tested.
  • There was also a tendency for activation rates to decrease and inactivation to increase instep with increasing anaesthetic concentration.
  • At the highest concentrations used, activation rates were significantly decreased for halothane, isoflurane and pentobarbitone and inactivation significantly decreased for isoflurane sevoflurane and pentobarbitone (Table 2).
  • Mean maximum slope of IBa traces, measured before and after (in) the slope turning point at peak amplitude.
  • Significant statistical differences of slopes compared to control values (marked with an asterisk) were evaluated using Student’s two tailed, paired t-test at the 5% level, n = 5 for each data set.

3) The effect of anaesthetics on the current-voltage relationship of IBa

  • To determine the effect of drugs on the current-voltage relationship, I−V plots were constructed for mean peak and end-pulse current recorded from several cells and normalized to control values of IBa(max).
  • Similar families of I−V curves were produced for isoflurane, sevoflurane and pentobarbitone, which differed principally in their dose-response profile.
  • The slope coefficients for peak currents show wider variation compared to those of end-pulse currents, where the regression slopes are divergent.
  • Hence, the relative ability of the volatile anaesthetics to depress IBa are different when comparing peak and end-pulse IBa(max) regressions of dose-response.
  • CC-BY-NC-ND 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

DISCUSSION

  • The aim of these experiments was to compare the effects of a number of general anaesthetic agents on whole cell calcium channel currents recorded from identified light yellow cells, located in the central ganglia of Lymnaea stagnalis.
  • The results show that these agents alter calcium channel function, represented as the dose-dependent depression of a calcium channel current, often associated with a decreased rate of activation and accelerated inactivation.
  • IBa appears to have two HVA components, Isus and Itrans, which were indistinguishable by their steady state inactivation kinetics and the pharmacological probes used in this study.
  • The copyright holder for this preprintthis version posted December 18, 2020.
  • The authors results show that a variety of general anaesthetics, including the non-volatile pentobarbitone, produce dose-dependent depression of whole cell HVA Ca2+ channel current, IBa.

HIROTA, K., KUDO, M., KUDO, T., KITAYAMA, M. KUSHIKATA, T., LAMBERT, D.G. & MTSUKI, A. (2000).

  • Barbiturates inhibit K+-evoked noradrenaline and dopamine release from rat striatal slices – involvement of voltage sensitive Ca2+ channels.
  • Halothane blocks low-voltage-activated calcium current in rat sensory neurons.

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A COMPARATIVE STUDY OF ANAESTHETIC AGENTS ON HIGH VOLTAGE ACTIVATED CALCIUM
CHANNEL CURRENTS IN IDENTIFIED MOLLUSCAN NEURONS
Terrence J. Morris
1
, Philip M. Hopkins
2,3
and William Winlow
4,5
1
Department Science and Technology - Biology, Douglas College, 700 Ryal Avenue, New Westminster, British Columbia,
Canada;
2
Leeds Institute of Medical Research at St James’s, School of Medicine, University of Leeds, Leeds, United Kingdom;
3
Malignant Hyperthermia Investigation Unit, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds,
LS9 7TF, United Kingdom;
4
Department of Biology, University of Naples Federico II, Via Cintia 26, 80126, Naples, Italy;
5
Institute of Ageing and Chronic Diseases, University of Liverpool, Liverpool, United Kingdom.
Corresponding author: William Winlow
Key Words: General anaesthetic, calcium channels, Lymnaea, light yellow cells
SUMMARY
1. Using the two electrode voltage clamp configuration, a high voltage activated whole-cell Ca
2+
channel current (I
Ba
) was recorded from a cluster of neurosecretory ‘Light Yellow’ Cells (LYC) in the
right parietal ganglion of the pond snail Lymnaea stagnalis.
2. Recordings of I
Ba
from LYCs show a reversible concentration-dependent depression of current
amplitude in the presence of the volatile anaesthetics halothane, isoflurane and sevoflurane, or the
non-volatile anaesthetic pentobarbitone at clinical concentrations.
3. In the presence of the anaesthetics investigated, I
Ba
measured at the end of the depolarizing test
pulse showed proportionally greater depression than that at measured peak amplitude, as well as
significant decrease in the rate of activation or increase in inactivation or both.
4. Within the range of concentrations used, the concentration-response plots for all the
anaesthetics investigated correlate strongly to straight line functions, with linear regression R
2
values
> 0.99 in all instances.
5. For volatile anaesthetics, the dose-response regression slopes for I
Ba
increase in magnitude, in
order of gradient: sevoflurane, isoflurane and halothane, a sequence which reflects their order of
clinical potency in terms of MAC value.
.CC-BY-NC-ND 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted December 18, 2020. ; https://doi.org/10.1101/2020.12.17.423182doi: bioRxiv preprint

INTRODUCTION
General anaesthetics form a chemically diverse group of agents which have in common the
property of inducing narcosis and analgesia to varying degrees. They tend to depress neuronal
excitability and synaptic transmission, though detailed responses vary for the particular drug and are
often cell specific. Work with both vertebrate and invertebrate neuronal preparations has shown both
[Ca
2+
]
i
(intracellular calcium concentration) and Ca
2+
influx to be dramatically affected by a number of
anaesthetics. Increases in [Ca
2+
]
i
in the presence of volatile anaesthetics has been shown in CA1
hippocampal cells in rats (Mody et al., 1991) and cultured molluscan neurons in the absence of
extracellular Ca
2+
(Ahmed et al, 2020; Winlow et al., 1995), implying an anaesthetic triggered release
of Ca
2+
from intracellular stores. Voltage-gated calcium channels within the cell membranes also
appear to be important targets for these agents and calcium influx has been shown to decrease in a
dose-dependent manner in their presence (Yar & Winlow, 2016). T-type calcium currents (see below)
have also been shown to be differentially sensitive to volatile anaesthetics at clinical concentrations in
various cell types (McDowell et al., 1999). These are interesting findings but the dual action of Ca
2+
adds complexity to understanding global effects on cell activity. Ca
2+
is also a major second messenger
and plays a central role in the control of a variety of cell processes, so that alterations of calcium influx
and [Ca
2+
]
i
have the potential to modify numerous, interrelated neuronal functions. Transient
increases in [Ca
2+
]
i
may be initiated by release from intracellular storage sites associated with the
endoplasmic reticulum (Yamaguchi, 2019) and/or an increase in Ca
2+
permeability of the plasma
membrane associated with neural activity or the actions of neurotransmitters (Miller, 1991) and may
operate by a calcium-induced calcium release mechanism (Sandler and Barbara, 1999; Petrou et al,
2017).
In vertebrate tissues, calcium channels have been classified by their electrophysiological and
biochemical properties. Nowycky et al. (1985) identified three types of Ca
2+
channel in whole-cell
currents recorded from chick dorsal root ganglion cells, called L-type, T-type and N-type. They have
become the prototypes that form the basis of a widely accepted system of calcium channel
classification (Catterall, 2011; Catterall, et al, 2019, 2020) . The transient T-type current is activated
by small depolarisations, termed Low-Voltage-Activated (LVA), whilst sustained L-type currents are
activated by large depolarisations - High-Voltage-Activated (HVA) - and blocked by organic calcium
channel antagonists. N-type currents are also included in the HVA category but can be transient or
sustained. An increasing number of calcium channels from both vertebrate (Hoehn et al., 1993) and
non-vertebrate systems (Pearson et al., 1993) have proven difficult to identify within this scheme.
.CC-BY-NC-ND 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted December 18, 2020. ; https://doi.org/10.1101/2020.12.17.423182doi: bioRxiv preprint

Molluscan neurons in particular can display HVA Ca
2+
currents with conflicting pharmacological and
electrophysiological profiles (Kits & Mansvelder, 1996), but L-type currents have clearly been
identified as the sole HVA current in isolated, cultured pedal I cluster neurons of Lymnaea stagnalis
(Yar and Winlow, 2016).
The molluscan CNS (central nervous system) has several specific advantages for the
neurobiologist exemplified in Lymnaea (Kerkut, 1989; Leake & Walker, 1980); nerve cells are
accessible, relatively simply organised, easily identified and in many cases large enough for two
electrode work. Moreover, volatile anaesthetics produce many changes in behavior and neuronal
activity in Lymnaea that equate well to those found in mammals (McCrohan et al, 1987; Winlow &
Girdlestone, 1988; Girdlestone et al 1989) and facilitate its use as a single “model” system in studies on
anaesthetic mechanisms at behavioral and cellular levels (Winlow, 1984; Winlow, et al, 2018;
Moghadam et al, 2019).
The HVA calcium currents recorded from the cultured pedal I cluster neurons of Lymnaea (Yar
and Winlow, 2016) using single electrode voltage clamp showed a reversible, dose-dependent
suppression of Ba
2+
mediated current by halothane at concentrations ranging between 05 to 40
percent. Here we report on data using the two-electrode voltage clamp technique to investigate
calcium channel currents recorded from the Light Yellow Cell (LYC) group of neurosecretory neurons
in the right parietal ganglion of Lymnaea in the intact brain, which play a general role in body fluid
regulation (Benjamin and Kemenes, 2020). They lie on the ventral lobe of the right parietal ganglion
and can be observed from either the dorsal or ventral surface of the ganglion. LYCs have large somata
and fire spontaneous bursts of spikes (van Swigchem, 1979). Their action potentials have a
prominent shoulder or pseudoplateau phase, believed to be largely Ca
2+
driven (Aldrich, Jr. et al., 1979;
van Swigchem, 1979).
Studies of the effects of general anaesthetics on voltage gated Ca
2+
channels have often involved
the use of a variety of preparations and cell type, frequently at concentrations outside the clinical
range. The purpose of this study was, therefore, to determine the action of a number of general
anaesthetics, at clinical concentrations, on calcium currents recorded from the same identified cell
group in a single model system. In this way the dose-response profile and relative potency of each
agent can be directly compared. Here, we characterize the electrophysiology and pharmacology of the
LYC Ca
2+
currents, and the effects upon them of clinical concentrations of the volatile anaesthetics
halothane, isoflurane and sevoflurane and the systemic anaesthetic sodium pentobarbital, which is
now mostly used in veterinary anesthesia (Lester et al, 2012).
.CC-BY-NC-ND 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted December 18, 2020. ; https://doi.org/10.1101/2020.12.17.423182doi: bioRxiv preprint

METHODS
Snail brains were prepared according to the methods of Benjamin & Winlow (1981) in a HEPES
buffered snail saline (see below) at room temperature, approximately 20 C. Briefly, intact central
ganglia were pinned out in the perfusion chamber, ventral surface uppermost, and the sheath of
connective tissue removed from the right parietal ganglion with fine ground forceps. The inner cell
integument was softened with several drops of protease solution (Pronase from Streptomyces griseus,
Boehringer Mannheim Biochemica, in a solution of 4 mg/ml of snail saline) applied directly to the
ganglia, and washed off thoroughly with saline after about 3 minutes. The preparation was then
perfused continuously at 3.5 ml per minute with aerated saline. After 10-15 minutes the perfusing
medium was switched to the recording solution, also at room temperature, after which a cell within
the LYC cluster was selected for microelectrode penetration.
Solutions - Preliminary dissection and perfusion prior to recording was carried out in a snail saline
(Benjamin & Winlow, 1981) containing (mmol l
-1
): Na
+
594, K
+
20, Mg
2+
20, Ca
2+
40, Cl
380,
HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) 500, and glucose 03. The pH was
corrected to 7.8 with 2M NaOH.
All current measurements were made from cells in the intact brain, bathed in recording solution
which contained (mmol l
-1
): Na
+
65, Cs
+
20, Mg
2+
15, Ba
2+
10, Cl
23, Br
30, tetraethylammonium
(TEA) 30, 4-aminopyridine 10, HEPES 10, glucose 5 and pyruvate 10. The whole cell currents
measured were Ba
2+
currents rather than Ca
2+
currents per se. Ba
2+
was used as the charge carrying
ion since no currents were detectable when Ba
2+
was replaced by Ca
2+
. Possible explanations for this
are first, that the calcium channels in these cells are much more permeant to Ba
2+
than to Ca
2+
,
thereby increasing the signal to noise ratio to a resolvable level and, second, Ca
2+
entering the cell
might produce Ca
2+
-dependent inactivation of the channels being studied. Ba
2+
also has the advantage
that it blocks contaminating K
+
currents, which were further blocked by the presence of TEA
+
and Cs
+
in the recording solution. [Na
+
]
out
was kept low to exclude voltage-dependent Na
+
currents. The
addition of pyruvate was found to increase the recording time of cells considerably. Organic Ca
2+
-
channel blockers, verapamil (Sigma) and nifedipine (Sigma), were dissolved initially in ethanol to give
stock solutions of 1 mg ml
-1
before being diluted in the recording solution to the required
concentration.
.CC-BY-NC-ND 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted December 18, 2020. ; https://doi.org/10.1101/2020.12.17.423182doi: bioRxiv preprint

The pipette filling solution, modified from Orchard et al. (1991), contained
(mmol l
-1
): KCl 2500, calcium buffer ethyleneglycol-bis (-amino-ethyl ether) N,N'-tetra-acetic acid
(EGTA) and K-ATP 10.
Administration of anaesthetics - Volatile anaesthetics were vaporized into air using Ohmeda vaporizers
set to the desired percentage mixture. The anaesthetic-air mixture was bubbled at 1 litre per minute
into a small volume (about 150 ml) of recording solution in a 250 ml flask and vented though a closed
extraction system. Percentage vapour concentration was routinely calibrated using a Normac
anaesthetic agent monitor. Equilibration time was taken as 15 -20 minutes (Girdlestone et al., 1989)
after which a stopper containing an underwater seal air inlet was inserted and the solution used
immediately via a closed delivery system. Millimolar concentrations of isoflurane at 1, 2 and 4% were
determined by gas-liquid chromatography as (mean SD for n = 3): 044 0.05, 076 018 and 1.89
0.37 respectively (in an ideally equilibrated solution a 1% vol/vol concentration of gas represents 042
mM). These values approximate those for equilibrated halothane solutions (Winlow et al., 1998) and
are very close to the normal clinical concentration of halothane in arterial blood (Davies et al., 1972).
The clinical use of pentobarbitone in humans is nowadays rare, although it may be used in
veterinary anesthesia (Lester et al, 2012). Therefore, most uptake studies are on barbiturates used in
contemporary anaesthesia, thiopentone sodium in particular. Thiopentone sodium has the same
clinical potency as pentobarbitone (Dundee, 1974) but possesses contrasting and more desirable
pharmacokinetic properties (Lant, 1982). The concentration range of pentobarbitone used in this
investigation was 200 to 800 M, which equates to approximately 50 to 200 g per ml of recording
solution. The median dose of thiopentone required to induce anaesthesia is about 3.5 mg/kg body
weight, equivalent to approximately 100g/ml plasma concentration (Dundee et al., 1982).
Recording from cells - Micropipettes (resistance 810 M) were pulled on a one stage vertical puller
using filamented borosilicate glass (Clarke Electromedical Instruments). An Axoclamp 2A amplifier
was used to clamp cells and acquire data via proprietary software (PClamp 6.0) running on a 486 DX
33MHz IBM clone PC through an Axoclamp Digidata 1200 digital-analogue interface. Data were
sampled at 5 kHz, with automatic leak subtraction, estimated electronically before each test pulse as
the sum of currents developed during a series of four inverted pulse steps at ¼ amplitude of the test
pulse itself. A Gaussian filter with 500 Hz cut-off was applied to the raw data after acquisition to
attenuate noise.
.CC-BY-NC-ND 4.0 International licenseavailable under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprintthis version posted December 18, 2020. ; https://doi.org/10.1101/2020.12.17.423182doi: bioRxiv preprint

Figures (5)
Citations
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Book
01 Jan 1987
Abstract: Abstract : This book is a compendium of the written contributions submitted by the invited speakers to the 40th Annual Meeting of the Society of General Physiologists. There were also 118 abstracts of contributed papers submitted to this meeting, which have been published in the December 1986 issue of The Journal of General Physiology. Partial Contents: Regulation of Cytosolic Free Calcium, The Plasma Membrane in the Control of the Signaling Function of Calcium, Calcium-permeable Channels in Vascular Smooth Muscle: Voltage-activated, Receptor-operated, and Leak Channels, Calcium and Magnesium Movements in Cells and the Role of Inositol Trisphosphate in Muscle, Receptor-mediated Changes in Intracellular Calcium, Mechanisms Involved in Receptor-mediated Changes of Intracellular Ca2 + in Liver, The Role of Phosphatidylinositides in Stimulus-Secretion Coupling in the Exocrine Pancreas, Modulation of Membrane Transport by Intracellular Calcium, The Role of Cyclic AMP-dependent Phosphorylation in the Maintenance and Modulation of Voltage-activated Calcium Channels, Multiple Roles for Calcium and Calcium-dependent Enzymes in the Activation of Peptidergic Neurons of Aplysia, Calcium Involvement in Intracellular Events, The Relationship Between the Cytosolic Free Calcium Ion Concentration and the Control of Pyruvate Dehydrogenase, Membrane and Microfilament Organization and Vasopressin Action in Transporting Epithelia.

14 citations



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TL;DR: The results suggest that dihydropyridines bind preferentially to the inactivated state of the calcium channel, and that the development of use-dependent block is related to the ionization constants of the compounds.
Abstract: We have investigated the mechanisms of blockade of calcium channel current by the dihydropyridines, eg nisoldipine, nitrendipine, and nicardipine Membrane current was recorded in isolated calf Purkinje fibers using a two-microelectrode voltage-clamp technique, and voltage protocols were designed to identify voltage- and use-dependent block by these compounds systematically Our results show that calcium channel blockade by dihydropyridine derivatives is strongly modulated by membrane potential Block is more pronounced when current is measured from depolarized holding potentials, but in contrast to verapamil, this voltage-dependent block occurs in the absence of repetitive depolarizations Use-dependent block by dihydropyridines is observed at pulse frequencies greater than 1 Hz Our results suggest that dihydropyridines bind preferentially to the inactivated state of the calcium channel, and that the development of use-dependent block is related to the ionization constants of the compounds Furthermor

3 citations


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Abstract: By using both optical and mechano-electric detectors, we have shown that the squid giant axon swells when an action potential is generated. The maximum swelling is reached at the peak of the action potential. The undershoot of the membrane potential is associated with a marked shrinkage of the axon. We have also demonstrated these mechanical changes in axons from which a major portion of the axoplasm has been removed. We have examined the effects of changing the tonicity of the external medium and of applying several chemical reagents.

2 citations


References
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TL;DR: Evidence is reported for the coexistence of three types of Ca channel in sensory neurones of the chick dorsal root ganglion and the dihydropyridine Ca agonist Bay K 8644 strongly increases the opening probability of L-, but not T- or N-type channels.
Abstract: How many types of calcium channels exist in neurones? This question is fundamental to understanding how calcium entry contributes to diverse neuronal functions such as transmitter release, neurite extension, spike initiation and rhythmic firing. There is considerable evidence for the presence of more than one type of Ca conductance in neurones and other cells. However, little is known about single-channel properties of diverse neuronal Ca channels, or their responsiveness to dihydropyridines, compounds widely used as labels in Ca channel purification. Here we report evidence for the coexistence of three types of Ca channel in sensory neurones of the chick dorsal root ganglion. In addition to a large conductance channel that contributes long-lasting current at strong depolarizations (L), and a relatively tiny conductance that underlies a transient current activated at weak depolarizations (T), we find a third type of unitary activity (N) that is neither T nor L. N-type Ca channels require strongly negative potentials for complete removal of inactivation (unlike L) and strong depolarizations for activation (unlike T). The dihydropyridine Ca agonist Bay K 8644 strongly increases the opening probability of L-, but not T- or N-type channels.

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"A comparative study of anaesthetic ..." refers background in this paper

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    [...]


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01 Oct 1984-Nature
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1,244 citations


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833 citations


"A comparative study of anaesthetic ..." refers background in this paper

  • ...In addition, divalent cation concentrations in the perfusate are known to reduce the potency of these drugs (Lee & Tsien, 1983)....

    [...]

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Frequently Asked Questions (2)
Q1. What are the contributions mentioned in the paper "A comparative study of anaesthetic agents on high voltage activated calcium channel currents in identified molluscan neurons" ?

In this paper, the effects of volatile anaesthetics on the Ca2+ channel were investigated in both vertebrate and invertebrate neuronal preparations. 

( Haung et al, 2010 ), but further work will be required to demonstrate this with certainty. It has been shown, using the same model system, that a calcium-dependent pseudoplateau of action potentials is abbreviated in the presence of halothane ( Winlow et al., 1982 ; Winlow et al., 1989 ; Winlow et al., 1992 ). Contrasting with the findings of this study and those of Yar and Winlow ( 2016 ), in which volatile anaesthetics produce little or no displacement of the I−V curve along the voltage axis, DHPs tend to shift calcium channel inactivation to more negative potentials. Conversely, volatile anaesthetic induced depression of Ca2+ influx through L-type and DHP insensitive voltage operated channels is not relieved by increasing [ Ca2+ ] out ( Gross & Macdonald, 1988 ), indicating that anaesthetic action is independent of changes in surface potential.