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Biomedical subjects

J R Elliott

Publications and source records attributed to J R Elliott.

At least 37 records · Page 2Linked to original sources
PubMed1992

Effects of n-alkanols and a methyl ester on a transient potassium (IA) current in identified neurones from Helix aspersa.

1. A two-microelectrode voltage clamp was used to determine the effects of n-butanol, n-hexanol, n-octanol, n-decanol and methyl hexanoate on a transient potassium (IA) current in identified Helix aspersa neurones. Experiments were carried out at a temperature of 10-12 degrees C. 2. Each n-alkanol reversibly reduced the amplitude of the IA current. Logarithmic dose-response curves for the current reduction by each homologue were sigmoidal and had slope factors of around four. The concentrations required to reduce the peak (with time) current at -30 mV by 50% (ED50 +/- fitted standard error) were: 57 +/- 5 mM (n-butanol); 2.0 +/- 0.1 mM (n-hexanol); 0.28 +/- 0.02 mM (n-octanol) and 0.016 +/- 0.001 mM (n-decanol). Methyl hexanoate also reduced the current amplitude, with an ED50 of 1-2 mM. The Helix IA current thus showed a similar sensitivity to n-alkanols to that of squid and rat sodium currents but was rather more sensitive than the squid delayed rectifier potassium current. 3. The n-alkanol ED50 concentrations were used to calculate a standard free energy per methylene group for adsorption to a site of action in the cell of -3.1 +/- 0.2 kJ/mol. This suggested a hydrophobic site or sites of action. The regularity of the change in free energy with chain length was maintained up to, and including, n-decanol. This implied that the site(s) could accommodate a ten-carbon chain as readily as an eight-carbon chain. 4. The voltage dependencies of IA current activation and steady-state inactivation were not consistently altered by treatment with n-alkanols at concentrations around or above their current suppression ED50 concentrations. 5. The kinetics of current activation and inactivation were affected, particularly by lower chain length compounds. At 60 mM n-butanol reduced the time constant for development of inactivation of open channels (tau b) by 56%, while 0.016 mM n-decanol produced only a 13% reduction. n-Butanol (60 mM) also caused a substantial (76%) reduction in the time constant for development of inactivation in channels which were presumed to be closed. The effects of n-alkanols on the current time-to-peak (tc) were complex, showing both increases and decreases, but these actions also declined with chain length. Methyl hexanoate (1 mM) reduced tau b by around 30% and tc by around 20%. 6. n-Alkanols have now been shown to inhibit a number of voltage-gated ion conductances.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1991

The influence of charge on the effects of n-octyl derivatives on sodium current inactivation in rat sensory neurones.

1. The whole-cell patch-clamp technique was used to determine the actions of n-octyl sulphate (OS-) anions and n-octyl trimethylammonium (OTMA+) cations on sodium current steady-state inactivation and peak amplitude in cells isolated from dorsal root ganglia of neonatal rats and maintained in short-term tissue culture. This paper concentrates on the effects of external addition but the actions of internal OS- and OTMA+ are briefly considered. 2. The main action of external OS- was to cause a hyperpolarizing shift in the voltage dependence of the steady-state inactivation parameter, h infinity. At 1-6 mM OS- caused a shift in the mid-point of the h infinity curve of around -30 mV. The shape of the h infinity curve was altered in a concentration-dependent manner. Internal OS- had no discernible effect on the shape or position of the h infinity curve. 3. External OS- produced a relatively small (less than 25%) reduction in the maximum current achieved following pre-pulses sufficiently negative to remove resting steady-state inactivation. 4. By contrast, external OTMA+ had little effect on the voltage dependence of h infinity and produced a small, but significant, increase in the maximum sodium current. 2 mM-external OTMA+ moved the mid-point of the h infinity curve (Vh) 5 mV in the depolarizing direction (relative to the mean of control and reversal curves) and increased the maximum current by 13%. One millimolar internal OTMA+ induced a frequency-dependent current block. 5. Raising the external calcium concentration from 2 to 20 mM (in the presence of 2 mM-magnesium and 5 mM-cobalt) caused an 18 mV depolarizing shift in Vh, consistent with a reduction in the negativity of an external surface charge. The maximum current was reduced by 22%. 6. One millimolar OS- reduced the surface potential of egg phosphatidylcholine (EPC) monolayers (at an air-0.5 M-NaCl interface) by 35 mV but 1 or 2 mM-OTMA+ produced only a 2-3 mV increase. The quantitative agreement between the effects of OS-, on Vh in the rat and on monolayer surface potential, decreased with increasing concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkanesulfonates↗
PubMed1990

Effects of age and sex on bone density at the hip and spine in a normal Caucasian New Zealand population.

We have studied a normal adult caucasian population (462 females, 264 males age range 20-84) using dual photon absorptiometry to establish patterns of bone reduction at the spine and hip. Subjects were either randomly selected from the electoral roll or volunteers. Bone mineral density reduction at the lumbar spine in females appeared to increase at 40 years and was sustained until 60 years. In males bone mineral density at the spine was preserved. The density at the hip in females decreased throughout adult life beginning before the menopause. In males bone density was preserved at the femoral neck and trochanteric region but not at Wards triangle where reduction occurred throughout life. When compared with other normal populations there was higher bone mineral density at the spine in postmenopausal New Zealand females but no significant difference at the hip.

Absorptiometry, Photon↗
PubMed1989

The effects of homologous series of anaesthetics on a resting potassium conductance of the squid giant axon.

The effects of n-alkanes (n-pentane to n-octane), n-alkanols (n-pentanol to n-undecanol) and two carboxylic esters (methyl pentanoate and methyl octanoate) on the conductance of squid giant axons in a high potassium, zero sodium bathing solution have been examined. Sodium and delayed rectifier potassium channels were as far as possible pharmacologically blocked. A substantial fraction of the measured conductance is attributed to a recently-described, voltage-independent, potassium channel. Anaesthetics block this channel but its sensitivity is markedly different from those of other squid axon ion channels.

Anesthetics↗
PubMed1989

The role of inactivation in the effects of n-alkanols on the sodium current of cultured rat sensory neurones.

1. The whole-cell patch-clamp technique has been used to investigate the actions of n-butanol, n-pentanol, n-hexanol and n-octanol on the sodium current of cells isolated from the dorsal root ganglia (DRGs) of neonatal rats and maintained in short-term tissue culture. 2. The influence of n-alkanols on the level of steady-state inactivation of the sodium current was investigated by a standard two-pulse protocol. All alkanols increased the level of resting inactivation and this was manifested as a hyperpolarizing shift of the relationship between the steady-state inactivation parameter (h infinity) and membrane potential. The mid-point of the h infinity curve was moved by up to -30 mV. 3. The relationship between the shift in the mid-point of the inactivation curve (delta Vh) and aqueous n-alkanol concentration has been derived for each n-alkanol. These are complex in shape and do not appear consistent with a hypothesis that the increase in inactivation results from 1:1 binding of an alkanol molecule to a single site on the channel protein. 4. The aqueous concentrations used ranged from 70 mM-n-butanol to 0.05 mM-n-octanol. However, equal fractional saturations of n-alkanols produced approximately equal shifts in the h infinity curve, particularly in the range 0.01-0.07 saturated. This implies a hydrophobic site of action, with a standard free energy per methylene group for adsorption to the site from the aqueous phase of ca -3.2 kJ/mol. 5. The increase in resting inactivation was not the sole means by which n-alkanols reduced the sodium current. The current was still reduced in cells pre-pulsed to sufficiently negative potentials to remove steady-state inactivation even in the presence of alkanols. The concentration required to reduce the current by 50% (ED50) has been interpolated for each n-alkanol. From these data it was estimated that the standard free energy per methylene group for adsorption to the site of action was ca -3.1 kJ/mol, similar to that calculated for the effect on inactivation. The concentration dependence of this residual block indicated the involvement of more than one n-alkanol molecule. 6. The n-alkanols increase the level of inactivation of rat DRG cell sodium channels at potentials around the resting membrane potential and this effect contributes to their local anaesthetic action.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1988

Observations concerning the nature of sites of anaesthetic action in Gammarus.

We report the effects of n-alkanols (n-butanol to n-octanol), methyl carboxylic esters (methyl propionate to methyl octanoate) and n-alkyl ketones (2-pentanone to 2-nonanone) on a fast reflex escape response to a mechanical stimulus in Gammarus. ED50 concentrations and the relationships between In ED50 and chain length are given for each compound and series. For the n-alkanols, this relationship is well fit by a straight line (r2 = 1.000), with no evidence for a plateau between hexanol and heptanol. The standard free energy of transfer of a methylene group from water to a site of action in Gammarus is given for each series. The value for the esters is significantly smaller than that for the n-alkanols and ketones. These free energies are compared with those from other model systems, with the conclusion that further investigation of the differences between n-alkanols and esters will increase our understanding of the physico-chemical nature of the site(s) of action of general anaesthetics.

Alcohols↗
PubMed1987

Local anaesthetic effects of benzene and structurally related molecules, including benzocaine, on the squid giant axon.

(1). The effects of benzene and several of its derivatives on sodium currents in the voltage-clamped squid giant axon have been studied. Substances tested were benzene, aniline, benzyl alcohol, propiophenone, 4-amino-propiophenone, methyl benzoate, ethyl benzoate, and 4-amino ethyl benzoate (benzocaine). (2.) All substances tested reduced the sodium current in both intact axons and axons internally perfused with CsF. (3.) There were four major actions of benzene on the sodium current: (a) an increase in the resting level of inactivation, (b) an increase in the depolarization required to produce the maximum current, (c) a decrease in the maximum sodium conductance, and (d) an increase in the rate of inactivation. (4.) 4-amino ethyl benzoate (benzocaine) had actions on the sodium current which were very similar to those of benzene with the exception that the rate of inactivation was scarcely affected and, at comparable shifts, the slope of the steady state inactivation curve was slightly smaller. (5.) The results obtained with the substances structurally intermediate between benzene and 4-amino ethyl benzoate allow some conclusions to be drawn as to the role of each functional group.

Anesthetics, Local↗
PubMed1987

The mechanisms of sodium current inhibition by benzocaine in the squid giant axon.

(1) The effects of benzocaine on the ionic currents in the voltage-clamped squid giant axon have been examined under various conditions; intact axons, axons internally perfused with CsF and axons dialysed with tetraethylammonium ions were used. (2) Both the steady state outward (potassium) current and the early transient (sodium) current were reduced by ca. 50% by benzocaine (1 mM). (3) Plots of the changes produced by benzocaine (1 mM) in the Hodgkin-Huxley parameters for the steady state activation (m infinity), the steady state inactivation (h infinity) and the time constants (tau m and tau h) for activation and inactivation of the sodium current are shown. The m infinity and h infinity curves are shifted in positive and negative directions respectively on the voltage axis. The time constants are not greatly affected. (4) In axons in which the sodium current inactivation had been largely removed by treatment with chloramine T, the sodium current was still reduced by ca. 50% by 1 mM benzocaine and the positive shift in activation remained unchanged. (5) The dependence on benzocaine concentration (for less than or equal to 2 mM) of the peak sodium current reduction and the shift in steady state inactivation have been determined. (6) It is concluded that in the squid axon the effects on inactivation are not the main reason for the reduction of the sodium current by benzocaine and that, in common with many other neutral anaesthetics, there are at least two sites at which benzocaine acts.

Animals↗
PubMed1987

Local anesthetic action of carboxylic esters: evidence for the significance of molecular volume and for the number of sites involved.

The effects of the homologous series of carboxylic esters, methyl propionate to methyl decanoate, on the steady-state inactivation of the sodium current in squid axons have been studied. The esters moved the relationship between the inactivation parameter, h infinity, and the membrane potential in the hyperpolarizing direction, thus reducing the number of sodium channels available at the resting potential. The concentration dependence of the shift at the mid-point of the curve of h infinity against potential has been measured for all esters except decanoate, which was almost inactive. Two aspects of these concentration dependences suggest that molecular volume is an important determinant of the effectiveness of each ester. Firstly, there is a sharp decline in activity above methyl hexanoate. This cut-off in activity resembles that for hydrocarbons where it has been suggested [e.g., Haydon, D.A., Urban, B.W. 1983, J. Physiol. (London) 341:411-427] to a result from a decrease in uptake with increasing molecular volume. (Further data for the hydrocarbons n-butane to n-heptane are reported here.) Secondly, the smallest compounds, methyl propionate and methyl butyrate, are less effective than would be predicted if equal membrane concentrations of each ester produced the same shift. The aqueous concentration dependences for these esters indicate that below methyl hexanoate, as the series is descended, progressively higher membrane concentrations are required to produce a given shift. This would be expected if the volume of ester in the membrane, rather than the number of molecules, is important.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics, Local↗
PubMed1987

The effects of external and internal application of disopyramide on the ionic currents of the squid giant axon.

1 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltage-clamped squid axon have been investigated, by use of both extra-axonal and intra-axonal routes of application. 2 Extra-axonal application of 0.1 mM disopyramide produced no significant effects on the membrane currents. External disopyramide at 1.0 mM caused small, poorly reversible inhibition of both sodium and potassium currents. This block was use-dependent and was enhanced by use of test stimuli to more positive membrane potentials. 3 Intra-axonal application of 0.1 mM disopyramide caused a 40% reduction in the first-pulse sodium current (tonic block) and an additional use-dependent block. Analysis of first-pulse currents in terms of the Hodgkin-Huxley formalism indicated that the block resulted mainly from a reduction in the maximum available sodium conductance (gNa); there were no effects on the voltage dependence of the steady-state activation and inactivation parameters, m infinity and h infinity. 4 The use-dependent actions of disopyramide were investigated with a double voltage-clamp pulse protocol. The significant use-dependent effects of the drug were a further reduction in gNa and an increase in the time constant of inactivation (tau h). 5 Disopyramide appears to enter a blocking site in the sodium channel which is only readily accessible from the axoplasmic phase. Partition to the site depends on membrane voltage and on the state of the channel gates. Disopyramide binds at a significant rate to both open and inactivated forms of the sodium channel.

Animals↗
PubMed1986

Surface potential changes in lipid monolayers and the 'cut-off' in anaesthetic effects of N-alkanols.

The effects of 0.09 saturated solutions of the n-alkanols n-hexanol to n-tridecanol on the surface (compensation) potential of lipid monolayers have been examined. Actions on monolayers spread from pure egg phosphatidylcholine have been compared with effects on a system containing 2:1 mole ratio of egg phosphatidylcholine and cholesterol. The mean compensation potential for the pure phospholipid system was 475 +/- 9 mV; addition of cholesterol increased the potential to 503 +/- 10 mV. All n-alkanols tested reduced the surface potential in both systems. The reduction was larger in the pure phospholipid system but the difference in effect between lipid systems declined as the n-alkanol chainlength increased, becoming negligible by n-tridecanol. These results are considered in relation to the 'cut-off' in biological activity of n-alkanols around n-tridecanol.

Anesthetics↗
PubMed1985

A quantitative explanation of the effects of some alcohols on gramicidin single-channel lifetime.

The effects of n-decanol, n-hexadecanol, n-octyl(oxyethylene)3 alcohol and cholesterol on gramicidin single-channel lifetime in planar lipid bilayers have been determined. The bilayers used were formed from a solution of monoolein in squalene. Measurements have also been made of the above compounds' effects on membrane thickness (as measured by electrical capacity and optical reflectance technique) and surface tension (as derived from bulk interfacial tension and bilayer-lens contact angle measurements). The reduction in single-channel lifetime caused by the n-alkanols may be accounted for quantitatively in terms of the effects of these compounds on bilayer thickness and surface tension. The n-octyl(oxyethylene)3 alcohol caused an increase in single-channel lifetime which is also consistent with the thickness/tension theory. The reduction in channel lifetime caused by cholesterol, however, was much larger than would be predicted from its effects on bilayer thickness and surface tension.

Alcohols↗
PubMed1985

Inactivation of the sodium current in squid giant axons by hydrocarbons.

The voltage dependence of the steady state inactivation parameter (h infinity) of the sodium current in the squid giant axon is known to be shifted in the hyperpolarizing direction by hydrocarbons and it has been suggested that the shifts arise from thickness changes in the axon membrane, analogous to those produced in lipid bilayers (Haydon, D. A., and J. E. Kimura, 1981, J. Physiol. [Lond.], 312:57-70; Haydon, D. A., and B. W. Urban, 1983, J. Physiol. [Lond.], 338:435-450; Haydon, D. A., J. R. Elliott, and B. M. Hendry, 1984, Curr. Top. Membr. Transp., 22:445-482). This hypothesis has been tested systematically by examining the effects of a range of concentrations of cyclopentane on the high-frequency capacitance per unit area both of the axonal membrane and of lipid bilayers formed from monoolein plus squalene. A similar comparison has been made for cyclopropane and n-butane, both at a pressure of 1 atm. The results are consistent with the notion that thickness increases in the axolemma produce the shifts in h infinity. Except at very high concentrations, however, the thickness changes in the lipid bilayer were too small to account for the h infinity shifts. A possible explanation of this finding is discussed.

Animals↗
PubMed1985

Further evidence that membrane thickness influences voltage-gated sodium channels.

The short-chain phospholipid, diheptanoyl phosphatidylcholine, at 520 microM, reduced the maximum inward sodium current in voltage-clamped squid giant axons by greater than 50%. Analysis of these currents by means of the Hodgkin-Huxley equations showed this reduction to be mainly the result of a large depolarizing shift in the voltage dependence of the steady state activation parameter, m infinity. The voltage dependence of the steady state inactivation parameter, h infinity, was also moved in the depolarizing direction and the axonal membrane capacitance per unit area measured at 100 kHz was increased. A longer chain length derivative, didecanoyl phosphatidylcholine, had no significant effect on the axonal sodium current at concentrations of 3.7 and 18.5 microM. Dioctanoyl phosphatidylcholine was intermediate in its effects, 200 microM producing approximately the same current suppression as 520 microM diheptanoyl phosphatidylcholine, together with depolarizing shifts in m infinity and h infinity. These effects may be contrasted with those of the normal and cyclic alkanes (1-3), which tend to move both m infinity and h infinity in the hyperpolarizing direction and to reduce the capacitance per unit area at 100 kHz. The above results are all consistent with the hypothesis that small hydrocarbons thicken, while short-chain phospholipids thin, the axonal membrane. Thus membrane thickness changes may be of considerable importance in determining the behavior of the voltage-gated sodium channel.

Animals↗