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Biomedical subjects

D A Haydon

Publications and source records attributed to D A Haydon.

At least 37 records · Page 2Linked to original sources
PubMed1985

Dual effects of internal n-alkyltrimethylammonium ions on the sodium current of the squid giant axon.

The actions of members of the homologous series of alkyl cations CH3 (CH2)n-1 N+ (CH3)3 (Cn TMA) on the sodium current in giant axons of Loligo forbesi have been investigated. The substances tested correspond to n = 6, 8, 10, 12, 14 and 16. These cations only produced significant sodium current suppression when applied inside the axon. Actions on first-pulse sodium currents and use-dependent effects were separately studied. The shorter members of the series (C6TMA and C8TMA) produced suppression of first-pulse sodium currents without causing significant use dependence. The first-pulse suppression arose partly from a positive shift along the voltage axis of the steady-state activation parameter (m infinity) and partly from a reduction in the maximum sodium conductance (gNa). C12TMA and C14TMA produced little first-pulse suppression but caused clear use dependence. C10TMA showed intermediate properties while C16TMA was inactive. The use-dependent actions have been quantitatively investigated using a double-pulse protocol. The results are consistent with a model in which the cations enter a blocking site on the ion-channel via the intra-axonal aqueous phase. The cations appear able to bind to inactivated sodium channels at significant rates. The possible molecular locations of the sites responsible for m infinity shifts and use dependence are discussed. It is argued that the existence of two separate sites may help to explain certain distinctions between the actions of neutral general anaesthetics and clinical local anaesthetics on the sodium channel.

Action Potentials↗
PubMed1984

The influence of n-alkanols on the capacity per unit area of planar lipid bilayers.

The electrical capacities per unit area of planar lipid bilayers formed from monoolein/n-hexadecane, monoolein/ squalane (or squalene) and monoolein/triolein have been measured in the presence of a range of n-alkanols. For monoolein/n-hexadecane bilayers, the effects of the n-alkanols are complicated but can be rationalized in terms of the likely changes in lipid chain order and the influence of the n-alkanol in the Plateau-Gibbs border. Monoolein/ squalane (or squalene) and monoolein/triolein bilayers exhibit behaviour quite different from the n-hexadecane membranes. For both the squalane and triolein bilayers the shorter chain alkanols increase the capacity per unit area while the longer homologues have little effect. These results help to account for the influence of the n-alkanols on gramicidin single-channel lifetimes.

Alcohols↗
PubMed1984

The asymmetrical effects of some ionized n-octyl derivatives on the sodium current of the giant axon of Loligo forbesi.

The effects of octyltrimethylammonium ions (OTMA+), octyl sulphate ions (OS-) and octanoic acid (OA) on the sodium current of the voltage-clamped squid giant axon have been investigated using intracellular and extracellular application of the test substances. OTMA+ applied externally at concentrations of 0.8-5.0 mM produces a small reversible increase in the peak inward sodium current in both intact and CsF-perfused axons. Intracellular application of OTMA+ at 0.8 mM to CsF-perfused axons causes a reversible 50% suppression of peak inward sodium current. The inhibition of peak inward current by internal OTMA+ arises largely from a shift of the steady-state activation parameter (m infinity) in the depolarizing direction along the voltage axis. There is little use dependence of the current suppression by OTMA+ OA applied either internally or externally is more effective at suppressing peak inward sodium current at pH 6.0 than at pH 7.4. At pH 6.0 external application of 5 mM-OA to perfused axons causes approximately 60% suppression. This is associated with a depolarizing shift of m infinity of about 13 mV and a hyperpolarizing shift of the steady-state inactivation (h infinity) curve of about 4 mV. The effects of internal and external OA are broadly similar except that the h infinity shift is not seen with internal application. OS- at concentrations above 2.0 mM produces complete irreversible loss of sodium current. At 2.0 mM, OS- produces 10% current suppression and a small depolarizing shift of the m infinity curve. Internal and external applications of OS- differ little except that external OS- causes a 25% increase in the time constant of activation (tau m). The possible origins of these effects are discussed. It is proposed that the shift of m infinity caused by internal OTMA+ is due to a diminution of the lipid dipole potential at the internal surface of the membrane caused by OTMA+ adsorption. This effect could also account for the m infinity shift caused by OA. The results showing that OA produces shifts of opposite sign in the voltage dependence of m infinity and h infinity are discussed with respect to their implications for models of sodium channel gating.

Action Potentials↗
PubMed1984

Anaesthetic action of esters and ketones: evidence for an interaction with the sodium channel protein in squid axons.

The effects of methyl butyl ketone, methyl heptyl ketone and methyl pentanoate on the sodium current of the squid giant axon have been examined. The peak inward current in intact axons was reduced reversibly by each substance. Sodium currents were recorded in intracellularly perfused axons before and during exposure to the test substances and the records were fitted with equations similar to those proposed by Hodgkin & Huxley (1952). Shifts in the voltage dependence of the steady-state activation and inactivation parameters (m infinity and h infinity), reductions in the peak heights of the activation and inactivation time constants (tau m and tau h) and changes in the maximum sodium conductance (gNa) caused by these substances have been tabulated and compared with the effects of methyl octanoate (Haydon & Urban, 1983b). Each compound shifted the voltage dependence of the steady-state inactivation parameter in the hyperpolarizing direction and that of the steady-state activation parameter in the depolarizing direction. The shifts produced by the ketones are compared with those produced by methyl pentanoate and by methyl octanoate. The possible role of an interaction between the carbonyl oxygen of the test substance and the sodium channel protein in producing the h infinity shift is discussed. The peak time constants are reduced and the voltage dependences of tau m and tau h are shifted in a direction commensurate with the shifts in steady-state properties. The maximum sodium conductance is not much affected either by the ketones or by methyl pentanoate. Large reductions in peak inward current coupled with little effect on gNa have been reported for the n-alkanols and other surface-active compounds (Haydon & Urban, 1983b). This lack of a large effect on gNa indicates that whatever direct interaction does take place between the test substance and the channel protein, it does not result in a blockage of the channel.

Animals↗
PubMed1983

The effects of bilayer thickness and tension on gramicidin single-channel lifetime.

Measurements have been made of gramicidin single-channel lifetimes in monoacylglycerol bilayers chosen so that their thickness ranged from above to below the length of the gramicidin channel. Contact angles, electrical capacities and bulk-phase interfacial tensions have also been determined for these systems. The mean channel lifetime decreased with the hydrocarbon thickness of the membrane until the latter reached 2.2 nm, after which the lifetime was relatively constant. A theoretical model has been proposed which relates the mean channel lifetime (or dissociation constant) to both the thickness and the tension of the bilayers. The analysis of the present results and of those of previous studies has led to the idea that aggregates of water molecules may play an important rôle in the dissociation of the gramicidin channel.

Glycerides↗
PubMed1983

Tensions and free energies of formation of "solventless" lipid bilayers. Measurement of high contact angles.

A method is described for the accurate measurement of the interfacial tension of lipid bilayer membranes containing little or no solvent. The tensions were obtained from the interfacial tensions of the equilibrium film-forming solution in the Plateau-Gibbs border, measured by conventional techniques, and the contact angle between the border and the bilayer. The contact angles in these systems are large (greater than 10 degrees) and were estimated by a new method that involved the injection of small known volumes of lipid solution into the bilayer so as to form a lens. Results have been obtained for monoolein-triolein, monoolein-squalene, and monoolein-squalene-decane systems. Half bilayer tensions in these systems were up to approximately 1 mN m-1 less than the single interface tensions. Although bilayer tension tended to increase with bilayer thickness, the interdependence of these quantities varied with the alkane solvents present. In the monoolein-squalene-decane systems, small concentrations of decane have a larger effect on tension than on thickness. Free energies of formation of the near-solventless bilayers were much greater than estimated from the simple application of Lifshitz theory.

Lipid Bilayers↗
PubMed1983

The action of hydrocarbons and carbon tetrachloride on the sodium current of the squid giant axon.

The effects of the n-alkanes propane to hexane, cyclopropane, cyclopentane and cyclohexane and carbon tetrachloride on the ionic currents and electrical capacity of the squid giant axon membrane have been examined. Both the peak inward and steady-state outward currents were reduced reversibly by each substance, though propane at 1 atm had very little effect. The membrane capacity at 100 kHz was reduced by all substances except propane at 1 atm. Na currents were recorded in intracellularly perfused axons before and during exposure to the hydrocarbons and the records were fitted with equations similar to those proposed by Hodgkin & Huxley (1952). Shifts in the curves of the steady-state activation and inactivation parameters (m infinity and h infinity) against membrane potential, changes in the peak heights of the activation and inactivation time constants (tau m and tau h) and reductions in the maximum Na conductance (gNa) have been tabulated. The effects of the various hydrocarbons and carbon tetrachloride on the parameters of the Hodgkin-Huxley equations suggest that the suppression of the Na current by these substances originates from several different phenomena. The underlying physico-chemical events are considered in the light of the observed capacity changes and of information on artificial pore-containing membranes.

Action Potentials↗
PubMed1983

The action of alcohols and other non-ionic surface active substances on the sodium current of the squid giant axon.

The effects of several n-alkanols and n-alkyl oxyethylene alcohols, methyl octanoate, glycerol 1-monooctanoate and dioctanoyl phosphatidylcholine on the ionic currents and electrical capacity of the squid giant axon membrane have been examined. The peak inward current in voltage-clamped axons was reduced reversibly by each substance. For n-pentanol to n-decanol the concentrations required to suppress the peak inward current by 50% were determined. From these data, it was estimated that the standard free energy per CH2 for adsorption to the site of action was -3.04 kJ mole-1, as compared with -3.11 kJ mole-1 for adsorption into phospholipid bilayers or an n-alkane/aqueous solution interface. The membrane capacity at 100 kHz was not greatly by any of the test substances at concentrations which reduced the inward current by 50%. Na currents under voltage clamp were recorded in intracellularly perfused axons before, during and sometimes after exposure to the test substances and the records were fitted with equations similar to those proposed by Hodgkin & Huxley (1952). Shifts in the curves of the steady-state activation and inactivation parameters (m infinity and h infinity) against membrane potential, changes in the peak heights of the activation and inactivation time constants (tau m and tau h) and reductions in the maximum Na conductance (gNa) have been tabulated. All of the test substances shifted the voltage dependence of the steady-state activation in the depolarizing direction and lowered the peak time constants for both activation and inactivation. The origins of these effects, and of the differences in the present results from those of the hydrocarbons (Haydon & Urban, 1983), have been discussed in terms of the physico-chemical properties of the two groups of substances and with reference to their effects on artificial membranes.

Alcohols↗
PubMed1983

The effects of some inhalation anaesthetics on the sodium current of the squid giant axon.

The effects of diethyl ether, methoxyflurane, halothane, dichloromethane and chloroform on the ionic currents and electrical capacity of the squid giant axon have been examined. The peak inward current in voltage-clamped axons was reduced reversibly by each substance. Sodium currents under voltage clamp were recorded in intracellularly perfused axons before, during, and sometimes after exposure to the test substances, and the records were fitted with equations similar to those proposed by Hodgkin & Huxley (1952). Shifts in the dependence of the steady-state activation and inactivation parameters (m infinity and h infinity) on membrane potential, reductions in the peak heights of the activation and inactivation time constants (tau m and tau h) and decreases in the maximum Na conductance (gNa) have been tabulated. For each of the anaesthetics the steady-state inactivation curve was shifted in the hyperpolarizing direction though less markedly than for the hydrocarbons. The steady-state activation curve was in each instance shifted in the depolarizing direction, as for the alcohols and other surface active substances. In common with both the hydrocarbons and the surface active substances the peak time constants were invariably reduced. The membrane capacity at 100 kHz was affected significantly only by methoxyflurane, where decreases of ca. 9% were observed for 3 mM solutions. The extent to which the results can be accounted for in terms of the perturbation of membrane lipid has been discussed.

Anesthetics↗
PubMed1982

The influence of n-alkanols and cholesterol on the duration and conductance of gramicidin single channels in monoolein bilayers.

The mean lifetime of gramicidin A channels in bilayers formed from monoolein and squalane was sharply reduced by the absorption of a range of n-alkanols and cholesterol. Results are shown for n-hexanol, n-octanol, n-decanol, n-dodecanol, n-tetradecanol, n-hexadecanol, n-octadecanol and cholesterol. The longer chain n-alkanols were apparently more effective than the shorter members and cholesterol was the most effective of the substances examined. The single channel conductance was also affected, though to a much lesser extent than the mean channel lifetime, the n-alkanols producing increases and cholesterol a decrease. It is suggested that membrane fluidity changes are not likely to be primarily responsible for the reductions in channel lifetimes but that the bilayer tension, which is known to be increased by n-octanol, could be significant.

Alcohols↗
PubMed1982

Nerve impulse blockage in squid axons by n-alkanes: the effect of axon diameter.

1. The anaesthetic effects of aqueous solutions of the n-alkanes pentane to nonane on the propagated action potential of squid axons have been investigated for a range of axon diameters. 2. By the use of small axons (approx. 200 microns diameter) to minimize effects due to long diffusion times and alkane depletion it was found that n-pentane and n-hexane caused a rapid reversible inhibition of the impulse, while higher homologues had progressively less effect, n-nonane being apparently inert. 3. The rate of action potential decline due to the n-alkanes was found to be strongly dependent on axon diameter. For n-hexane, n-heptane and n-octane the rate of decline was inversely proportional to the square of the axon diameter. 4. The mechanisms which may underly the increased sensitivity of small axons to impulse blockade by n-alkanes are discussed. A quantitative comparison is made between the effects of n-hexane, n-heptane and n-octane on the action potential. It is argued that this supports the idea of a real decline in anaesthetic potency on ascending the homologous series, rather than an effect due to long diffusion times and solution depletion.

Action Potentials↗
PubMed1981

A mean-field model of the alkane-saturated lipid bilayer above its phase transition. II. Results and comparison with experiment.

Equilibrium properties of a model lipid bilayer saturated with an n-alkane are presented. The model exhibits a cut-off in absorption as the chain length of the alkane increases which is similar to that observed with black lipid films. The reasons for this cut-off are explored in detail. The model provides qualitative agreement with the experimental enthalpies of transfer of the various alkanes from bulk pure liquid to the bilayer, and with results of electrical compression experiments on black films. Distributions of alkane across the bilayer for different volume fractions in the membrane are presented. For small volume fractions of alkane, its distribution is fairly even across the bilayer and the alkane chains line up essentially parallel to the lipid chains. For larger volume fractions, the alkane distribution is strongly peaked in the center of the membrane. The alkane chains in the outer regions of the membrane line up essentially parallel to the lipid chains, while those in the center are almost completely disordered. The model suggests that the chains (both lipid and alkane) are in an essentially liquid state with no well defined interface between opposing monolayers. It gives a possible explanation for the discrepancy between the experimental free energy of thinning of some lipid membranes formed from the longer chain length alkanes and the theoretical values estimated from Lifshitz's theory.

Alkanes↗
PubMed1981

Some effects of n-pentane on the sodium and potassium currents of the squid giant axon.

1. Sodium and potassium currents have been recorded in intracellularly perfused squid giant axons before, during and after exposure to solutions of n-pentane in artificial sea water. 2. The currents were fitted with equations similar to those proposed by Hodgkin & Huxley (1952) and the changes in the parameters of these equations in the presence of pentane were calculated. 3. In the range of membrane potential -40 to 40 mV, the time constants for activation (tau m) and inactivation (tau h) of the Na current, and for activation (tau n) of the K current were all reduced by the pentane. 4. The curve of the steady-state inactivation parameter (h infinity) for the Na current against membrane potential was shifted by the pentane in a hyperpolarizing direction (at h infinity = 0.5 this shift was approx. -15 mV in 275 microM-pentane) and the slope at all potentials was reduced. 5. The curve of the steady-state activation parameter (m infinity) for the Na current against membrane potential was also shifted by the pentane in a hyperpolarizing direction (in 153 microM-pentane, 10 mV at m infinity = 0.5). 6. The maximum Na and K conductances gNa and gK were lowered by the pentane, though not usually completely reversibly. 7. The changes in position and slope of the steady-state inactivation curve have been tentatively accounted for in terms of an increase in membrane thickness.

Animals↗
PubMed1980

Ion movements in gramicidin pores. An example of single-file transport.

Experimental results on ion movement through gramicidin membrane channels are presented and discussed in terms of ion transport in the simplest single-file pore (for review see Urban, B.W. and Hladky, S.B. (1979) Biochim. Biophys. Acta 554, 410-429). Single-channel conductance and bi-ionic potential data for Na+, K+, Cs+, NH4+ and Tl+ are used to assign values to the rate constants of the model. Not all of the rate constants can be determined uniquely and simplifications are introduced to reduce the number of free parameters. The simplified model gives good quantitative fits to the experimental results for Na+, K+, Cs+ and NH4+. For Tl+, although the model accounts qualitatively for the salient features of the results, the quantitative agreement is less satisfactory. Predictions calculated from the model and the fitted rate constants are compared with independent data from blocking and tracer-flux measurements. In agreement with experiment, the model shows that only Tl+ blocks the Na+ conductance significantly. Furthermore, the exponent, n, in the tracer flux ratio rises, as observed, well above unity. The values for the rate constants suggest internal consistency of the model in that entry is always slower to singly occupied pores than to empty pores while exit is always faster from doubly as compared to singly occupied pores. The agreement between model prediction and experimental results suggests that the main features of ion transport in the gramicidin channel arise from cation-cation interaction in a single-file pore.

Cations, Monovalent↗
PubMed1980

The adsorption of nonpolar molecules into lipid bilayer membranes.

Thermodynamic considerations show that the adsorption of nonpolar molecules into lipid bilayer membranes should depend upon the curvature of the membranes. Estimations of the differences in adsorption of a small n-alkane between a planar phospholipid bilayer and liposomal vesicles have been attempted. For spherical multilamellar liposomes exposed to saturated solutions of alkane in water the adsorption is calculated to be 17-65% of the value for the planar bilayer, depending on the assumptions in the model.

Adsorption↗
PubMed1980

Some effects of aliphatic hydrocarbons on the electrical capacity and ionic currents of the squid giant axon membrane.

1. The electrical properties of squid giant axons were examined by means of admittance bridges at frequencies from 0.5 to 300 kHz. A simple equivalent circuit was used to estimate the membrane capacity. 2. The calculated membrane capacities decreased monotonically over the whole frequency range. 3. At 100 kHz and higher frequencies the membrane capacity was independent of potential. 4. At frequencies greater than 20 kHz, exposure of the axons to saturated or 0.9 saturated solutions of n-pentane (275-306 micrometer) reduced the capacity per unit area by 0.1-0.15 micro F cm-2. 5. At 1 kHz the effect of the saturated pentane solutions depended on the membrane potential. In axons having potentials between -60 and zero mV the pentane solutions lowered the capacity, whereas for potentials between -160 and -60 mV they produced little or no change. 6. Saturated solutions of n-hexane, n-heptane and n-octane exhibited qualitatively similar, but quantitatively smaller influences on the membrane capacity, the changes declining as the chain length increased. 7. Under voltage clamp, the peak inward and steady-state outward currents were partially suppressed by the hydrocarbons. Saturated solutions of n-pentane usually reduced the former (reversibly) by 60-80% and the latter by 20-40%. Solutions of n-hexane, n-heptane and n-octane appeared to have successively less effect. Except in deteriorating axons, none of the hydrocarbons produced any consistent changes in the passive membrane resistance, the resting potential or in the reversal potential of the transient inward current. 8. Both the changes in the clamp currents and in the membrane capacity were largely, though not usually completely, reversible. In the hydrocarbon solution the axons deteriorated more rapidly than normal. 9. The responses of axons of Doryteuthis plei to the hydrocarbons were very similar to those of Loligo forbesi with the exception that for the former all observed changes were some five times faster. 10. The time courses of the peak inward and steady-state outward currents on exposure of the axons to n-pentane resembled the time course of the change in membrane capacity at 100 kHz. 11. The simplest interpretation of the high frequency capacity results is suggested to be that, as for lipid bilayers, the membranes become thicker through adsorption of the hydrocarbon.

Alkanes↗
PubMed1979

The interaction of n-octanol with black lipid bilayer membranes.

The electrical capacities of black lipid films formed from monoolein + n-hexadecane and monoolein + squalane (or squalene) solutions have been measured in the presence of various concentrations of n-octanol. In addition, partition coefficients for n-octanol between n-hexadecane and 0.1 M NaCl, dielectric constants for octanol-hexadecane mixtures and the interfacial tension of films and film-forming lipid solutions against the aqueous phases have been determined. It is concluded that in "solvent-free" bilayers the octanol is unlikely to have changed the bilayer thickness by more than about 1 A. The bilayer tension, on the other hand, increases appreciably in the presence of octanol.

Electrochemistry↗