Pressure Reversal of Anaesthesia

Lever, M. J.; Miller, Keith W.; Patón, W. D. M.; Smith, E. B.

doi:10.1038/231368a0

Cited by 248 publications

(102 citation statements)

References 19 publications

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“…Any model of the anaesthetic site should share the pharmacological properties of general anaesthesia itself, including pressure reversal (Lever et al, 1971); lack of stereoselectivity between enantiomeric pairs of secondary alkanols (Alifimoff et al, 1987); and cut-off (Janoff & Miller, 1982). Anaesthetic cut-off has been observed in several series of homologous compounds, including the primary alkanols, alkanes, and fluorocarbons (for a review see Miller, 1987).…”

Section: Discussionmentioning

confidence: 99%

Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site

Alifimoff

Firestone

Miller

1989

British J Pharmacology

158

123

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1 We have redetermined the anaesthetic potencies (EC50 s) for a series of primary alkanols, to resolve uncertainties about the molecular dimensions of the anaesthetic site resulting from the use of data from different laboratories. 2 For each alkanol, concentration-response relationships for loss of righting reflex (LRR) were plotted for over one hundred tadpoles, and the median effective concentrations determined. Aqueous concentrations present during potency assays were determined independently, and for alkanols with chain length greater than nonanol, correction was made for depletion from the aqueous phase.3 The EC50 s were found to decrease logarithmically with increasing number of carbon atoms in the hydrocarbon chain of the alkanol (CN), such that, on average, each additional methylene group was associated with an approximately four fold increase in potency. 4 The relationship between log EC50 and CN was best described by the quadratic equation, log EC o = 0.022 (+0.0038) CN2 + 0.76 (±0.051) CN + 3.7 (±0.14) (r2 = 0.9951). 5A previously described correlation between the apparent changes in the free energy of binding of an additional methylene group both to luciferase and to the sites for LRR in tadpoles was not confirmed. 6 A cut-off in potency beyond dodecanol was established in experiments where tadpoles were maintained in supersaturated solutions of tridecanol for 20 h without demonstrable LRR. 7 These findings indicate that the soluble enzyme firefly luciferase does not adequately model the anaesthetic site. Specifically, there are discrepancies in the position of cut-off, and the apparent changes in the free energy of binding, per methylene group, of an alkanol to luciferase do not parallel that for tadpoles.

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Section: Discussionmentioning

confidence: 99%

Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site

Alifimoff

Firestone

Miller

1989

British J Pharmacology

158

123

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“…This result is particularly intriguing because the physiological effect can also be reversed by moderate pressures (4). Recently, Trudell (5) developed a phenomenological theory of anesthesia based on the concept of lateral phase separation in the membrane.…”

mentioning

confidence: 99%

Effect of anesthetics and pressure on the thermotropic behavior of multilamellar dipalmitoylphosphatidylcholine liposomes.

Mountcastle¹,

Biltonen²,

Halsey³

1978

Proc. Natl. Acad. Sci. U.S.A.

139

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The effects of gaseous anesthetics and pressure on the thermotropic behavior of multilamellar dipalmitoylphosphatidylcholine liposomes were studied by using a highsensitivity differential scanning calorimeter. It was found that halothane and enflurane decreased the transition temperature and increased the width of the transition without affecting the enthalpy change for the main gel-to-liquid crystalline transition. This emonstrated that the anesthetics decreased the degree of cooperative interaction between phospholipid molecules within the bilayer. Increasing the pressure increased the transition temperature but did not affect the transition width or enthalpy change. However, the increase in pressure reversed the effect of anesthetic on both the transition temperature and transition width. It is sugested that an understanding of the effect of anesthetics on the degree of cooperative interaction between phospholipids may be a key to understanding anesthetic action.The physiological effect of inhalation anesthetics is likely a manifestation of the perturbation of membrane functions associated with synaptic transmission of nerve impulses. This conclusion is primarily based on the high degree of correlation between anesthetic potency and lipid solubility (1, 2). Although it is possible that the primary sites of the action of anesthetics are specific membrane proteins, an attractive alternative is that such action is the result of induced changes in the dynamic structure of the lipid matrix.Trudell and coworkers (3) have demonstrated that general anesthetics decrease the gel-to-liquid crystalline phase transition temperature of phospholipid bilayers and that this effect can be reversed by application of moderate pressures [-100 atmospheres (atm) (10 MPa)] to the system. This result is particularly intriguing because the physiological effect can also be reversed by moderate pressures (4). Recently, Trudell (5) developed a phenomenological theory of anesthesia based on the concept of lateral phase separation in the membrane. This theory focuses on the absolute increase in fluidity of the phospholipid matrix caused by anesthetics. It was suggested that, when phase separation no longer exists, membranes are less able to facilitate the protein conformational changes necessary for normal physiological function.In order to assess carefully the effect of the gaseous anesthetics on the thermotropic behavior of lipid bilayers, a detailed study was initiated using a highly sensitive differential scanning calorimeter. In addition, the influence of pressure on this behavior was ascertained by using a pressure cell adapted for this calorimeter. The results of this study show that the general anesthetics halothane (CF3CHBrCl) and enflurane (CHF2OCF2CHFCI) decrease the transition temperature without affecting the enthalpy change for the transition but that the degree of cooperative interaction between phospholipid molecules is decreased. Both these effects can be reversed by the application of moderate pressures. We there...

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“…Firstly, the initial observation that narcotized newts regain their normal motility at pressure (Johnson & Flagler, 1950;Lever et al, 1971) and the subsequent demonstration that high pressure reverses the effects of anaesthetic chemicals, measured behaviourally, in mammals (Halsey, Wardley-Smith & Green, 1978) shows that the effect of the anaesthetic agent on the central nervous motor system is reversed and implies some form of sensory restoration. Taking the term anaesthesia in its literal connotation, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Experimentally, high ambient pressures have been shown to antagonize the effects of anaesthetic chemicals administered to a wide variety of animals (Johnson & Flager, 1950;Lever, Miller, Paton & Smith, 1971;Halsey, Eger, Kent & Warne, 1975;Miller, 1975). This pressure 'reversal' of anaesthesia has been rationalized in terms of the critical volume hypothesis of anaesthetic action in which it is proposed that anaesthetics cause the expansion of certain neuronal membranes and that an anaesthetic state results if this expansion exceeds a certain critical volume (Miller, Paton, Smith & Smith, 1973).…”

Section: Introductionmentioning

confidence: 99%

Pressure Reversal of the Effect of Urethane on the Evoked Somatosensory Cortical Response in the Rat

Angel

Gratton

Halsey

et al. 1980

British J Pharmacology

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The cerebral response evoked by stimulation of the forepaw in the rat shows an increase in latency and decrease in the amplitude of its initial components as anaesthetic dose (urethane) is increased. These changes are reversed if the ambient pressure is increased with helium and the electrocorticogram shows an increase in basic frequency. The dose of urethane needed to prevent reflex response to tail stimulation is increased as pressure increases. The implications of these behavioural and somatosensory responsiveness changes as pressure is increased are discussed.

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Pressure Reversal of Anaesthesia

Cited by 248 publications

References 19 publications

Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site

Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site

Effect of anesthetics and pressure on the thermotropic behavior of multilamellar dipalmitoylphosphatidylcholine liposomes.

Pressure Reversal of the Effect of Urethane on the Evoked Somatosensory Cortical Response in the Rat

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