Some Physical Mechanisms in Narcosis.

Mullins, L. J.

doi:10.1021/cr60168a003

Cited by 340 publications

(120 citation statements)

References 21 publications

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“…For example, both the simple rare gas xenon (which is a single atom) and the complex halogenated agent halothane (CF3CHClBr) are excellent general anesthetics. On the other hand, there is a size limitation, which is illustrated by the so-called cutoff effect: as one ascends an homologous series of anesthetics, aqueous-phase potencies steadily increase until, rather abruptly, they disappear completely (12)(13)(14)(15). For example, dodecanol is the most potent n-alcohol, whereas tetradecanol is completely impotent as a general anesthetic.…”

Section: General Considerationsmentioning

confidence: 99%

“…The modern interpretation of the classical work of Meyer (16) and Overton (17) has been that general anesthetics dissolve in lipid-bilayer regions of nerve cell membranes and so alter the properties of lipids (e.g., fluidity, thickness, surface tension, lateral surface pressure) surrounding crucial membrane proteins (usually assumed to be ion channels) that protein function is compromised (2,3,14,(20)(21)(22). The attraction of these lipid theories has been that, in most cases, it has been possible to experimentally demonstrate that anesthetics can indeed produce the advertised effects; it was largely for this reason that lipid theories reached a height of popularity some 10 years ago.…”

Section: Are the Primary Target Sites Proteins Or Lipids?mentioning

confidence: 99%

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Mechanisms of general anesthesia.

Franks

Lieb

1990

Environ Health Perspect

120

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Although general anesthetics are often said to be nonspecific agents, it is likely that they act at a much more restricted set of target sites than commonly believed. The traditional view has been that the primary targets are lipid portions of nerve membranes, but recent evidence shows that the effects on lipid bilayers of clinically relevant levels of anesthetics are very small. Effects on most proteins are also small, but there are notable examples of proteins that are extremely sensitive to anesthetics and mimic the pharmacological profile of anesthetic target sites in animals. Such target sites are amphiphilic in nature, having both hydrophobic and polar components. The polar components appear to behave as good hydrogenbond acceptors but poor hydrogen-bond donors. Although the targets can accept molecules with a wide variety of shapes and chemical groupings, they are unaffected by molecules exceeding a certain size. Overall, the data can be explained by supposing that the primary target sites underlying general anesthesia are amphiphilic pockets of circumscribed dimensions on particularly sensitive proteins in the central nervous system.

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Section: General Considerationsmentioning

confidence: 99%

Section: Are the Primary Target Sites Proteins Or Lipids?mentioning

confidence: 99%

Mechanisms of general anesthesia.

Franks

Lieb

1990

Environ Health Perspect

120

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“…Compounds associated with a narcotic effect in mammals, fish, and aquatic invertebrates include inert gases, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, alcohols, ethers, ketones, aldehydes, weak acids and bases, and some aliphatic nitro compounds (24)(25)(26)(27)(28)(29)(30). Based on the research of Ferguson (31) and Mullins (32), Veith et al. (25) proposed that acute narcosis in fish should be directly proportional to the 1-octanol/water partition coefficient (log P).…”

Section: Predictive Toxicology Andmentioning

confidence: 99%

Fish acute toxicity syndromes and their use in the QSAR approach to hazard assessment.

McKim

Bradbury

Niemi

1987

Environ Health Perspect

180

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Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity relationship (QSAR) models as rapid and predictive screening tools to select more potentially hazardous chemicals for in-depth laboratory evaluation has been proposed. Further implementation and refinement of quantitative structure-toxicity relationships in aquatic toxicology and hazard assessment requires the development of a "mode-of-action" database. With such a database, a qualitative structure-activity relationship can be formulated to assign the proper mode of action, and respective QSAR, to a given chemical structure. In this review, the development of fish acute toxicity syndromes (FATS), which are toxic-response sets based on various behavioral and physiological-biochemical measurements, and their projected use in the mode-of-action database are outlined. Using behavioral parameters monitored in the fathead minnow during acute toxicity testing, FATS associated with acetylcholinesterase (AChE) inhibitors and narcotics could be reliably predicted. However, compounds classified as oxidative phosphorylation uncouplers or stimulants could not be resolved. Refinement of this approach by using respiratory-cardiovascular responses in the rainbow trout, enabled FATS associated with AChE inhibitors, convulsants, narcotics, respiratory blockers, respiratory membrane irritants, and uncouplers to be correctly predicted.

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“…The means by which the non-polar anaesthetics influence the ion-channel-forming proteins in nerve axons has received relatively little attention (Mullins, 1954(Mullins, , 1971(Mullins, , 1975Seeman, 1972) and there is no general agreement on the basic question of whether these substances exert their influence by direct interaction with the proteins, or whether they act indirectly by perturbing the membrane lipid. One obstacle to progress has been the lack of detailed knowledge of how lipophilic molecules perturb lipid bilayers, and how such perturbations affect simple ion channels embedded in the bilayers.…”

Section: Introductionmentioning

confidence: 99%

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

Haydon¹,

Requena²,

Urban³

1980

The Journal of Physiology

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SUMMARY1. 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 AM) reduced the capacity per unit area by 0 1-0-15 ,#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 solutions 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.

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Some Physical Mechanisms in Narcosis.

Cited by 340 publications

References 21 publications

Mechanisms of general anesthesia.

Mechanisms of general anesthesia.

Fish acute toxicity syndromes and their use in the QSAR approach to hazard assessment.

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

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