Fourteen polyhalogenated, completely halogenated (perhalogenated), or perfluorinated compounds were examined for their anesthetic effects in rats. Anesthetic potency or minimum alveolar anesthetic concentration (MAC) was quantified using response/nonresponse to electrical stimulation of the tail as the end-point. For compounds that produced excitable behavior, and/or did not produce anesthesia when given alone, we determined MAC by additivity studies with desflurane. Nine of 14 compounds had measurable MAC values with products of MAC x oil/gas partition coefficient ranging from 3.7 to 24.8 atm. Because these products exceed that for conventional inhaled anesthetics (1.8 atm), they demonstrate a deviation from the Meyer-Overton hypothesis. Five compounds (CF3CCIFCF3, CF3CCIFCCIFCF3, perfluorocyclobutane, 1,2-dichloroperfluorocyclobutane, and 1,2-dimethylperfluorocyclobutane) had no anesthetic effect when given alone, had excitatory effects when given alone, and tended to increase the MAC for desflurane. These five compounds had no anesthetic properties in spite of their abilities to dissolve in lipids and tissues, to penetrate into the central nervous system, and to be administered at high enough partial pressures so that they should have an anesthetic effect as predicted by the Meyer-Overton hypothesis. Such compounds will be useful in identifying and differentiating anesthetic sites and mechanisms of action. Any physiologic or biophysical/biochemical change produced by conventional anesthetics and deemed important for the anesthetic state should not be produced by nonanesthetics.
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...
The correlation between the potency of inhaled anesthetics and their solubility in a hydrophobic phase provides an opportunity to define better the characteristics of the anesthetic site of action. The correlation implies that inhaled anesthetics act in a hydrophobic site and that the solvent used has properties representative of the true site of anesthetic action. We sought to characterize this site more accurately by testing for the solvent that provided the best correlation for a diverse group of anesthetics. We determined the solubility of halothane, enflurane, cyclopropane, fluroxene, isoflurane, sevoflurane, and desflurane in benzene, olive oil, Intralipid, n-octanol, and lecithin. We used established MAC values for rats, dogs, and humans for all but sevoflurane and desflurane, for which we determined MAC in rats to be 2.80% +/- 0.24% (mean +/- standard deviation) and 7.71% +/- 0.65%, respectively. Lecithin gave the lowest coefficient of variation for the product of potency (MAC) x solubility, but the difference was statistically significant only for a comparison of the products for lecithin and olive oil. The values for lecithin were within the range of values produced by biological variation. More important, the correlation of log MAC and log solubility had an average slope of unity (-1.04 +/- 0.07) for lecithin, but a slope differing from unity for benzene (-0.82 +/- 0.05) and olive oil (-0.87 +/- 0.05). We conclude that lecithin is probably more representative of the site of action of these anesthetics than the other solvents.
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