To the Editor:-In a recent Editorial, lipid membranes were discredited for the possible anesthetic action sites on the grounds that (1) temperature elevation does not induce anesthesia, (2) perfluroalkanes do not obey the Meyer-Overton rule, and (3) stereoselectivity of anesthetic actions.
Biologic activities increase with increase of temperature, reach a maximum, Toptimum(the temperature that gave the maximum value), and then decrease. Fluidity increases monotonously with the temperature increase. Therefore, “activity” and “fluidity” are different properties and are incomparable. The increase of biologic activity is caused by the Arrhenius activation energy, and the decrease is caused by the reversible thermal denaturation of lipids and proteins. Anesthetics reversibly denature membranes and proteins at any temperature by binding to the macromolecule. Heat denatures only when the temperature is higher than Toptimum, by increasing the molecular motion. When heated at temperatures below Toptimum, the activities of animals, enzymes, channels, and others, e.g., muscle contractile force, heart rate, nerve conduction velocity, always increase because of the activation, regardless of the presence or absence of anesthetics. For this reason, temperature elevation does not induce anesthesia. Heat is energy, anesthetics are matter; their effects cannot be compared by the same standard.
Perfluorocarbons (perfluoroalkanes, perfluoroethers, and perfluoroalkanols) lack anesthetic potency. In micelle chemistry, however, it is well known that perfluorocarbons and hydrocarbons (lipids and proteins) do not mix well. The immiscibility is recognizable by the polytetrafluorethylene-coated (perfluorocarbon) kitchen utensils, to which nothing sticks. Perfluorocarbons lack anesthetic potency because they hardly stick to proteins and lipid membranes.
The Meyer-Overton rule has been widely misinterpreted. The rule does not specify that the anesthetic action site is lipid membranes. There are no similarity between oil and lipid membranes, except that they are both hydrophobic. Although there is no specific parameter for hydrophobicity, one may use dielectric constant. The dielectric constant of olive oil is approximately 10. The higher the number, the lower the hydrophobicity becomes. The dielectric constant of water is approximately 80. The dielectric constant of the core of lipid bilayers is 1.9. Therefore, olive oil is dissimilar to lipid membranes. What the Meyer-Overton rule really means is that anesthetic molecules prefer to stay at the hydrophobic environment in which the dielectric constant is approximately 10, which happen to be lipid-water and protein-water interfaces. Perfluorocarbons stay at the interfaces, dictated by the Meyer-Overton rule, but do not interact with (stick to) lipid membranes and proteins. Partially fluorinated molecules, such as inhalation anesthetics, belong to a different category.
Stereoselectivity and stereospecificity must be clearly distinguished. Stereospecificity is observed on specific ligand binding to a specific receptor on a specific protein. The difference in their effects between the isomers exceeds 100-fold. Stereoselectivity is so termed because of the low degrees of discrimination. In intact animals, the activity difference is typically in the single digit. The difference in minimum alveolar concentration values of isoflurane stereoisomers in rats were reported to be 1.06 versus 1.62%(1.53-fold change)and 1.44 versus 1.69%(1.17-fold change)by two independent groups. Any chiral surface discriminates stereoisomers at low degrees by nonspecific adsorption. Consider that stereoisomers of anesthetics are prepared by chromatography on the cyclodextrin series, not on proteins. Lipid membrane surfaces are also chiral. The demonstration of small differences between stereoisomers on lipid membranes, however, has problems. This is because the binding of anesthetics to lipid membranes is often estimated by the decrease of the phase-transition temperature of lipid membranes under the assumption that these molecules bind exclusively to the fluid membranes. However, anesthetics bind to solid and fluid membranes both, with different affinity, and the change in the transition temperature represents the difference in the bound numbers between the solid and liquid membranes. The total binding cannot be obtained by observing the depression of the transition temperature. When the solid and liquid membranes discriminate stereoisomers similarly, the transition temperatures do not change. Stereoselectivity is observed in nonspecific adsorption to all chiral surfaces and does not indicate that there is a specific receptor on a specific protein.
Issaku Ueda, M.D.
Professor; Department of Anesthesia; University of Utah School of Medicine and Department of Veterans Affairs; Medical Center; Salt Lake City, Utah;firstname.lastname@example.org
(Accepted for publication August 28, 1998.)