We contend that anesthesia is caused by a nonspecific change in physical properties of lipid membranes and proteins. The changes involve the properties of water/macromolecule (membranes and proteins) interface as well as their structures. According to thermodynamics, the pressure antagonism of anesthesia indicates that a volume in excess of the size of the incorporated anesthetic molecules is created in the total system under anesthesia. The origins of this excess volume are multiple, but the main contributing factor is proposed to be a change in the state of the water structure clustered at the surface of macromolecules (membranes and proteins). Interfacial water molecules are strongly compressed by the electrostatic force from the ionized sites (electrostriction) and by the dipole force of the macromolecular surface. When these water clusters are released, the system volume expands by the balance between the condensed structure and expanded bulk water structure. Conformational change in the macromolecules and other factors also contribute to the excess volume expansion. Anesthetics interfere with water-macromolecule association. Macromolecular structures, regardless of whether they are proteins or lipid membranes, are supported by association with the hydrogen-bonded matrix of water molecules. Anything that weakens this interaction induces disorder in the macromolecule and expand the structure. In this context, anesthetics are not a membrane stabilizer but a destabilizar. To prove or disprove this hypothesis, anesthetic effects upon interfacial properties of membranes and proteins are examined with emphasis on water interaction. The proposed methods are standard in colloid and interface chemistry, and have been successfully used in the applicant's laboratory. The macroscopic properties are evaluated by interfacial tension, solution densimetry for partial molal volumes, surface and bulk viscosity, interfacial potential, differential scanning microcalorimetry, etc. The obtained data are analyzed by applying thermodynamic and statistical thermodynamic principles. The microscopic properties are measured by nuclear magnetic resonance spectroscopy, fluorescence spectrophotometry, Raman and Fourier-transform infrared spectroscopy, etc.
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