Abstract
The accumulation of halothane in brain homogenates was compared with halothane accumulation in brain during inhalation at anesthetic and subanesthetic levels. Anesthesia is achieved at a tissue concentration well below the halothane solubility in brain tissue. Analysis of halothane in the particulate solids of brain homogenate and in purified subcellular membranes indicates that a membrane constituent (presumably the lipids) acts as an ideal solvent in which halothane is fully miscible. Therefore, membranes offer a local microenvironment in which halothane accumulation deviates from Henry's law. Specifically, we observe that even slight increases of halothane in a saline medium result in a relatively large increase in the concentration of halothane in subcellular membranes suspended in the medium, eventually leading to solvation of the membrane in halothane. This observation offers a ready explanation for the high degree of positive correlation between MAC and lipid solubility and the small difference between anesthetic and lethal concentrations of halothane during inhalation. The rate of halothane increase in myelin exceeded the rate in other brain subcellular membranes, indicating that a major site of halothane localization is within this subcellular membrane.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Duncan W. A. M., andRaventos, J. 1959. The Pharmacokinetics of Halothane (Fluothane) Anaesthesia. Brit. J. Anaesth. 31:303–315.
Divakaran, P., Joiner, F., Rigor, B. M., andWiggins, R. C. 1980. Accumulation and Persistence of Halothane in Adult and Fetal Rat Brain as a Result of Subanesthetic Exposure. J. Neurochem. 34:1543–1546.
Divakaran, P., Rigor, B. M., andWiggins, R. C. 1981. Halothane Accumulation in Rat Brain and Liver. Neurochem. Res. 6:77–85.
Larson, Jr. C. P., Eger, II, E. I. andSeveringhaus, J. W. 1962. The Solubility of Halothane in Blood and Tissue Homogenates. Anesthesiology, 23:349–355.
Eger, II, E. I., andLarson, Jr. C.P. 1964. Anaesthetic Solubility in Blood Tissues: Values and Significance. Brit. J. Anaesth. 36:140–149.
Eichberg, J., Whittaker, V. P., andDawson, R. M. C. 1964. Distribution of Lipids in Subcellular Particles of Guinea-Pig Brain. Biochem. J. 92:91–100.
Cohen, E. N., andHood, N. 1969. Application of Low-Temperature Autoradiography to Studies of the Uptake and Metabolism of Volatile Anesthetics in the Mouse. Anesthesiology 31:553–559.
Cohen, E. N., Chow, K. L., andMathers, L. 1972. Autoradiographic Distribution of Volatile Anesthetics within the Brain. Anesthesiology 37:324–331.
Trudell, J. R., Hubbell, W. L., andCohen, E. N., 1973. The Effect of Two Inhalation Anesthetics on the Order of Spin-labeled Phospholipid Vesicles. Biochim. Biophys. Acta 291:321–327.
Trudell, J. R., andHubbell, W. L., 1976. Localization of Molecular Halothane in Phospholipid Bilayer Model Nerve Membranes. Anesthesiology 44:202–205.
Rosenberg, P. H. 1979. Effects of Halothane, Lidocaine, and 5-Hydroxytryptamine on Fluidity of Synaptic Plasma Membranes, Myelin Membranes and Synaptic Mitochondrial Membranes. Naunyn-Schmiedeberg's Arch. Pharm. 307:199–206.
Rosenberg, P. H., Eibl, H., andStier, A. 1975. Biphasic Effects of Halothane in Phospholipid and Synaptic Plasma Membranes: A Spin Label Study. Mol. Pharm. 11:879–882.
Rosenberg, P. H., Jansson, S.-E., andGripenberg, J. 1977. Effects of Halothane, Thiopental, and Lidocaine on Fluidity of Synaptic Plasma Membranes and Artificial Phospholipid Membranes. Anesthesiology 46:322–326.
Sachsenheimer, W., Pai, E. F., Schulz, G. E., andSchirmer, R. H. 1977. Halothane Binds in the Adenine-Specific Niche of Crystalline Adenylate Kinase. FEBS Letters 79:310–312.
Vanderkooi, J. M., Landesberg, R., Selick II, H. andMcDonald, G. G., 1976. Interaction of General Anesthetics with Phospholipid Vesicles and Biochemical Membranes. Biochim. Biophys. Acta 464:1–6.
Mastrangelo, C. J., Trudell, J. R., Edmunds, H. N., andCohen, E. N. 1978. Effects of Clinical Concentrations of Halothane on Phospholipid-Cholesterol Membrane Fluidity. Mol Pharm. 14:463–467.
Sandhoff, K., andPallmann, B. 1978. Membrane-Bound Neuroaminidase from Calf Brain: Regulation of Oligosialoganglioside Degradation by Membrane Fluidity and Membrane Components. Proc. Natl. Acad. Sci. 75:122–126.
Pellkofer, R., andSandhoff, K. 1979. Halothane Increases Membrane Fluidity and Stimulates Sphingomyelin Degradation by Membrane-Bound Neutral Sphingomyelinase of Synaptosomal Plasma Membranes from Calf Brain Already at Clinical Concentrations. J. Neurochem. 34:988–992.
Pang, K.-Y. Y., Braswell, L. M., Chang, L., Sommer, T. J., andMiller, K. W. (1980) The Perturbation of Lipid Bilayers by General Anesthetics. Mol. Pharmacol. 18:84–90.
Blanck, T. J. J., Gruener, R., Suffecoul, S. L., andThompson, M. 1981. Calcium Uptake by Isolated Sarcoplasmic reticulum: Examination of halothane inhibition, pH Dependence, and CA2+ Dependence of Normal and Malignant Hyperthermic Human Muscle. Anesth. Analg. 60:492–498.
Wiggins, R. C., Miller, S. L., Benjamins, J. A., Krigman, M. R., andMorrell, P. 1976. Myelin Synthesis During Postnatal Nutritional Deprivation and Subsequent Rehabilitation. Brain Res. 107:257–273.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., andRandall, R. J. 1951. Protein Measurement with the Folin Phenol Reagent. J. Biol. Chem. 193:265–275.
Norton, W. T. (1976) Formation, structure and biochemistry of myelin Pages 74–99,in Siegel, G. J., Albers, R. W., Katzmann, R., andAgranoff, B. W. (eds.), Basic Neurochemistry, Boston: Little Brown and Co.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Divakaran, P., Wiggins, R.C. Relative halothane accumulation in brain subcellular membranes in vitro. Neurochem Res 7, 1347–1358 (1982). https://doi.org/10.1007/BF00966063
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00966063