Mechanism of Anesthetic Action: Oxygen Pathway Perturbation Hypothesis

Hu, Huping and Wu, Maoxin (2001) Mechanism of Anesthetic Action: Oxygen Pathway Perturbation Hypothesis. Medical Hypotheses, 57 (5). pp. 619-627.

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The mechanism of anesthesia is relevant to the neural and biological aspects of cognitive sciences. Although more than 150 years have past since the discovery of general anesthetics, how they precisely work remains a mystery. We propose a novel unitary mechanism of general anesthesia verifiable by experiments. In the proposed mechanism, general anesthetics perturb oxygen pathways in both membranes and oxygen-utilizing proteins such that the availabilities of oxygen to its sites of utilization are reduced which in turn triggers cascading cellular responses through oxygen-sensing mechanisms resulting in general anesthesia. Despite the general assumption that cell membranes are readily permeable to oxygen, exiting publications indicate that these membranes are plausible oxygen transport barriers. The present hypothesis provides a unified framework for explaining phenomena associated with general anesthesia and experimental results on the actions of general anesthetics. If verified by experiments, the proposed mechanism also has other significant medical and biological implications.

Item Type:Article
Uncontrolled Keywords:anesthetic action, anesthesia, oxygen, oxygen pathway, perturbation
Subjects:Q Science > QD Chemistry
Q Science > Q0 Interdisciplinary sciences > Q01 Interdisciplinary sciences (General)
Q Science > QP Physiology
1. Scholz, A., Appel, N., Vogel, W. Two types of TTX-resistant and one TTX-sensitive Na channel in rat dorsal root ganglion neurons and their blockade by halothane. Eur. J. Neurosci. Suppl. 1998; 10: 2547-2556.

2. Zhang, L., Oz, M., Stewart, R. R., Peoples, R. W., Weight, F. F. Volatile general anaesthetic actions on recombinant nACh alpha 7, 5-HT3 and chimeric nACh alpha 7-5-HT3 receptors expressed in Xenopus oocytes. Br. J. Pharmacol. 1997; 120: 353-355.

3. Krnjevic, K. Cellular and synaptic actions of general anaesthetics. Gen. Pharmacol. 1992; 23: 965-975.

4. Pancrazio, J. J. Halothane and isoflurane preferentially depress a slowly inactivating component of Ca2+ channel current in guinea-pig myocytes. J. Physiol. (London) 1996; 494: 91-103.

5. Harrison, N. L., Kugler, J. L., Jones, M. V., Greenblatt, E. P., Pritchett, D. B. Positive modulation of human gamma-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane. Mol. Pharmacol. 1993; 44: 628-632.

6. Violet, J. M., Downie, D. L., Nakisa, R. C., Lieb, W. R., Franks, N. P. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology 1997; 86: 866-874.

7. Jenkins, A., Franks, N. P., Lieb, W. R. Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells. Br. J. Pharmacol. 1996; 117: 1507-1515.

8. Kaech, S., Brinkhaus, H., Matus, A. Volatile anesthetics block actin-based motility in dendritic spines. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 10433-10437.

9. Meyer, H. H. Arch. Exp. Pathol. Pharmakol 1899; 42: 109-118.

10. Seeman, P. The membrane actions of anesthetics and tranquilizers. Pharmacol. Rev. 1972; 24: 583-655.

11. Trudell, J. R. A unitary theory of anesthesia based on lateral phase separations in nerve membranes. Anesthesiology 1977; 46: 5-10.

12. O’Leary, T. J. Effects of small nonpolar molecules on membrane compressibility and permeability. A theoretical study of the effects of anesthetic gases. Biophys. Chem. 1982; 15: 299-310.

13. Miller, K. W., Firestone, L. L., Alifimoff, J. K., Streicher, P. Nonanesthetic alcohols dissolve in synaptic membranes without perturbing their lipids. Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 1084-1087.

14. Cantor, R. S. The lateral pressure profile in membranes: a physical mechanism of general anesthesia. Biochemistry 1997; 36: 2339-2344.

15. Franks, N. P., Lieb, W. R. Molecular and cellular mechanisms of general anaesthesia. Nature (London) 1994; 367: 607-614.

16. Langmoen, I. A., Larsen, M., Berg-Johnsen, J. Volatile anaesthetics: cellular mechanisms of action. Eur. J. Anaesthesiol. 1995; 12: 51-58.

17. Harrison, N. L. Optical isomers open a new window on anesthetic mechanism. Anesthesiology 1998; 88: 566-568.

18. Magistretti, P. J., Pellerin, L, Martin, J.L. Brain Energy Metabolism: An Integrated Cellular Perspective in: Psychopharmocology, the Fourth Generation of Progress (Online Edition):

19. Weisiger, R.A. Impact of Extracellular and Intracellular Diffusion on Hepatic Uptake Kinetics in: Whole Organ Approach to Cellular Metabolism, Bassingthwaighte, J.B., Goresky, C. A., & Linehan, J. H. Eds. (Springer Verlag, New York 1998) pp 389-423.

20. Simon, S. A., Gutknecht, J. Solubility of carbon dioxide in lipid bilayer membranes and organic solvents. Biochim. Biophys. Acta 1980; 596: 352-358.

21. Kosztolowicz, T., Mrowczynski S. Membrane Boundary Condition LANL e-Print Archives 2000:

22. Subczynski, W.K., Hyde, J.S., Kusumi, A. Oxygen permeability of phosphatidylcholine--cholesterol membranes. Proc. Natl Acad. Sci. U. S. A. 1989; 86: 4474-4478.

23. Subczynski, W.K., Hopwood, L.E., Hyde, J.S. Is the mammalian cell plasma membrane a barrier to oxygen transport? J. Gen. Physiol. 1992;100: 69-87.

24. Kikeri, D., Sun, A., Zeidel, M. L., Herbert, S. C. Cell membranes impermeable to NH3. Nature 1989; 339:478-480.

25. Morse, P. D. 2nd, Swartz, H. M. Measurement of intracellular oxygen concentration using the spin label TEMPOL. Magn. Reson. Med. 1985; 2: 114-127.

26. Hu, H. P., Sosnovsky, G., Swartz, H. M. Simultaneous measurements of the intra- and extra-cellular oxygen concentration in viable cells. Biochim. Biophys. Acta 1992; 1112:161-166.

27. James, P. E., Grinberg, O. Y., Michaels, G., Swartz, H. M. Intraphagosomal oxygen in stimulated macrophages. J. Cell. Physiol. 1995; 163: 241-247.

28. Swartz, H. M. Measurements of intracellular concentrations of oxygen: experimental results and conceptual implications of an observed gradient between intracellular and extracellular concentrations of oxygen. Adv. Exp. Med. Biol. 1994; 345: 799-806.

29. Kaibara, M., Tsong, T. Y. Voltage pulsation of sickle erythrocytes enhances membrane permeability to oxygen. Biochim. Biophys. Acta 1980; 595:146-150.

30. Jones, D. P., Kennedy, F. G. Intracellular oxygen supply during hypoxia. Am J Physiol 1982; 243: C247-253.

31. Richards, C. D., Martin, K., Gregory, S., Keightley, C. A., Hesketh, T. R., Smith G. A., Warren G. B., Metcalfe, J. C. Degenerate perturbations of protein structure as the mechanism of anaesthetic action. Nature 1978; 276:775-779.

32. Lee, A. G. Interactions between anesthetics and lipid mixtures. Normal alcohols. Biochemistry 1976; 15: 2448-1454.

33. Chiou, J. S., Ma, S. M., Kamaya, H., Ueda, I. Anesthesia cutoff phenomenon: interfacial hydrogen bonding. Science 1990; 248: 583-585.

34. Franks, N. P., Lieb, W. R. Do general anaesthetics act by competitive binding to specific receptors? Nature 1984; 310:599-601.

35. Hasinoff, B. B., Davey, J. P. The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity. Biochem. J. 1989; 258: 101-107.

36. Eckenhoff, R. G., Johansson, J. S., Molecular interactions between inhaled anesthetics and proteins. Pharmacol. Rev. 1997; 49: 343-367.

37. Chandel, N.S., Schumacker, P. T. Cellular oxygen sensing by mitochondria: old questions, new insight. J. Appl. Physiol. 2000; 88:1880-1889.

38. Lahiri, S. Historical perspectives of cellular oxygen sensing and responses to hypoxia. J. Appl. Physiol. 2000; 88: 1467-1473.

39. Prabhakar, N. R. Oxygen sensing by the carotid body chemoreceptors. J. Appl. Physiol. 2000; 88: 2287-2295.

40. Hochachka, P. W., Buck L. T., Doll, C. J., Land, S. C. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc. Natl. Acad. Sci. U. S .A. 1996; 93: 9493-9498.

41. Jiang C., Haddad, G. G. A direct mechanism for sensing low oxygen levels by central neurons. Proc. Natl. Acad. Sci. U. S. A. 1994; 91:7198-7201.

42. Whalen, W. J. Riley J., Nair, P. A microelectrode for measuring intracellular PO2. J. Appl Physiol 1967; 23:798-801.

43. Whalen, W. J. Intracellular oxygen microelectrodes. Adv. Exp. Med. Biol. 1973; 37A: 17-22.

44. Longmuir, I. S., Knopp, J. S. A new histochemical stain for intracellular oxygen. Adv. Exp. Med. Biol. 37A: 55-57.

45. Benson, D. M., Knopp, J. A., Longmuir, I. S. Intracellular oxygen measurements of mouse liver cells using quantitative fluorescence video microscopy. Biochim. Biophys. Acta 1980; 591: 187-197.

46. Sugano, T., Oshino, N., Chance, B. Mitochondrial function under hypoxic conditions: the steady states of cytochrome alpha+alpha3 and their relation to mitochondrial energy states. Biochim. Biophys. Acta 1974; 368: 298-310.

47. Chance, B., Oshino, N., Sugano, T., Mayevsky, A. Basic principles of tissue oxygen determination from mitochondrial signals. Adv. Exp. Med. Biol. 1973; 37A: 277-292.

48. Chance, B., Barlow, C., Nakase, Y., Takeda H., Mayersky, A., Fischette, R., Graham, N., Sorge, J. Heterogeneity of oxygen delivery in normoxic and hypoxic states: a fluorometer study. Am J Physiol 1978; 235: H809-820.

49. Chen, K., Morse, P. D. 2nd, Swartz, H. M. Kinetics of enzyme-mediated reduction of lipid soluble nitroxide spin labels by living cells. Biochim. Biophys. Acta 1988; 943: 477-484.

50. Chen, K., Glockner, J. F., Morse, P. D. 2nd, Swartz, H. M. Effects of oxygen on the metabolism of nitroxide spin labels in cells. Biochemistry 1989; 28: 2496-2501.

51. Shulman, R. G., Rothman, D. L., Hyder, F. Stimulated changes in localized cerebral energy consumption under anesthesia. Proc. Natl. Acad. Sci. U.S.A.1999; 96: 3245-3250.

52. Hodge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., Pike, G. B. Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex. . Proc. Natl. Acad. Sci. U.S.A.1999; 96: 9403-9408.

53. Saiki, C., Mortola, J. P. Effect of 2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats. J. Appl. Physiol. 1997; 83: 537-542.

54. Rohlicek, C. V., Saiki, C., Matsuoka, T., Mortola, J. P. Oxygen transport in conscious newborn dogs during hypoxic hypometabolism. J. Appl. Physiol. 1998; 84: 763-768.

55. Winter, P. M., Smith, R. A., Smith, M., Eger, E. I. 3rd Pressure antagonism of barbiturate anesthesia. Anesthesiology 1976; 44: 416-419.

56. Mihic, S. J., Ye, Q., Wick, M. J., et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors Nature 1997; 389: 385-389.

57. Mascia, M. P., Trudell, J. R., Harris, R. A. Specific binding sites for alcohols and anesthetics on ligand-gated ion channels. Proc.Natl.Acad.Sci.U.S.A. 2000; 97: 9305-9310.

58. Lovinger, D. M., White, G., Weight, F. F. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 1989; 243:1721-1724.

59. Kyeder, M., Pifat, G., Jeloyecki, A., Klai, B., Pecar, S., Schara, M. The EPR study of LDL perturbed by alcohols with different molecular architecture. Alcohol 2000; 21: 141-147.

60. Adams, H. A., Werner, C. From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance? Anaesthesist 1997; 46:1026-1042.

61. Lerner, R. A. A hypothesis about the endogenous analogue of general anesthesia. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13375-13377.

62. Mantz, J. Neuroprotective effects of anesthetics. Ann. Fr. Anesth. Reanim. 1999; 18: 588-592.

63. Almaas, R., Saugstad, O. D., Pleasure, D. & Rootwelt, T. Effect of Barbiturates on Hydroxyl Radicals, Lipid Peroxidation, and Hypoxic Cell Death in Human NT2-N Neurons. Anesthesiology 2000; 92:764-774.

64. Berthoud, M. C., Reilly, C. S., Adverse effects of general anaesthetics. Drug Saf. 1992; 7: 434-459.

ID Code:134
Deposited By: Huping Hu
Deposited On:18 Sep 2010 21:04
Last Modified:06 Feb 2021 14:41

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