Evidence that hypoxia induced in cortical neurons is the mechanism of general anaesthesia

Despite much research the mode of action of gaseous anaesthetic agents has proven elusive since the first, ether, was used in 1842. As anaesthetic gas mixtures contain at least 21% oxygen and the minimum alveolar concentration of an anaesthetic agent producing an effect does not change over a wide range of inspired oxygen concentrations,1 it appears unlikely that
hypoxia is involved. However, a significant reduction in the respired oxygen concentration always causes loss of consciousness.

The intrepid balloonists James Glaisher and Henry Coxwell first discovered this on their ascent to the height of Everest over Wolverhampton in 1862: details were published in the Lancet the following year. Normal levels of oxygen in
blood cannot ensure adequate oxygen tensions in cells and intracellular oxygen concentrations cannot be measured.

However, the discovery of the Hypoxia-inducible transcription factor 1 (HIF-1) provides a unique marker for cellular hypoxia.2 HIF-1 is a heterodimer of alpha and beta components, with the level of HIF-1α controlled by its destruction by the Von Hippel
Lindau protein (VHL). A fall in cellular oxygen tension reduces the production of VHL, allowing HIF-1α to persist, which binds to HIF-1β to produce the transcription factor HIF-1.

Anaesthesia can be produced by xenon and oxygen mixtures3 and evidence that xenon produces cellular hypoxia has come from use of the gas by athletes in performance enhancement. HIF-1 and the effector hormone, erythropoietin, are up-regulated by the inhalation of xenon/oxygen mixtures with sufficient oxygen to sustain consciousness4 and the
effect lasts many hours longer than a hypoxia exposure induced by breathing a low oxygen partial pressure. As xenon is inert with no known compounds, it would seem unlikely that its action is to lower VHL production as can be achieved chemically, for example, by using cobalt compounds. Cortical neurons are exquisitely sensitive to hypoxia and their activity is abolished at oxygen levels well above that associated with irreversible cell damage.5 Xenon may induce a reversible change in cellular and/or mitochondrial membranes impairing oxygen transport and ATP production. The loss of consciousness induced by gaseous anaesthetic agents that have a high water/lipid solubility ratio like xenon may, therefore, be due to hypoxia of cortical neurons. This can be tested by determining if HIF-1 is up-regulated in other forms of gaseous anaesthesia and it may be possible to investigate if conformational changes of cell membranes occur and the mechanism by using a physical model.

Philip B. James
Emeritus Professor of Medicine
The University of Dundee
Nethergate
Dundee DD1 4HN

References

1. Eger EI II. Minimal alveolar concentration. Chapter 1 in: Anesthetic uptake and action. Williams and Williams
   Company, Baltimore, Maryland, 1974.
2. Wang GL, Jiang B-H, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS
   heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci 1995;92:5510-14.
3. Cullen SC, Gross EG. The anesthetic properties of xenon in animals and human beings with additional
   observations on krypton. Science 1951;113:580-82.
4. Ma D, Lim T, Xu J, Tang H, et al. Xenon preconditioning protects against ischemic-reperfusion injury via HIF-
   1α activation. J Am Soc Nephrol 2009;20:713-20.
5. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia – the ischemic penumbra. Stroke 1981;12:723-