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ANESTHETIC PHARMACOLOGY

Anesthetic Properties of the Ketone Bodies ß-Hydroxybutyric Acid and Acetone

Liya Yang, PhD^*, Jing Zhao, MD^*, Pavle S. Milutinovic, MS, Robert J. Brosnan, DVM, PhD, Edmond I. Eger, II, MD^*, and James M. Sonner, MD^*

From the *Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; Peking Union Medical College, Beijing, China; University of Pittsburg School of Medicine, Pittsburg, Pennsylvania; and Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, California.

Address correspondence to Dr. Sonner, MD, Department of Anesthesia, S-455, University of CA, San Francisco, CA 94143-0464. Address e-mail to sonnerj{at}anesthesia.ucsf.edu.

BACKGROUND: We tested the hypothesis that two metabolites that are elevated in ketosis (ß-hydroxybutyric acid, and acetone) modulate ion channels in a manner similar to anesthetics and produce anesthesia in animals.

METHODS: ₁ß_22s-aminobutyric acid type A (GABA_A), ₁ glycine, NR1/NR2A N-methyl-d-aspartate, and two pore domain TRESK channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The effect of ß hydroxybutyric acid and acetone on channel function was measured. The anesthetic effects of these drugs were measured in X. laevis tadpoles.

RESULTS: Both ß hydroxybutyric acid and acetone enhanced glycine receptor function in the concentration range that is obtained in ketoacidosis in humans. Beta hydroxybutyric acid also enhanced GABA_A receptor function at these concentrations. Both acetone and ß-hydroxybutyric acid anesthetized tadpoles, with an EC₅₀ for acetone of 264 ± 2 mM (mean ± se) and for ß-hydroxybutyric acid of 151 ± 11 mM at pH 7.0. Acetone enhanced GABA_A receptors at concentrations of 50 mM and above. Inhibition of TRESK channel function was seen with 100 mM acetone or larger concentration. N-methyl-D-aspartate receptor function was inhibited at concentrations of acetone of 200 mM and larger.

CONCLUSIONS: Beta hydroxybutyric acid and acetone are anesthetics. Both ketone bodies enhance inhibitory glycine receptors at concentrations observed clinically in ketoacidosis. In addition, ß-hydroxybutyric acid enhances GABA_A receptor function at these concentrations. Subanesthetic concentrations of these drugs may contribute to the lethargy and impairment of consciousness seen in ketoacidosis.

This article has been cited by other articles:

				E. I. Eger II, D. E. Raines, S. L. Shafer, H. C. Hemmings Jr, and J. M. Sonner Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility? Anesth. Analg., September 1, 2008; 107(3): 832 - 848. [Abstract] [Full Text] [PDF]

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				L. Yang and J. M. Sonner The Anesthetic-Like Effects of Diverse Compounds on Wild-Type and Mutant {gamma}-Aminobutyric Acid Type A and Glycine Receptors Anesth. Analg., March 1, 2008; 106(3): 838 - 845. [Abstract] [Full Text] [PDF]

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999