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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.

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