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


METHODS
alpha1beta2gamma2sgamma-aminobutyric acid type A (GABA(A)), alpha1 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 beta hydroxybutyric acid and acetone on channel function was measured. The anesthetic effects of these drugs were measured in X. laevis tadpoles.


RESULTS
Both beta 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 beta-hydroxybutyric acid anesthetized tadpoles, with an EC50 for acetone of 264 +/- 2 mM (mean +/- se) and for beta-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, beta-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.
Yang
Liya
L
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464, USA.
Zhao
Jing
J
Milutinovic
Pavle S
PS
Brosnan
Robert J
RJ
Eger
Edmond I
EI
Sonner
James M
JM
D020155:3-Hydroxybutyric Acid / Q000378:metabolism / Q000494:pharmacology*; D000096:Acetone / Q000378:metabolism / Q000494:pharmacology*; D000777:Anesthetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016883:Diabetic Ketoacidosis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007473:Ion Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D009068:Movement / Q000187:drug effects*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects; D018009:Receptors, Glycine / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D014982:Xenopus laevis
D000777:Anesthetics; C546240:GABRA1 protein, human; C546279:GABRG2 protein, human; C546242:Gabra1 protein, rat; C502185:Gabrb2 protein, rat; C546281:Gabrg2 protein, rat; D007473:Ion Channels; D007657:Ketone Bodies; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D015221:Potassium Channels; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D000096:Acetone; D020155:3-Hydroxybutyric Acid