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ANESTHETIC PHARMACOLOGY

Isovaleric, Methylmalonic, and Propionic Acid Decrease Anesthetic EC₅₀ in Tadpoles, Modulate Glycine Receptor Function, and Interact with the Lipid 1,2-Dipalmitoyl-Sn-Glycero-3-Phosphocholine

Yun Weng, PhD^*, Tienyi Theresa Hsu, BS, Jing Zhao, MD, Stefanie Nishimura, PhD, Gerald G. Fuller, PhD, and James M. Sonner, MD

From the *Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; Department of Chemical Engineering, Stanford University, California; and Department of Anesthesia, Peking Union Medical College, Beijing, China.

Address correspondence to Dr. James M. Sonner, Department of Anesthesia and Perioperative Care, Room S-455i, University of California, San Francisco, CA 94143-0464. Address e-mail to sonnerj{at}anesthesia.ucsf.edu.

INTRODUCTION: Elevated concentrations of isovaleric (IVA), methylmalonic (MMA), and propionic acid are associated with impaired consciousness in genetic diseases (organic acidemias). We conjectured that part of the central nervous system depression observed in these disorders was due to anesthetic effects of these metabolites. We tested three hypotheses. First, that these metabolites would have anesthetic-sparing effects, possibly being anesthetics by themselves. Second, that these compounds would modulate glycine and -aminobutyric acid (GABA_A) receptor function, increasing chloride currents through these channels as potent clinical inhaled anesthetics do. Third, that these compounds would affect physical properties of lipids.

METHODS: Anesthetic EC₅₀s were measured in Xenopus laevis tadpoles. Glycine and GABA_A receptors were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. Pressure-area isotherms of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayers were measured with and without added organic acids.

RESULTS: IVA acid was an anesthetic in tadpoles, whereas MMA and propionic acid decreased isoflurane’s EC₅₀ by half. All three organic acids concentration-dependently increased current through ₁ glycine receptors. There were minimal effects on ₁β_22s GABA_A receptors. The organic acids increased total lateral pressure (surface pressure) of DPPC monolayers, including at mean molecular areas typical of bilayers.

CONCLUSION: IVA, MMA, and propionic acid have anesthetic effects in tadpoles, positively modulate glycine receptor function and affect physical properties of DPPC monolayers.