The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels.
Urethane is widely used as an anesthetic for animal studies because of its minimal effects on cardiovascular and respiratory systems and maintenance of spinal reflexes. Despite its usefulness in animal research, there are no reports concerning its molecular actions. We designed this study to determine whether urethane affects neurotransmitter-gated ion channels. We examined the effects of urethane on recombinant gamma-aminobutyric acid(A), glycine, N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. Urethane potentiated the functions of neuronal nicotinic acetylcholine, gamma-aminobutyric acid(A), and glycine receptors, and it inhibited N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in a concentration-dependent manner. At concentrations close to anesthetic 50% effective concentration, urethane had modest effects on all channels tested, suggesting the lack of a single predominant target for its action. This may account for its usefulness as a veterinary anesthetic. However, a large concentration of urethane exerts marked effects on all channels. These findings not only give insight into the molecular mechanism of anesthetics but also caution that neurophysiologic measurements from animals anesthetized with urethane may be complicated by the effects of urethane on multiple neurotransmitter systems. Our results also suggest that small changes in multiple receptor systems can produce anesthesia.


CONCLUSIONS
Urethane modestly affects multiple neurotransmitter systems at an anesthetic concentration. Our findings suggest that these degenerate effects of urethane can produce anesthesia and that urethane has a potential to influence neuronal measurements made in in vivo preparations.
Hara
Koji
K
Waggoner Center for Alcohol and Addiction Research and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712-1095, USA.
Harris
R Adron
RA
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D018118:Chloride Channels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects*; D009865:Oocytes / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins; D014520:Urethane / Q000494:pharmacology*; D014982:Xenopus laevis
D018686:Anesthetics, Intravenous; D018118:Chloride Channels; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D014520:Urethane