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Anesthesiology Service, Department of Veterans Affairs, VA Medical Center, San Francisco, California
Address correspondence to Donald D. Koblin, PhD, MD, Anesthesiology Service (129), Department of Veterans Affairs, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121. Address e-mail to KoblinD{at}anesthesia.ucsf.edu
Urethane [ethyl carbamate (NH2COOCH2CH3)] is a common compound that we are exposed to every day. We consume urethane in very small quantities in alcoholic beverages (highest levels in stone-fruit brandies and sake), soy sauce, and bread (levels increased approximately threefold with toasting) (1). At larger doses, urethane has anesthetic properties.
Urethane is a commonly used anesthetic for animal experiments and has been used for thousands of studies. It is popular because a single injection (typically 1.0 to 1.5 g/kg) provides immobility for surgical procedures of long duration (several hours) and because there is a general impression that it produces minimal changes in circulation and respiration, preserves reflex responses, and minimally interferes with the physiological relevance of data collected in anesthetized animals (2). For example, recent studies in this journal have examined cats anesthetized with urethane to study comparative inhibitory effects of xenon and nitrous oxide on spinal dorsal horn neurons (3), and rodents anesthetized with urethane to study the role of prostaglandin E2 and nitric oxide on allodynic pain (4). An underlying assumption of these studies is that background urethane anesthesia does not interfere with the measurement of electrophysiological responses or with the production and analyses of biochemical mediators associated with stimuli-evoked pain.
Urethane, however, is not the ideal anesthetic. It has been recognized for some time that cardiac and respiratory function is depressed at larger urethane doses (
1.5 g/kg) and that even smaller urethane doses will produce a variety of endocrine effects and increase blood levels of glucose and epinephrine (2,5,6). Intraperitoneal injection of urethane may damage intraabdominal organs and produce even more profound alterations in the physiological state (2,5,6). More recent examples of the unsuitability of urethane include the finding that a background anesthetic that includes urethane alters the influence of halothane on central nervous system cardiovascular control (7), and the suggestions that urethane be avoided in experiments involving sepsis (urethane protects against toxic effects of lipopolysaccharide) (8) and lung inflammatory processes (urethane suppresses cyclooxygenase and nitric oxide synthase mRNA levels) (9).
In this issue of Anesthesia & Analgesia, Hara and Harris (10) examine the influence of urethane on recombinant neurotransmitter receptors in frog oocytes. This study is important for two reasons. First, it provides a reminder that urethane is not an inert compound and that it alters the flow of ions through many neurotransmitter receptor/channel complexes. Second, this study provides insight into possible molecular mechanisms of action of urethane. It was not surprising to find that urethane, like most IV and inhaled anesthetics, enhanced the currents of inhibitory receptors (GABAA, glycine) and inhibited current responses of excitatory receptors (NMDA, AMPA) in a dose-dependent manner (10). It was surprising that urethane, unlike most other anesthetics, enhanced the function through neuronal nicotinic acetylcholine receptors and did not exhibit a preferential action at one type of neurotransmitter receptor. Instead, urethane had detectable but relatively small effects on all of the ion channels examined, with the implication that it has a wide spectrum of effects and that its mechanism of action differs from most other anesthetics (10).
A key factor in the design and the interpretation of in vitro experiments involving urethane is the choice of concentration. Plasma concentrations of 10–15 mM urethane are required to permit invasive surgical procedures (2). After intraperitoneal injection of 1.4 g/kg urethane in the mouse, blood concentrations of urethane decrease with time from 
16 mM 1 h after injection to 12 mM 6 h after injection (11). The experiments by Hara and Harris evaluated urethane at aqueous concentrations of 0.1 to 300 mM, with 10 mM urethane enhancing the currents of inhibitory receptors (GABAA, glycine) by 23%–33%, enhancing function of neuronal acetylcholine receptors by 15%, and inhibiting current responses of excitatory receptors (NMDA, AMPA) by 10%–18% (10). Of concern, however, is whether plasma urethane concentrations measured during surgical anesthesia can be directly compared to aqueous urethane concentrations used for in vitro experiments. Any binding of urethane to plasma proteins and lipids would decrease aqueous urethane concentrations and thus such concentrations associated with surgical anesthesia may be less than plasma urethane concentrations (12). It should also be noted that urethane is a volatile compound (1,13) and that, depending on the storage conditions of aqueous urethane solutions and the experimental preparation, calculated concentrations of urethane may overestimate the true concentrations used.
Early in the previous century, urethane was given to patients for its hypnotic effects (14), briefly used to treat malignancies (15), and used as a solvent vehicle for many drugs and cosmetics (16). However, with the recognition that urethane is mutagenic, carcinogenic, and hepatotoxic (1,13,17), it is no longer administered to patients. The toxic effects of urethane are probably due to its metabolism to reactive breakdown products (1,18). Would a nontoxic, urethane-like molecule be of clinical use? Perhaps. As noted above, urethane reduces organ injury and mortality after injection of lipopolysaccharide in a rat model of sepsis (8). Another urea analog, dimethylthiourea [CH3NHCSNHCH3], is anesthetic (abolishes response to tail clamp) in rats at a dose of 2 g/kg, and is also a scavenger of free radicals (19). A compound that simultaneously protects against organ injury and provides sedation could be helpful in the treatment of critically ill patients. Studies similar to those described by Hara and Harris (10) may be useful in screening for such a compound.
References
release. J Appl Physiol 1996; 81: 2304–11.This article has been cited by other articles:
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  M. P. Sceniak and M. B. MacIver Cellular Actions of Urethane on Rat Visual Cortical Neurons In Vitro J Neurophysiol, June 1, 2006; 95(6): 3865 - 3874. [Abstract] [Full Text] [PDF]
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D. A. Nicholson and J. H. Freeman Jr. Developmental Changes in Evoked Purkinje Cell Complex Spike Responses J Neurophysiol, October 1, 2003; 90(4): 2349 - 2357. [Abstract] [Full Text] [PDF]
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