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PubMed1988

Influence of copper and zinc on urethan-induced adenoma development in mice.

Female Swiss mice were exposed to zinc chloride (0 to 500 ug/mL) or copper sulfate (0 to 200 ug/mL) in their drinking water for 15 weeks. After 3 weeks of the exposure period, the mice were administered urethan (1.5 mg/g) intraperitoneally. Urethan-induced pulmonary adenoma formation was evaluated 12 weeks later. Zinc exposure increased the number of adenomas produced but reduced the mean tumor diameter in the intermediate treatment groups, 50 and 200 ug/mL. Exposure to copper had no effect on tumor size or on tumor number. Weight gains in the mice were not affected by copper or zinc treatment, although a dose-dependent reduction in water consumption was observed with copper. Water consumption in mice exposed to zinc was elevated in one treatment group (50 ug/mL). Urethan-induced sleeping times, which reflect the rate of urethan excretion, were prolonged by zinc exposure but were unaffected by copper exposure. This finding suggests that zinc exposure impairs the elimination of urethan and enhances its carcinogenic activity, which is manifested by increased tumor formation.

Adenoma↗
PubMed1987

Stimulation of the hypothalamic-pituitary-adrenal axis and inhibition of growth hormone release via increased central noradrenaline neuronal activity by urethane anaesthesia in the rat: blockade by clonidine.

Computerized gas chromatography-mass spectrometry was used to measure precisely the hypothalamic levels of noradrenaline (NA), dopamine and serotonin together with those of their major neuronal metabolites 3,4-dihydroxyphenylethyleneglycol (DHPG), 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in normal male rats 45 min after stimulation of hypothalamic-pituitary-adrenal function by urethane (1.3 g/kg) administration. Urethane treatment resulted in a significant elevation of central noradrenergic neuronal activity (NNA) as assessed from marked rises in hypothalamic DHPG concentrations and the ratio (DHPG/NA). At the same time there was significant stimulation of ACTH and corticosterone release and inhibition of growth hormone release. These hormonal and central effects of urethane (but not anesthesia) were inhibited when the alpha 2-agonist clonidine (150 micrograms/kg) was co-administered. Urethane had no major effect on hypothalamic dopamine or serotonin status. We propose that the release of ACTH and the suppression of growth hormone release following urethane anaesthesia is a result of activation of central NNA and suggest that the hormonal responses are mediated via hypothalamic noradrenergic facilitation of corticotrophin releasing factor and somatostatin release to the anterior pituitary.

Adrenocorticotropic Hormone↗
PubMed1986

Effect of maternal urethane administration on the manifestation of cleft lip and palate in CL/Fr mice.

To determine whether the administration of urethane also decreases the associated cleft palate in CL/Fr mice, pregnant CL/Fr mice (30% of their offspring have spontaneous cleft lip with associated cleft palate [CL/P]) were treated with various doses of urethane on different days of pregnancy. In the groups treated with 250, 500, and 750 mg/kg urethane on day 9 of pregnancy, the frequency of CL/P decreased with the dose to 18%, 14%, and 11% of term fetuses, respectively. In the group treated with 1,000 mg/kg urethane on day 9, the frequency of CL/P decreased to 6%, but isolated cleft palate (CP) was observed in 23% of term fetuses. Most fetuses in the same group had severe tail anomaly (absence of tail or stub tail), and showed marked loss in body weight. The CP observed in the group treated with 1,000 mg/kg urethane on day 9 might possibly be due to the teratogenicity of the drug.

Animals↗
PubMed1986

Effects of strain and age on prophylaxis and co-carcinogenesis of urethan-induced mouse lung adenomas by butylated hydroxytoluene.

A single i.p. injection of butylated hydroxytoluene (BHT) 6 h before a single urethan injection had varying effects on lung tumorigenesis in mice of different strains and ages. Strains exhibiting both high (A/J, SWR/J) and low (BALB/cByJ, 129/J, C57BL/6J) susceptibility to urethan tumorigenesis were tested in this study. BHT treatment decreased tumor multiplicity by an average of 32% in adult A/J mice but acted as a cocarcinogen by increasing tumor number 48% in adult SWR/J mice, 240% in adult C57BL/6J mice, 655% in adult 129/J mice, and 38% in 14-day-old A/J mice. The numbers of both alveolar type 2 cell-derived and bronchiolar Clara cell-derived lung adenomas were similarly affected by these BHT treatments. Such BHT pre-treatment had no effect on adenoma multiplicity in either young or adult BALB/cByJ mice. Multiplicity in young BALB/cByJ mice was also unaffected by chronic BHT administration following urethan, even though multiplicities increased several-fold with such treatment in adult mice of this strain. Since the mice showing co-carcinogenesis by BHT include strains which are both highly susceptible and relatively resistant to urethan induction of lung tumors, our results support a distinction between genes regulating susceptibility to urethan carcinogenesis and to tumor modulation by BHT.

Adenoma↗
PubMed1981

[Effect of atropine, propranolol, phentolamine, and orciprenaline on minute-rhythmic fluctuations of heart rate in urethane-anesthetized mice].

The effects of atropine, propranolol, phentolamine, and orciprenaline on the minute-rhythmic fluctuations of the heart rate were investigated in urethane-anaesthetized mice. These drugs influenced the parameters of the minute rhythm (amplitude, length of period). However, the rhythm was not suppressed over any length of time. After blocking the vagus with atropine, the rhythm was maintained unchanged. In the other cases, the rhythm was not demonstrable only during the transition to a new level of heart rate. Immediately after the injection of each drug, the amplitude of the minute rhythm was very low for the most part but gradually increased in size again. After the injection of each drug, there existed the same correlations between the length of period of the fluctuations of heart rate and the respective mean rate (i.e., the arithmetic mean of both extreme values of a period) as after the injection of urethane alone. The same rhythms as are characteristic for the respective ranges of heart rate after the injection of urethane alone were also observed. The possible central and peripheral mechanism of origin of this minute rhythm are discussed. Since neither the blockade of the vagus nor the blockade of the sympathetic innervation could suppress the occurrence of periodic fluctuations of the heart rate for a long time, a peripheral origin of this minute rhythm may be assumed. Moreover, because there are no indications for a direct influence of urethane on the cardiac pacemaker, urethane might be supposed to produce the conditions for a pronounced appearance of the latently existing autogenic rhythm of the heart by acting on the central nervous system. Therefore, the visceral nervous system would be responsible only for the modification of the parameters (amplitude, length of period) of this rhythm.

Anesthesia↗
PubMed1977

Determination of urethane in wines by gas-liquid chromatography and its confirmation by mass spectrometry.

A gas-liquid chromatographic (GLC)-mass spectral (MS) method for the determination and confirmation of urethane in wines has been developed. Analyses of domestic and imported wines indicated urethane to be present at levels ranging from 1 to 20 microng/L. Recoveries of urethane from wines fortified at 10 ppb (microng/L) ranged from 50 to 100% with an average value of 71%. GLC-MS was used to confirm the identity of urethane in wine extracts in which GLC indicated the presence of urethane.

Chromatography, Gas↗
PubMed1996

Stimulation of cortical actin polymerization in the sea urchin egg cortex by NH4Cl, procaine and urethane: elevation of cytoplasmic pH is not the common mechanism of action.

Previous studies have demonstrated that the penetrating weak base NH4Cl and the anesthetics procaine and urethane disrupt the normal attachment of cortical granules to the cortex of the sea urchin egg. Hylander and Summers (1981: Dev. Biol. 86:1-11) hypothesized that this effect may be caused by a pH-induced polymerization of cortical actin. We have tested this hypothesis by measuring the intracellular pH of eggs of the sea urchins S. purpuratus and A. punctulata treated with NH4Cl, procaine, or urethane, and determining the effects of these agents on the organization of cortical actin. Intracellular pH was determined by the ratiometric measurement of the fluorescent dye BCECF, and filamentous actin organization was examined by confocal laser scanning microscopy of BODIPY-phallocidin stained eggs. Treatment of eggs with either NH4Cl or procaine resulted in a rapid and reversible increase in cytoplasmic pH of up to 1 pH unit and a dose-dependent increase in the intensity of fluorescent staining of the cortex, indicating an increase in the content of filamentous actin. While urethane also induced a dramatic polymerization of cortical actin, no effect on cytoplasmic pH could be detected. These results demonstrate that NH4Cl, procaine and urethane all induce an increase in the amount of filamentous actin in the sea urchin egg cortex that may participate in the detachment of cortical granules. However, these compounds do not share a common mechanism of action based on the elevation of cytoplasmic pH.

Actins↗
PubMed1998

Ki-ras gene mutations and absence of p53 gene mutations in spontaneous and urethane-induced early lung lesions in CBA/J mice.

Ki-ras and p53 genes are involved in human lung carcinogenesis; however, the role of these genes in experimental lung tumors is not well known. In our study, the CBA/J mouse strain was used to investigate the presence of Ki-ras and p53 alterations in lung carcinogenesis of spontaneous tumors and tumors induced with high and low doses of urethane (ethyl carbamate). To study the presence of these alterations in the early stages of lung carcinogenesis and in very small lung tumors, restriction fragment length polymorphism and single-strand conformation polymorphism analyses were performed on polymerase chain reaction-amplified DNA from microdissected tumoral and normal lung samples. Ki-ras gene mutations in codons 12 and 61 were detected in all types of lung lesions, even in small and preneoplastic lesions, and their incidence increased with progression from lung hyperplasias (18%) to adenomas (75%) and to carcinomas (80%). Urethane exposure, in both high and low doses, increased the incidence of Ki-ras mutations in lung tumors, especially in adenomas. The presence of Ki-ras gene mutations in very small urethane-induced lung tumors and the absence of hyperplasias among the treated-group lesions may indicate that urethane accelerates tumoral progression. No p53 mutations were detected in exons 5-8 in any of the epithelium-derived lung tumors. Only one p53 mutation in exon 5 was found in a spontaneous lymphoma. Therefore, p53 mutations do not seem to cooperate with Ki-ras gene mutations or represent an alternative molecular pathway in murine carcinogenesis.

Adenoma↗
PubMed2004

Interactions between N-acetylcysteine and sodium selenite in modulating the clastogenicity of urethane and 2-acetylaminofluorene in mice.

Combined treatment with different agents represents a promising approach in cancer chemoprevention. Therefore, it is useful to assess in preclinical models the efficacy of combinations that are selected by taking into account mechanistic considerations. We designed 2 studies evaluating the interaction between N-acetylcysteine (NAC) and sodium selenite (Se), both given with the drinking water to Balb/c mice, in modulating clastogenic effects in bone marrow polychromatic erythrocytes. In a first study, a single i.p. injection of urethane considerably enhanced the frequency of micronucleated cells. While NAC produced a significant inhibition, Se further enhanced urethane clastogenicity. When given in combination at the same doses, NAC prevented the adverse effect of Se. In a second study, a single i.p. injection of 2-acetylaminofluorene enhanced the frequency of micronucleated cells. Se did not reduce this effect to a significant extent, while NAC produced a dose-dependent inhibition. When tested at the lower dose in combination with Se, the protective effect of NAC was unchanged. Especially in association with Se, NAC also prevented the toxicity of 2-acetylaminofluorene by normalizing the ratio of polychromatic to normochromatic erythrocytes. In conclusion, NAC attenuated the clastogenicity of both urethane and 2-acetylaminofluorene and the toxicity of this aromatic amine. In addition, NAC prevented the clastogenic and toxic effects resulting from the interaction of Se with urethane. Together with the findings of previous studies, it appears that, besides its intrinsic protective properties in carcinogenesis, NAC is capable of attenuating the adverse effects of several cytotoxic drugs and chemopreventive agents.

2-Acetylaminofluorene↗
PubMed1982

Mammary tumor induction in inbred mouse strains with urethane is not accompanied by changes in expression of B- and C-type retroviral structural proteins.

Urethane administrated in the drinking water of breeding female mice of five inbred strains (DDf, KF, C3Hf, ddY and C57BL) leads to a higher incidence of mammary tumors at an extremely early age in four of these strains (DDf, KF, C3Hf and ddY). In the case of the DDf strain the tumors are adenoacanthomas, but in the case of the other strains adenocarcinomas are also observed. The effect of urethane in the drinking water on expression of endogenous retroviral structural proteins of the B and C type (MTV and MuLV) was studied in the milk by an immunodiffusion test and in organ extracts by radioimmunoassays (for MTVp27, MTVgp52 and MuLVp30). Organs tested include salivary glands, thymus and spleen from female and male animals. In addition, prostate and seminal vesicles were tested in male animals and uterus and mammary glands in females. Mammary tumors induced by urethane were also treated. Urethane does not induce or enhance endogenous retroviral antigen expression, either in these organs or in the mammary gland, one of the target organs for tumorigenesis by this agent.

Adenocarcinoma↗
PubMed1978

Solid-state dispersions employing urethan.

The dissolution rates of a number of drug-urethan solid-state dispersion systems were studied. A marked enhancement of the initial dissolution rates of several poorly water-soluble drugs was found when they were incorporated into a urethan matrix by heat fusion. These differences were considerable when pure substances such as griseofulvin, hydrocortisone, chloramphenicol, and acetaminophen were compared to the urethan-drug solid dispersion. Physical mixtures of the medicinal agents with urethan also gave a marked increase in the amount of drug in solution, with the value in most cases being over one-half that of the solid-state dispersion. Data are given, comparing ultrafiltration with samples filtered through cotton, regarding drug content remaining in solution.

Chloramphenicol↗
PubMed2000

Experimental urethane anaesthesia prevents digoxin intoxication: electrocardiographic and histological study in rabbit.

An electrocardiographic and histological study was performed in rabbit to detect the effects of urethane (ethyl carbamate) intraperitoneal (i.p.) anaesthesia in digoxin intoxication, since it has been previously shown that this anaesthetic and digitalis glycosides exert specific peripheral effects on the cardiovascular system involving central structures of the autonomic nervous system. We observed that i.p. urethane anaesthesia prevented the onset of the electrocardiographic signs of digitalis intoxication, as well as inhibiting the appearance of histological myocardial alterations after treatment with toxic digoxin doses. On the other hand, lethal arrhythmias and severe myocardial damage were observed in animals that had not undergone preliminary urethane anaesthesia. These results indicate that the effect exerted by urethane in preventing the toxic action of digoxin is probably due to a decrease of sympathetic activity in anaesthetized animals by centrally mediated sympathetic inhibition.

Anesthesia↗
PubMed1996

Anti-serotonergic effects of urethane and chloral hydrate may not be mediated by a blockade of 5-HT2 receptors. Short communication.

The general anesthetics urethane and chloral hydrate have profound anti-serotonergic effects both in the rat cortex in vivo and the rat aortic ring in vitro. The suggestion that these effects may be due to an action on 5-HT2 receptors was tested using ex vivo and in vitro [3H]ketanserin binding assays with membrane-enriched fractions from rat brain. Urethane did not alter [3H]ketanserin binding in the ex vivo assay. In the in vitro assay, urethane, chloral hydrate, and its active metabolite 2,2,2-trichloroethanol produced slight reductions (of 16%, 9%, and 18%, respectively) of [3H]ketanserin binding. These studies suggest that anti-serotonergic effects of urethane and chloral hydrate may not be mediated by a blockade of 5-HT2 receptors.

Anesthetics, Intravenous↗
PubMed1986

Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 1: General considerations.

The suitability of urethane anesthesia for physiopharmacological investigations is reviewed. Total dose administered and route of administration are recognized as factors having a great influence on both resting parameters and biological responses to drugs. A peculiar characteristic of urethane is represented by its ability to induce a surgical plane of anesthesia without affecting neurotransmission in various subcortical areas and the peripheral nervous system. This makes urethane a suitable general anesthetic for studying neural function in both central and peripheral nervous systems and accounts for the preservation of a number of reflex responses in urethane-anesthetized animals.

Acetylcholine↗
PubMed2000

Urethane suppresses rat lung inducible cyclooxygenase and nitric oxide synthase mRNA levels.

OBJECTIVE AND DESIGN: The purpose of the present study was to evaluate the effect of urethane, pentobarbital sodium and ketamine-xylazine anesthesia upon constitutive and inducible cyclooxygenase (COX-1; COX-2) and nitric oxide synthase (eNOS; iNOS) mRNA levels in the lung. METHODS: mRNA levels were determined by the semiquantitative RT-PCR technique. TREATMENT: Urethane (1.1 g/kg ip), Pentobarbital Sodium (40 mg/kg ip), and ketamine (85 mg/kg) - xylazine (15 mg/kg, im). Non-anesthetized animals served as controls. MATERIAL: Sprague-Dawley rat lungs RESULTS: Urethane significantly decreased COX-1 and COX-2 mRNA levels to 30% of control values. This agent had no effect upon eNOS, but completely suppressed iNOS mRNA levels. Pentobarbital sodium and ketamine had no effect on the mRNA levels for COX-1 and COX-2 the lung. CONCLUSIONS: Urethane has a suppressive effect on COX and iNOS RNA message in the lung and for this reason it should be avoided as an anesthetic when lung inflammatory processes are experimentally evaluated in the rat.

Anesthetics, Dissociative↗
PubMed1986

The interaction of urethane, an intravenous general anaesthetic, with phosphatidylcholine membranes.

The interaction of urethane (C2H5OCONH2), a neutral, intravenous general anaesthetic, with model membranes of egg-yolk phosphatidylcholine has been examined by 2H-NMR spectroscopy of deuterium-labelled lipids and anaesthetic as well as by 31P-NMR spectroscopy. Urethane interacts at the membrane/water interface to increase the interlipid separation in the bilayer. The presence of cholesterol does not significantly alter this behaviour. However, cholesterol does act to displace urethane from a second weakly bound membrane site which is in fast exchange with urethane free in bulk aqueous solution.

Cell Membrane↗
PubMed1977

Changes in liver nuclear protein metabolism after a single dose of urethane to suckling mice.

Treatment of 8-9-day-old C57BL/A mice with a single carcinogenic dose of urethane, at 1.2 mg/g body wt., resulted in an immediate decrease in liver DNA synthesis reaching a maximum at about 16-18 h after injection, the rate of synthesis returning to normal after 48 h. When the nuclear proteins were radiolabelled, the non-histone protein (NHP) fraction showed a significant decrease in specific activity 8-18 h after injection of urethane and slight increase in specific activity after 24 h. Histone and residual proteins did not show any significant change. The liver NHP were analysed by isoelectric focusing (IEF) and sodium dodecyl sulphate (SDS) electrophoresis in polyacrylamide gels. The latter technique failed to show any distinctive differences but IEF results indicated some quantitative and qualitative changes in protein content and synthesis were induced by the urethane treatment. The most noticeable change in the stained gels was an increase in a protein component having a pI of 7.35 and the appearance of new bands at pI's of 7.85 and 5.55 in the 18 h treated livers. However, the [3H]tryptophan labelling pattern indicated that this was not due to an increased synthesis of these components. 24 h after urethane there appeared to be an increased rate of synthesis of some of the major components of the mixture, particularly at the pI 5.65 region. Histone and residual protein fractions were also analysed by electrophoresis and showed no difference between treated and control livers.

Animals↗
PubMed1989

Urethane as an inhibitor of the firefly light reaction.

A study has been made to test the hypothesis that general anesthetics such as urethane are able to inhibit light from a firefly reaction mixture. Urethane was found to reduce light emission in a dose-dependent manner, the minimal effective concentration being about 20 mM. Dixon plots gave a Ki value in the range of 175 to 215 mM. Lineweaver-Burk plots showed that urethane increases the apparent Km for ATP and reduces Vmax for the reaction. This is taken to mean that urethane acts as both a competitive and non-competitive inhibitor of the firefly light reaction (mixed-type inhibition).

Animals↗