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Urethane and contraction of vascular smooth muscle.

1 In vitro studies were undertaken on rat aortic strips and portal vein segments in order to determine whether or not the anaesthetic, urethane, can exert direct actions on vascular smooth muscle. 2 Urethane was found to inhibit development of spontaneous mechanical activity. This action took place with a urethane concentration as little as one tenth of that found in anaesthetic plasma concentratios, i.e., 10(-3) M. 3 Urethane (10(-3 to 10(-1) M) dose-dependently attenuated contractions induced by adrenaline, angiotensin and KCl. These inhibitory actions were observed with urethane added either before or after the induced contractions. 4 Ca2+-induced contractions of K+-depolarized aortae and portal veins were also attenuated, dose-dependently, by urethane. 5 All of these inhibitory effects were completely, and almost immediately, reversed upon washing out the anaesthetic from the organ baths. 6 A variety of pharmacological antagonists failed to mimic or affect the inhibitory effects induced by urethane. 7 These data suggest that plasma concentrations of urethane commonly associated with induction of surgical anaesthesia can induce, directly, relaxation of vascular muscle.

Angiotensin II

Inhibiting effect of caffeine on spontaneous and urethan-induced lung tumors in strain A mice.

The i.p. injection of caffeine (8, 20, and 40 mg/kg) 3 times weekly for 8 weeks suppressed the development of spontaneous pulmonary adenomas in strain A mice. The same caffeine injection scheme suppressed urethan (0.25 and 1.0 mg/g)-induced lung tumor development when caffeine treatment started 1 week before urethan administration, but this suppression was not significant when caffeine treatment was initiated 1 week after urethan injection. The most pronounced suppression of lung tumor formation occurred when caffeine was given as only two injections 3 hr before and 3 hr after urethan administration. The incorporation of [3H]thymidine into lung tissue DNA of caffeine-treated mice was impaired at the time of urethan administration. Also, caffeine partially antagonized the effects of urethan on lung tissue, as measured by [3H]thymidine incorporation studies. One interpretation of these results is that caffeine-induced suppression of DNA synthesis interferes with pulmonary adenoma induction by decreasing the affinity of lung tissue DNA for urethan. The finding that chronic caffeine treatment produced continued suppression of [3H]thymidine incorporation into lung tissue DNA suggests that caffeine-induced inhibition of spontaneous pulmonary adenoma formation is due to a general suppression of lung DNA-synthetic activity.

Adenoma

Effect of urethan on the induction of ornithine decarboxylase in regenerating rat liver.

The effect of urethan on the induction of ornithine decarboxylase in the early stage of the regeneration of rat liver was studied. The induced activity of ornithine decarboxylase was suppressed by administration of urethan immediately after partial hepatectomy. Although ornithine decarboxylase was induced biphasically by partial hepatectomy, a single intraperitoneal injection of urethan resulted in the reduction of both phases. However, the ornithine decarboxylase activity induced by glucocorticoids and growth hormone was not suppressed by urethan. The increased level of 3',5'-cyclic adenosine monophosphate induced by partial hepatectomy was also reduced by urethan and this suppression was proportional to the suppression of ornithine decarboxylase activity. Reversal of the urethan-induced suppression of ornithine decarboxylase by administration of dibutyryl 3',5'-cyclic adenosine monophosphate was also observed.

Animals

The effects of urethane, sodium monohydrogen arsenate and selenocystine on crossing-over in Drosophila melanogaster.

The effects of 0 - 25 mM urethane, 0 - 50 muM selenocystine and 0 - 100 muM sodium monohydrogen arsenate on marker-exchange frequencies have been studied along a region of the X chromosome of Drosophila melanogaster marked by y, cv, v and f. Clear and consistent effects seen in concentration curves were usually but not always found significant in analyses of variance. Urethane concentration curves rose to a higher level at 0.5 to 3 mM and dropped to control levels between 10 and 25 mM. It is proposed that this reversibility was due to a competition between two categories of lesions mimicking natural recombination sites, those on unpaired regions of the chromosome competing with those on already paired regions for recombination-repair enzymes. Selenocystine affected exchange frequencies mainly toward the ends of the unmarked region, especially y - cv, negatively from 2 to 10 muM and positively above 10 muM. These effects are interpreted as being mediated by selenocystine control over restriction of synaptic pairing to terminal regions, especially y - cv. Interaction between urethane and selenocystine in two-chemical treatments satisfactorily support the above explantations for both the urethane and selenocystine effects. Sodium monohydrogen arsenate effects, tentatively attributed to the arsenate ion, differed markedly from those of the other chemicals: "arsenate" concentration curves for single-exchange classes tended to be broadly convex and those for double-exchange classes concave, while interactions with urethane tended to be synergistic or neutral except in one exchange class (that for single exchange in y - cv). No satisfactory explanation of the arsenate effects has yet been found. At 25 mM only, urethane caused male-specific, 95% pupal mortality.

Animals

A dose-response study on urethane carcinogenesis in rats and mice.

Sprague-Dawley rats and NMRI mice were treated with urethane in the drinking water for 2 years. In both species the daily doses were: 100, 500, 2,500, and 12,500 mug/kg. The frequency of animals with malignancies increased steadily with increasing doses, beginning from 500 mug/kg/day for rats, and from 100 mug/kg/day for mice. To evaluate the possible cancer risk for man due to urethane in beverages, the observed response rates were used to extrapolate responses at lower doses. At a daily dose of 0.14 mug/kg/day (corresponding to daily consumption of a beverage with 10 ppb urethane by a 70-kg man) the upper risk limits were estimated to be 3.2 in 100,000 for rats, and 470 in 100,000 for mice (modified Mantel-Bryan procedure). Problems in calculating a possible cancer risk for man on the basis of animal observations are discussed. Since treatment of beverages with diethyldicarbonate leads to the formation of urethane, and since a cancer risk to man from urethane cannot be excluded, replacement of diethyldicarbonate by a toxicologically unobjectionale compound is called for.

Animals

Effects of urethane on hippocampal unit activity in the rat.

The effect of urethane on hippocampal single unit activity in rats paralyzed with gallamine triethiodide was examined to determine possible influences of urethane as an anesthetic for electrophysiological recordings. With intravenous injections of urethane (1.0 g/kg body weight), hippocampal units responded initially with a substantial decrease in spontaneous firing rate. Activity in some cells recovered partially after a period of approximately 45 min. The activity of the remainder of cells recorded remained depressed for periods of time up to 1.5 hr. Longer periods of depression were observed in some cells. The difference in susceptibility to urethane in the population of hippocampal cells may offer a selective alteration in patterns of spontaneous activity in the hippocampus and systems efferent to the hippocampus. A knowledge of such alterations may prove important in interpreting the results of electrophysiological recording in preparations under urethane anesthesia.

Animals

Effect of reovirus infection on pulmonary tumor response to urethan in strain A mice.

The effect of reovirus type 3 infection on the pulmonary adenoma response to urethan in strain A mice was examined. Urethan carcinogenesis in this system was suppressed from 30 to 60% when mice were exposed to reovirus either 6 days before, on the same day as, or 14 days after urethan administration. These findings suggested that reovirus infection interfered with the progression of urethan-induced pulmonary adenoma rather than the induction of lung tumors by urethan. When mice received multiple exposures to reovirus, the lung tumor response was enhanced. These findings indicated that reovirus infection in particular and virus infection in general may play an important role in the carcinogenic response to environmental chemicals.

Adenoma

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

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

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

Failure of urethane anesthetic to block induction of pineal serotonin N-acetyltransferase activity in the rat.

Ability of urethane anesthetic to block induction of pineal serotonin N-acetyltransferase (SNAT; E.C.2.3.1.5) activity was measured in individual rat pineal glands in animals receiving urethane (25% w/v, IP, 1.2 g/kg) or saline, 6 hr prior to sacrifice. Using a radioenzymatic assay, SNAT determinations were made twice daily (at 1200 or 2400 hr) immediately after the sacrifice of each animal. The results show that urethane had no effect on the induction of SNAT activity: (1) implying that the neural activity of those structures involved in induction of SNAT activity (e.g., suprachiasmatic nucleus) is not substantially altered by this anesthetic and (2) suggesting that the central blockade of ovulation by urethane does not include alterations in suprachiasmatic nucleus activity.

Acetyltransferases

Effect of pentobarbital and urethane on the release of hypothalamic somatostatin and pituitary growth hormone.

Hypothalamic somatostatin release was investigated in the rat to elucidate the mechanism of anesthetic action on growth hormone (GH) release from the pituitary. Intraperitoneal injection of sodium pentobarbital (5 mg/100 gm B.W.) significantly elevated serum GH levels and increased hypothalamic somatostatin concentration from basal values of 0.98 +/- 0.01 to 1.21 +/- 0.06 ng/mg wet wt. In contrast, urethane (150 mg/100 gm B.W., IP) administration lowered serum GH levels and hypothalamic somatostatin concentration (0.64 +/- 0.04 ng/mg wet wt.). However, the mean concentration of pancreatic somatostatin showed no change in either case. In rats receiving passive immunization with 0.5 ml rabbit antiserum to somatostatin (SRIF-AS), serum GH levels were significantly increased (67.5 +/- 12.3 ng/ml) and did not differ from those in the group treated with normal rabbit serum (NRS) plus pentobarbital (101.3 +/- 18.5 ng/ml). However, serum GH levels in rats injected with SRIF-AS plus pentobarbital were increased to higher values than in rats given SRIF-AS alone. When urethane was administered to rats after passive immunization with SRIF-AS, urethane-induced suppression of serum GH levels was markedly inhibited (5.5 +/- 2.0 vs. 33.5 +/- 7.5 ng/ml). These results suggest a possibility that the changes in serum GH levels observed with pentobarbital or urethane administration may be induced at least in one part by somatostatin released from the hypothalamus.

Animals

[Effect of the tissue-specific lung adhesive factor on the urethane induction of pulmonary adenomas in mice].

The effect of adhesive factor (AF), urethane and their combination on the mechanical properties of lung tissue (this effect was assessed by the nuclei isolation during a standard dispersion procedure) and on adenoma induction was studied. As shown, the AF doses eliminating the primary action of urethane on the mechanical properties of the tissue significantly decreased the incidence of adenomas. High AF doses producing a contrary effect on the mechanical properties of the tissue failed to eliminate the primary effect of urethane and did not decrease the number of adenomas induced by urethane.

Adenoma

[Relationships between course of anesthesia, depth of anesthesia and acetylcholine content of the brain after urethane and pentobarbital administration in the rat].

Urethane (1.25 g/kg) and pentobarbital (0.06 g/kg) 30 min after i.v. application increase the content of acetylcholine in telencephalic areas but not in the brain stem. These acetylcholine levels are normalized again 120 min p.i.; but urethane treated animals show an elevated acetylcholine content in the brain stem at this time. A different course of anesthesia by pentobarbital and urethane respectively correlated with this result: Only in the presence of urethane a persistent depression of spontaneous motility was seen, whereas the effectivity of both anesthetics on pinna and corneal reflexes and in respect of pentobarbital also on active movements occurrence declined in the end of the test period.

Acetylcholine

Comparison of segmented polyether urethane with polyethylene IUDs in rabbits.

A segmented polyether urethane IUD was compared with a polyethylene IUD in rabbits. The contraceptive efficacy of urethane IUDs was excellent. Moreover, the purulent slippery deposit present with the polyethylene IUDs and observed by Davis et al. (1) was absent. Our studies indicate that the polyether urethane IUDs have a high degree of antifertility activity in rabbits and these IUDs have reduced inflammatory response, based on leucocytic infiltration and tissue debris in the uterine lumen. It is suggested that polyether urethane IUDs not requiring copper or other medication can be designed for high contraceptive efficacy, intrauterine compatibility and with the necessary rigidity for proper uterine retention in humans.

Animals

Effect of urethan on the synthesis of nucleic acids in thymus, spleen, and bone marrow.

Urethan, in a single dose of 1 mg/g body weight, exerts a strong inhibitory effect on DNA synthesis in lymphoid organs and bone marrow of rat. The inhibition observed in spleen and thymus is longer lasting than that exerted on bone marrow or regenerating liver, demonstrating a marked sensitivity of lymphoid cells to the drug. This effect can explain the rapid reduction of weight and cell number in thymus and spleen under urethan treatment, in absence of any lymphocytolytic action. The different effect of urethan on the different subpopulations of lymphoid cells therefore appears to be due to their kinetics rather than to a specific sensitivity of some of them.

Animals

[Effect of urethane and penthobarbital on the behaviour of the renin-angiotensin-system in rat (author's transl)].

The behaviour of the renin-angiotensin-system was investigated after urethane and penthobarbital anaesthesia in rats. The recent results support the early observation that urethane increases the plasma-renin-activity and the haematocrit. It was further shown that urethane in the customary anaesthetic dose causes hypoproteinaemia and a decrease in the pressor response to angiotensin and in renin substrate concentration. Based on these results, its use as an anaesthetic in experiments connected with the renin-angiotensin-system does not appear to be appropriate.

Anesthesia

The effect of urethane and pentobarbital anaesthesia and hepatic portal vein catheterization on liver blood flow in the rat.

The effect of urethane and pentobarbital anaesthesia and hepatic portal vein catheterization on liver blood flow was investigated in the rat. Liver blood flow with pentobarbital anaesthesia was 40% greater than with urethane. Hepatic portal vein catheterization had no effect under pentobarbital anaesthesia whereas it produced an 18% fall in liver blood flow with urethane.

Animals