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PubMed1988

Inhibiting effects of nicotinamide on urethane-induced malformations and tumors in mice.

The antipellagratic vitamin, nicotinamide, significantly suppressed urethane-induced malformations, when it was given intraperitoneally to pregnant JCL:ICR mice immediately after a single subcutaneous injection of urethane (1.0 mg/g) on the 9th day of gestation. The level of inhibition increased with the doses of nicotinamide: 33.0, 55.8, and 70.0% at doses of 0.1, 0.3, and 0.5 mg/g, respectively. Polydactyly and tail anomalies were markedly suppressed by the post-treatment with nicotinamide, while cleft palates were less effectively suppressed. Nicotinamide was still effective, when it was given during the period of 24-48 h after urethane treatment. Furthermore, dietary administration of nicotinamide also reduced urethane-induced malformations. The level of inhibition was 39.4 and 61.1% at 0.5 and 1.0% of nicotinamide in the diet, respectively. Higher doses of nicotinamide (3 and 5% in diet) also inhibited urethane-induced malformations, but not so effectively as lower doses. The inhibiting effects of nicotinamide on the spontaneous incidence of cleft lips and palates in CL/Fr mice were significant at a low dose (0.5% in diet), but not at a higher dose (1.0%). When [carbonyl-14C]nicotinamide was given to pregnant mice, nicotinamide and small amounts of nicotinamide adenine dinucleotide (NAD+), but not nicotinic acid, were detected chromatographically in the fetus and placenta, indicating that nicotinamide or NAD+ acts directly on the fetus to suppress urethane-induced malformations. A preliminary study revealed that urethane-induced lung tumorigenesis in JCL:ICR mice was also inhibited by post-treatment with nicotinamide in the diet. The level of inhibition was proportional to the dose of nicotinamide, that is, 35.0 and 62.8% at 1.0 and 2.5% of nicotinamide in the diet, respectively.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Induction of micronuclei in bone marrow of mice exposed to 1, 2 or 3 daily doses of urethane.

Urethane was studied for its potential to induce micronuclei in bone marrow of CD-1 mice following various dosing and sampling schedules. It was found that: (1) mice dosed for 3 days by gavage with urethane at daily doses of 300, 600 and 1200 mg.kg-1 showed no increases in micronuclei compared to normal control values; (2) mice injected with 3 daily intraperitoneal (i.p.) doses of urethane at 400 and 1200 mg.kg-1 demonstrated substantial and dose-related increases in micronuclei; (3) mice given urethane at i.p. doses of 400 mg.kg-1 for 1, 2 and 3 days showed protocol related micronucleus yields with triple greater than single greater than double dosing, while mice given urethane at i.p. doses of 1200 mg.kg-1 showed a different trend with double greater than single dosing, the triple-dosing regimen proving cytotoxic to the bone marrow; (4) mice exposed i.p. to 400 mg.kg-1 of urethane had more micronuclei when sampled at 24 h than at 48 h after 1 or 2 daily treatments, while mice dosed i.p. with 1200 mg.kg-1 of urethane showed more micronuclei at 48 h than at 24 h after a single treatment, the double-dosing protocol being toxic to the marrow; (5) female mice were more susceptible to bone-marrow micronucleus induction than males with both quantitative and qualitative sex differences noted, depending on dose, regimen and sample.

Animals↗
PubMed2006

Altered expression of connexins in urethane-induced mouse lung adenomas.

Lung carcinogenesis is a multistep process whose molecular alterations can be studied in mouse models. Urethane, a specific lung tumor carcinogen, can induce adenomas in mice. Mouse lung alveolar cells reportedly generate lung neoplasms, and express connexins 26, 32, 43 and 46. The aim of the present study was to evaluate the expression of connexins in urethane-induced lung adenomas. Fifteen-day-old CD1 male mice received 2 i.p. injections of urethane (1.5 g/kg bw). The mice were euthanized 25 weeks after urethane injection, and lung adenomas were quantified. Lung tissue and lung adenomas were harvested and the RNA was extracted. The expression of connexins 26, 32, 43 and 46 was evaluated by Real-Time PCR, and these proteins were identified by Western blot. Immunohistochemistry revealed the distribution pattern of these connexins in lung tissue and adenomas. The treatment with urethane was associated with the downregulation of Cx26, 32 and 46 expressions, and with the upregulation of Cx43 expression in lung tissue. Surprisingly, in lung adenomas Cx32 and Cx43 expressions were not detected, although the expression of connexins 26 and 46 was present. Western blot and immunohistochemistry corroborated the RT-PCR data. These results may indicate a role of Cx32 and Cx43 in urethane-induced lung carcinogenesis, since their absence may contribute to the development of urethane induced lung tumors. The role of Cx26 and Cx46 is yet to be determined.

Adenoma↗
PubMed1996

Cytogenotoxicities of sublimed urethane gas to the mouse embryo.

Urethane (ethyl carbamate) which has long been used for commonly used drugs and has proven to be useful in the formation of products in every-day use, is volatile, and small amounts sublime spontaneously. Pregnant ICR mice were maintained in the vinyl chamber (45 liter) which was ventilated 4 times per hour. To inhale urethane gas, air was passed first through a glass bottle containing 500 g of crystalline urethane and then into the vinyl chamber. Concentration of the sublimed urethane gas in the chamber was 1.28 +/- 0.08 mg/l, and sublimed urethane gas produced significantly high incidence of chromosomal aberrations in the cells of whole embryo, when mice inhaled it for 48 h from day 9 to day 11 of pregnancy. High and significant incidence of chromosomal aberrations (36.0%) was detected in the embryo 3 h after urethane gas inhalation, but decreased to 5.3% at 24 h after exposure and showed no significant differences from controls after 48 h, while the incidence in bone marrow cells from the adult (pregnant) mice was lower (21.5%) at 3 h after exposure but a significant increase remained until 72 h after exposure. A majority of chromosomal aberrations was chromatid types. As a consequence of cellular damages by urethane gas inhalation during pregnancy, significantly high incidence of fetal deaths and congenital malformations (cleft palate, polydactyly, tail anomaly etc.) was induced in the offspring. Thus, we must be aware of the risk of volatile chemicals, because it is difficult to perceive and avoid hazardous exposure via respiration.

Abnormalities, Drug-Induced↗
PubMed1996

Comparative study of the effects of nitric oxide synthase and cyclo-oxygenase inhibition on duodenal functions in rats anaesthetized with inactin, urethane or alpha-chloralose.

This study was undertaken to investigate the effects of a cyclo-oxygenase and a nitric oxide synthase (NOS) inhibitor on duodenal mucosal alkaline secretion (DMAS), motility and mucosal permeability in inactin-, urethane- and alpha-chloralose anaesthetized rats. Proximal duodenum was perfused with a 150 mM NaCl solution and DMAS was determined by back titration. Mucosal permeability was assessed by measuring blood to lumen clearance of 51Cr-EDTA and duodenal motility by measuring intraluminal pressure. Mean arterial blood pressure and mucosal permeability were significantly lower in urethane- than in inactin- or alpha-chloralose anaesthetized rats (urethane: 90 +/- 2 mm Hg and 0.15 +/- 0.02 mL min-1 100 g-1; inactin: 112 +/- 5 mm Hg and 0.62 +/- 0.15 mL min-1 100 g-1; alpha-chloralose: 111 +/- 4 mm Hg and 0.61 +/- 0.06 mL min-1 100 g-1, respectively). Basal (pre-drug) DMAS was significantly lower in urethane rats (6.2 +/- 1.0 mumol cm-1 h-1) than in alpha-chloralose (9.3 +/- 1.2 mumol cm-1 h-1), but not different from that in inactin-anaesthetized rats (7.5 +/- 0.8 mumol cm-1 h-1). No or very few spontaneous duodenal contractions occurred under the control (pre-drug) conditions in any group. All animals responded to the cyclo-oxygenase inhibitor indomethacin or the NOS inhibitor N-nitro-L-arginine-methyl-ester (L-NAME) with induction of duodenal motility and an increase in DMAS. The effect of indomethacin or L-NAME on mucosal permeability was similar in all anaesthetic groups except that L-NAME induced a transient increase in the inactin and alpha-chloralose groups but a sustained increase in urethane-anaesthetized animals. It is concluded that inactin- and alpha-chloralose anaesthetized rats do not differ regarding the studied basal values. Urethane-anaesthetized animals differed from rats given the other two anaesthetics in that basal mucosal permeability and mean arterial blood pressure were lower. Endogenous prostaglandins and NO contribute to the postoperative ileus and the low rate of DMAS also in urethane- and alpha-chloralose.

Anesthesia, General↗
PubMed1985

Distribution of urethane and its binding to DNA, RNA, and protein in SENCAR and BALB/c mice following oral and dermal administration.

Urethane produces threefold more skin papillomas when administered orally than dermally in SENCAR mice, a strain susceptible to tumorigenesis. To better understand the relation of distribution to the initiation stage, [14C]urethane (0.10 mg/kg, 2.5 muCi/25 g) was administered orally and dermally to male SENCAR and BALB/c mice. Absorption of urethane was greater in the first hour in SENCAR mice by both routes, as indicated by more label in the liver, lung, and stomach than found in these tissues in BALB/c mice. These differences were not observed at later time periods after oral administration. Following dermal application, higher levels were maintained in the liver, lungs, and stomach through 48 h in the SENCAR mice when compared to BALB/c mice. Binding of [14C]urethane (0.062 mg/g body weight, 20 microCi/20 g body weight) to DNA, RNA, and protein 6 h after oral administration varied with tissue (liver greater than stomach greater than skin = lung) but did not differ with strain. Binding to DNA in skin, lung, and stomach, RNA in stomach, and protein in stomach and liver after 48 h were significantly higher in SENCAR mice than in BALB/c mice. Dermal application of [14C]urethane resulted in severalfold higher binding to liver DNA of SENCAR mice than BALB/c mice, but DNA binding was comparable in other tissues after 6 h. At 48 h after dermal application, significantly higher levels of [14C]urethane remained bound to skin DNA, RNA, and protein in BALB/c mice, although all values were lower than at 6 h after treatment. Differences in the distribution and binding of urethane probably do not account for the discrepancies in tumor sensitivity. Liver DNA hydrolysates were examined after 48 h. Thin-layer chromatography showed little incorporation of the 14C into the normal deoxyribonucleotide or deoxyribonucleoside bases, and no modified bases were apparent. Radioactivity was present in the fraction that remained at the origin and was consistent with a dinucleotide fragment resistant to phosphodiesterase cleavage, such as a phosphotriester.

Administration, Oral↗
PubMed1997

Comparative study on germ cell mutation induced by urethane (ethyl carbamate) gas and X-rays in Drosophila melanogaster.

Although its mutagenicity has not been confirmed in mouse germ cells, urethane (ethyl carbamate) gas induces a significant increase of X-linked recessive lethal mutations in the germ cells of Drosophila melanogaster. The mutation frequency increased as the exposure time was changed from 3.5 to 5.5 h. Mutations were also induced by X-rays (20 to 40 Gy) and N-methyl-N-nitrosourea (MNU) (0.06 to 0.10%). However, no significant increase of chromosomal changes (partial loss of the Y chromosome, total loss of X or Y, and translocations) was produced by urethane, although these were readily induced by X-rays. There were large and significant increase in chromosomal changes caused by X-rays (20 Gy) compared to urethane (5.5 h) or MNU (0.06%). In contrast, there were no substantial differences among these three treatments as regards recessive lethal mutations. Urethane-induced DNA lesions detected as recessive lethals appear to be intragenic mutations. Complementation analysis with 15 reference single-site loci (cistrons) in the zeste-white region of the X chromosome revealed that 29 of 723 urethane-induced recessive lethals were located in the zeste-white region and all were restricted to a single locus. However, among 28 of 890 X-ray-induced lethals, 2 were non-complementary to 2 or 3 adjacent loci, indicating deletions encompassing 2 or 3 loci. In addition, 3 of these lethal chromosomes included mutations outside the zeste-white region. Another difference between urethane and X-rays was in the distribution of mutation sites. Urethane-induced mutations were strikingly non-random with two hot spots at zw-1 and zw-2, whereas the distribution of X-ray-induced mutations was more nearly random.

Animals↗
PubMed2006

Cellular actions of urethane on rat visual cortical neurons in vitro.

Urethane is widely used in neurophysiological experiments to anesthetize animals, yet little is known about its actions at the cellular and synaptic levels. This limits our ability to model systems-level cortical function using results from urethane-anesthetized preparations. The present study found that action potential discharge of cortical neurons in vitro, in response to depolarizing current, was strongly depressed by urethane and this was accompanied by a significant decrease in membrane resistance. Voltage-clamp experiments suggest that the mechanism of this depression involves selective activation of a Ba2+-sensitive K+ leak conductance. Urethane did not alter excitatory glutamate-mediated or inhibitory (GABA(A)- or GABA(B)-mediated) synaptic transmission. Neither the amplitude nor decay time constant of GABA(A)- or GABA(B)-mediated monosynaptic inhibitory postsynaptic currents (IPSCs) were altered by urethane, nor was the frequency of spontaneous IPSCs. These results are consistent with observations seen in vivo during urethane anesthesia where urethane produced minimal disruption of signal transmission in the neocortex.

Action Potentials↗
PubMed1989

Effect of yohimbine on urethane-induced hyperglycemia in rats.

Urethane is a widely used anesthetic and yohimbine is a well-known alpha 2-adrenergic antagonist. In fasted Wistar rats urethane at an anesthetic dose (1.25 g/kg, i.p.) caused an increase in plasma glucose, while pentobarbital at an anesthetic dose (40 mg/kg, i.p.) did not. Urethane caused no change in plasma glucose in adrenalectomized rats. The hyperglycemic effect of urethane was not inhibited by pretreatment with propranolol (1 mg/kg, p.o.) or prazosin (10 mg/kg, p.o.), but was reduced by pretreatment with phentolamine (10 mg/kg, p.o.) or yohimbine (10 mg/kg, p.o.). Urethane caused an elevation of plasma adrenaline, and yohimbine reduced the elevation. In addition, the pretreatment of yohimbine potentiated the urethane-induced increase in plasma insulin. These results indicate that yohimbine may inhibit the urethane-induced hyperglycemia that is mediated by the central and peripheral alpha 2-adrenergic systems.

Animals↗
PubMed1978

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↗
PubMed1982

Relationship of lung adenoma prevalence and growth rate to acute urethan dose and target cell number.

Outbred Swiss Cox mice of both sexes were given single ip injections of 0.5--2.0 mg urethan/g body weight. Lung adenomas began to grow about 7 days after urethan administration. The relationship of plateau tumor level to dose was slightly concave upward. However, the relationship of average tumor number per 10(6) surviving target cells or alveolar type II cells to dose was markedly concave upward. Thus the definition of the urethan dose-lung adenoma prevalence curve should take into account the urethan cytotoxicity. Tumor diameters followed a log normal distribution pattern. The rate of change of geometric mean tumor diameter was independent of sex and urethan dose. In another experiment Swiss Cox mice received ip injections of 1.5 mg urethan/g body weight, and 4 weeks later chronic exposure to urethan in the drinking water was begun. The growth rate of adenomas induced by the single urethan injection was unaffected by subsequent chronic-urethan administration. The results support the common assumption that tumor growth rate is independent of the rate of chronic administration of a carcinogen.

Adenoma↗
PubMed1980

Effect of commercial saccharin preparations on urethan-induced lung tumorigenesis in strain A mice.

The effect of commercial saccharin preparations on urethan-induced mouse lung tumorigenesis was assessed by gavaging groups of male strain A mice with 1-g/kg doses of each saccharin preparation on a daily basis 5 days/week. Gavage was initiated 1 week before i.p. injection of either a low (0.1 mg/g) or a high (1 mg/g) dose of urethan and continued until the mice were sacrificed 16 weeks after urethan administration. The average number of surface lung tumors per mouse for each group of mice was determined and was compared statistically with the appropriate control group. The commercial saccharin preparations did not produce an elevated lung tumor response when administered alone. One of the four saccharin preparations enhanced the lung tumor response to urethan when given in conjunction with the low dose of urethan, but this enhancement was not statistically significant. At the high urethan dose, all saccharin preparations produced a statistically significant enhancement of the lung tumor response to urethan.

Adenoma↗
PubMed2004

Development of urethane acrylate composite ion-exchange membranes and their electrochemical characterization.

With the objective of introducing antifouling characteristics into interpolymer types of cation and anion exchange membranes, the surface of these membranes was coated with a 12-microm-thick urethane acrylate layer and was cured by UV radiation of wavelengths 308 and 172 nm under a complete inert atmosphere. Different urethane acrylate composite ion exchange membranes developed were characterized in NaCl solution by measuring their ion-exchange capacity, volume fraction of water, contact angle with water, membrane conductance, and membrane potential. It was found that the electrochemical transport properties of urethane acrylate composite cation-exchange membranes were increased due to resonance stabilization of the urethane group, which acts as a weak acid and dissociates as a negatively charged urethane ion and a positively charged proton. This contributes toward the net charge density of the membrane matrix responsible for enhanced selectivity and conductivity, while for urethane acrylate composite anion-exchange membranes reduction in net charge density was responsible for reduction in electrochemical transport properties. Counterion transport number, permselectivity, and counterion diffusion coefficient values for these membranes were also estimated. Experiments were also carried out in higher homologs of sodium carboxylate solutions in order to observe the fouling tendencies of these membranes. It was concluded that it is possible to obtain antifouling characteristics of ion-exchange membranes by coating and curing thin hydrophilic layers of urethane acrylate on their surfaces without sacrificing their electrochemical transport properties.

Journal Article↗
PubMed1997

Dental application of binary urethane monomer mixtures:strengthened resin matrix.

The strengthened resin matrices in six experimental binary visible light-cured (VLC) urethane monomer mixtures were examined in terms of mechanical strength. A 60 wt% bis-GMA/40 wt% binary monomer mixture was used as a control sample. A dry state (1 day in air at 37 degrees C) and a wet state by immersion in distilled water (7 and 30 days at 37 degrees C) were investigated. The compressive strength and diametral tensile strength of urethane monomer samples had values equivalent to, or greater than those of a control sample in the dry state, but had increased values in the wet state. The nano-indentation hardness values in experimental urethane monomer mixtures were greater than that in a control sample in the dry state, showing that immersion in water gave increased strength (maximum increase was about 2.5 times) in six binary urethane monomer mixtures. The compressive strength of the samples in the dry and wet states exhibited linearly increasing elastic modulus values for the resin matrix in the range about 50 to 2600 MPa. The toughened resin matrix had smaller amounts of residual monomer in the urethane monomer mixtures (0.41 to 5.03 wt%) compared with that of the binary 60bis-GMA/40TEGDMA mixture (0.71 to 6.26 wt%). This study has revealed that resin matrices are strengthened by the use of four-functional urethane monomers in experimental binary urethane monomer mixtures.

Journal Article↗
PubMed1951

Age of the host and other factors affecting the production with urethane of pulmonary adenomas in mice.

Young, rapidly growing mice are greatly more responsive to the adenoma-inducing influence of urethane than are those just arriving at maturity. This is manifest both in the proportion of animals developing the tumors and in their number per individual. An amount of urethane per gram body weight which suffices to induce adenomas in only an occasional 8-week-old animal will cause them to appear in quantity in more than half the 3-week-old mice injected. There is an almost absolute inverse correlation between the rate of growth of the pulmonary tissue between the ages of 2 and 10 weeks and the response to urethane in terms of adenomas. Hence the conclusion seems justified that the natural proliferative activity of the alveolar cells during youth plays a major part in the formation of the tumors. After the 6th week the age differences become relatively slight, yet there is reason to think that they continue in some degree as life goes on. Urethane has no effect to promote multiplication of the cells it has rendered neoplastic, its whole role being to initiate neoplastic change. The abnormalities induced by urethane in the nucleus of normal and neoplastic cells, as observed by previous workers, have suggested that the substance brings about the adenomatous state by acting upon the nucleus. But colchicine, also a karyolytic poison causing pronounced nuclear changes, does not alter in the least the yield of adenomas to urethane when administered concurrently. Nor does fasting influence the yield, though it markedly reduces mitotic activity. The meaning of these facts is discussed.

Adenoma↗
PubMed1987

Inhibition of the localization of urethane in mouse tissues by ethanol.

[ethyl-1-14C]Urethane in water or in 12% ethanol was administered orally to male A/JAX mice and 1 hr later the mice were frozen and processed for whole-body autoradiography to identify sites of localization of radioactivity. When the [14C]urethane was administered in water, radioactivity was localized in the liver and bile, the salivary, seromucous and Harderian glands, the bone marrow and pancreas and the stomach and intestinal epithelia. When the labelled urethane was administered in 12% ethanol, localization of radioactivity in each of these sites was almost completely inhibited; radioactivity was still seen within the lumen of the stomach and intestine. Using a defined chemical system, no transesterification was observed between urethane and 12% aqueous [2H6]ethanol at pH 1.5 in 80 min. The inhibition of the localization of radioactivity in the tissues appears to be due most probably to blocking of the metabolism of urethane in tissues. This suggests that ethanol may inhibit the carcinogenicity of urethane in mice.

Animals↗
PubMed1978

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↗
PubMed1995

Pharmacological properties of endothelins and big endothelins in ketamine/xylazine or urethane anesthetized rats.

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor peptide formed through a specific conversion of its intermediate precursor, big ET-1, by an endothelin-converting enzyme (ECE). The present study evaluates the capacity of the ECE to convert the three big endothelins (big ET-1, big ET-2, and big ET-3), by comparing the pressor responses to these peptides with those induced by their respective metabolites (ET-1, -2, and -3) in the rat in vivo, anesthetized either with a mixture of ketamine/xylazine or with urethane. The mean basal arterial pressure under urethane anesthesia was not significantly different from that of ketamine/xylazine-treated animals (90/15 mg/kg; intramuscularly), although the basal heart rate was significantly higher in the former animals (urethane: 407 +/- 10 beats/min, ketamine/xylazine: 276 +/- 4 beats/min, P < .01; n = 8 to 17). In ketamine/xylazine and hexamethonium-treated rats (5-min infusion, 10 mg/kg intravenously), intravenous injection of ET-1 (1 nmol/kg) and big ET-1 (1 nmol/kg) induced potent vasopressor effects which lasted for more than 20 min. ET-2 (1 nmol/kg) produced similar pressor responses while big ET-2 (1-37) and big ET-2 (1-38) were twofold less potent than ET-2 (P < .05; n = 3 to 4). Big ET-3 induced a pressor effect only at 4 nmol/kg and was found to be at least 10 times less potent than ET-3. In animals anesthetized with urethane (1.5 g/kg intraperitoneally), the pressor responses induced by the endothelins and their intermediate precursors, as well as the pressor responses to angiotensin II and norepinephrine, were reduced by more than 60% (P < .01) when compared to ketamine/xylazine-treated animals. Big ET-3 was found inactive under urethane anesthesia. Ganglion blockade by hexamethonium did not affect the response to ET-1, big ET-1, ET-3, or big ET-3 in rats anesthetized with either ketamine/xylazine or urethane. On the other hand, big ET-2 (1-38), in contrast to ET-2 or big ET-1, did not release prostacyclin from the rat perfused lung, thus indicating that big ET-2 (1-38) is poorly converted in the pulmonary vasculature, and that the phosphoramidon-sensitive ECE responsible for the pressor effects of big ET-2 is localized elsewhere in the systemic circulation. Our results also show that the choice of anesthetics is crucial for the proper monitoring of the pressor responses to endothelins as well as other pressor agents. Nonetheless, even in what we consider as optimal conditions of anesthesia (threshold dose for the pressor response to ET-1 in ketamine/xylazine-treated rats: 0.01 nmol/kg), big ET-3 remains far less active than big ET-1 as a pressor peptide in the rat, suggesting a preferential processing of the latter by the ECE.

Anesthetics↗