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PubMed2005

Central and peripheral components of the pressor effect of anandamide in urethane-anaesthetized rats.

1. We wanted to search for the mechanism(s) responsible for the brief pressor response induced by anandamide in urethane-anaesthetized rats. 2. The anandamide-induced pressor effect was not modified by the antagonists of cannabinoid CB(1) and vanilloid TRPV(1) receptors, SR 141716A (3 micromol kg(-1)) and capsazepine (1 micromol kg(-1)), respectively, by bilateral vagotomy and by pithing. Replacement of urethane by pentobarbitone virtually abolished the pressor effect of anandamide, both in pithed and vagotomized and in 'intact' rats (i.e. not treated in this manner). 3. The pressor effect of anandamide was reduced by the nonselective TRPV family inhibitor ruthenium red (3 micromol kg(-1)) and by the blocker of L-type calcium channels nifedipine (1 micromol kg(-1)), both in pithed urethane-anaesthetized rats and in 'intact' urethane-anaesthetized rats. The nonselective beta-adrenoceptor antagonist propranolol (0.1 or 0.3 micromol kg(-1)) and the nonselective NMDA receptor antagonist MK-801 (1 micromol kg(-1)) diminished the anandamide-induced vasopressor response in 'intact' but not in pithed rats. The inhibitory effect of propranolol in 'intact' rats was mimicked by the beta(2)-adrenoceptor antagonist ICI 118551 (1 micromol kg(-1)), but not by the beta(1)-adrenoceptor antagonist CGP 20712 (1 micromol kg(-1)). 4. The present study revealed that two mechanisms may be responsible for the anandamide-induced pressor response in urethane-anaesthetized rats. The first involves the central nervous system (probably the medulla oblongata) and is sensitive to propranolol and MK-801. The second, which is located peripherally (most probably in blood vessels), is sensitive to nifedipine, ruthenium red and pentobarbitone and, hence, probably represents a Ca(2+)-dependent mode of action.

Adrenergic beta-Antagonists↗
PubMed1982

Differential effect of althesin versus chloralose-urethane anesthesia on in vivo LHRH and LH release in the proestrous rat.

Anesthetic doses of Althesin and chloralose-urethane were compared as to their effects on neuroendocrine reproductive processes in diestrous and proestrous rats. Proestrous rats treated with Althesin experienced a 5-fold increase in immuno-reactive luteinizing hormone releasing hormone (LHRH) concentration in methanolic extracts of pituitary stalk plasma. This LHRH increase was 67% greater than that of proestrous rats administered chloralose-urethane. Moreover, Althesin given before the onset of the critical period did not suppress the proestrous surge of LHRH in stalk plasma. The Duncan's multiple range test indicated stalk plasma LHRH activity was significantly elevated in proestrous rats anesthetized with Althesin (p less than 0.05) but not with chloralose-urethane. However, the luteinizing hormone (LH) concentration in peripheral plasma increased 14 to 18-fold in all proestrous rats, including those anesthetized with chloralose-urethane. Evidently, in chloralose-urethane-treated rats, the smaller LHRH surge during proestrus is sufficient to elicit maximum release of LH from the anterior pituitary gland. This suggest that under normal conditions the amount of LHRH secreted into portal blood during proestrus is approximately 2-fold greater than that necessary to elicit maximum secretion of LH. The results also show that picogram concentrations of LH in the stalk plasma will stimulate the release of nanogram quantities of LH into the peripheral plasma of the same rats. Moreover, the sensitivity of the pituitary gland to LHRH stimulation via the portal circulation increases nearly 3-fold between diestrus and proestrus.

Alfaxalone Alfadolone Mixture↗
PubMed1957

Studies of the mechanism of action of urethane in initiating pulmonary adenomas in mice. II. Its relation to nucleic acid synthesis.

The process of carcinogenesis following exposure of mice to urethane is demonstrated in the present work to be intimately related to nucleic acid synthesis. Injection of animals with a DNA hydrolysate immediately prior to a single exposure of the animals to urethane markedly reduced the number of pulmonary adenomas initiated. Aminopterin, known to interfere in nucleic acid synthesis (46), potentiated the carcinogenic action of urethane and this potentiation was blocked by injection of a DNA hydrolysate. Of the components and precursors of nucleic acids the pyrimidine series seemed especially concerned. Alterations in the utilization of oxaloacetate, ureidosuccinic acid, dihydro-orotic acid, orotic acid, cytidylic acid, and thymine appeared to be critical steps in the oncogenic process, following upon the primary disorder of cellular metabolism initiated by the carcinogen. All these substances except oxaloacetate profoundly reduced the number of tumors initiated by urethane. Oxaloacetate potentiated the carcinogenic effect. When these results are viewed together and in relation to known facts concerning nucleic acid synthesis they provide evidence suggesting that the point of action of the carcinogen is in the pathway of nucleic acid synthesis below orotic acid and perhaps at the level of ureidosuccinic acid. The potentiating influence of adenine, 4-amino-5-imidazole carboxamide, and aminopterin, the lack of effect of uracil, and the inhibitory influence of thymine together suggest that DNA rather than RNA is the nucleic acid critical to the oncogenic response of mice to urethane.

Adenine↗
PubMed1978

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↗
PubMed1995

Anticonvulsive effect of urethane on aminopyridine-induced epileptiform activity.

The effects of urethane anaesthesia on the development and spread of ictal-like epileptiform activity induced by 3-aminopyridine, was investigated on the somatosensory cortex of rats. Under urethane anaesthesia in most animals only one abortive ictal period appeared with dose-dependent latency. Urethane completely abolished high frequency afterdischarges (5-10 Hz) and prevented the development of recurrent seizures in both primary and mirror foci. Urethane also eliminated ongoing epileptiform activity induced previously by 3-aminopyridine under nembutal anaesthesia. The antiepileptic effects of urethane on ictal-like activity may be the consequence of a presynaptic action through reduction of glutamate-mediated excitation together with a depressant effect on responsiveness of cortical neurones. The afterdischarges of high frequency could be essential to development and stabilization of repetitive tonic events in the neocortex.

Aminopyridines↗
PubMed1975

An autoradiographic and morphological study of mouse bone marrow littoral cells during and after treatment with urethane.

This study demonstrates that the labeling index of mouse marrow littoral cells can be markedly altered as a result of treatment with ethyl carbamate (urethane). Young C57/BL mice were given daily intraperitoneal urethane injections for periods up to 6 days. Following treatment each day, as well as daily over a 10 day recovery period, a group of animals was administered tritiated thymidine every 3 hr over a 24 hr period and sacrificed 1/2 hr after the last injection. Marrow was embedded in epon and 0-5 mum sections cut for autoradiographic and light microscopic analysis. A thirty-five-fold increase in the percentage labeled littoral cells was observed after three injections of urethane. The labeling index of littoral cells fluctuated during the treatment period and during the 10 day recovery period. The albeling data are discussed in relation to the possible effects of urethane on the cell cycle of mouse marrow littoral cells; the morphological sequela to urethane treatment and the possibility that littoral cells may act as stem cells.

Animals↗
PubMed2006

Effects of isoflurane, pentobarbital, and urethane on apoptosis and apoptotic signal transduction in rat kidney.

BACKGROUND: Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Anesthetic agents have been shown to modulate apoptotic signal transduction in various tissues. We examined the effects of 6 h of different general anesthetic techniques on renal cell apoptosis in rat kidneys. METHODS: Twenty-one male Sprague-Dawley rats were randomly allocated into four groups: (i) control, non-anesthetized rats (n= 3) and rats anesthetized with (ii) inhaled isoflurane (n= 6), (iii) intraperitoneal pentobarbital (n= 6), and (iv) intraperitoneal urethane (n= 6). Animals were sacrificed 6 h after the induction of anesthesia. RESULTS: Apoptosis was assessed by terminal deoxynucleotidyl transferase-fluorescein end-labeling analysis. RNA was extracted from the left kidney to probe cDNA microarrays. Gene expression was measured as a percentage of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and subsequently confirmed using reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with the control (no anesthesia), urethane significantly (P < 0.001) induced apoptosis in both the renal cortex and medulla. Isoflurane significantly (P < 0.001) inhibited apoptosis in the medulla. Microarray analysis revealed that urethane up-regulated more (74) genes than pentobarbital (16) and isoflurane (10). Isoflurane down-regulated more genes (85) than pentobarbital (74) and urethane (12). These anesthetic-induced modulations were significant (P < 0.05) for 60 isoflurane-, 30 pentobarbital- and 4 urethane-modulated genes. CONCLUSION: Our results suggest that general anesthetic drugs have an effect on renal cell apoptosis and apoptotic signal transduction, and thus may potentially affect the risk of subsequent acute renal failure.

Animals↗
PubMed1980

Effect of urethane on folate contents of chick embryos measured with a microbial assay.

In earlier studies it was found that the effects of urethane could be reversed by folic acid and thymidine but not by uridine. It was further shown that urethane-treated chick embryos were unable to convert serine to glycine, homocysteine to methionine and uridine to thymidine, all of which are folate-dependent reactions. Due to the sensitivity of folic acid auxotrophs towards small amounts of folates present in the biological material, the folic acid contents of urethane-trewated and untreated chick embryos are studied, using microbial assay. It is found that there is a statistically significant reduction in the total folate content of chick embryos treated with urethane as compared to those from the untreated controls. It is conluded that urethane has an antifolate action.

Animals↗
PubMed1997

Enhanced myopathy following administration of hypolipidemic agents under urethane anesthesia.

The enhanced effect of urethane anesthesia on the serum creatine kinase (CPK) level following administration of hypolipidemic agents was examined to develop a convenient experimental screening method for drug-induced myopathy. After oral administration of a hypolipidemic agent to rats, 25% urethane solution was infused intravenously at a very low rate using a microinfusion pump. Blood samples were collected 7 h after drug administration and the risk of myopathy was evaluated based on the CPK level. When bezafibrate (BF), simvastatin (SV), or pravastatin (PV) (50-500 mg/kg) was orally administered under urethane infusion, enhanced elevation of the serum CPK level was observed dose dependently for BF and SV, but not for PV. The elevation of serum CPK was much higher with BF than with SV or PV. In addition, when SV or PV (50-500 mg/kg) was coadministered with 50 mg/kg of BF, there was a striking increase in the serum CPK level as compared with the drug alone. Without urethane infusion, no significant elevation in serum CPK level was observed even at a high dose of these hypolipidemic agents. These phenomena suggest that the urethane anesthesia enhanced the elevation of the serum CPK level following administration of hypolipidemic agents. We propose that this method is a simple and speedy screening test for drug-induced myopathy.

Anesthesia↗
PubMed1988

Different responses to beta-adrenoceptor blocking drugs of the blood pressure and heart rate in the urethane-anesthetized dog and rat.

I.v. propranolol (Prop) produced sustained pressor responses in rats but not in dogs under urethane anesthesia. In the dogs there was a progressive reduction in systolic blood pressure (SBP) in accordance with a significant heart rate (HR) reduction. Even at the i.v. dose (5 mg/kg) where vasoconstrictor response to i.v. norepinephrine (NE) is changed to the vasodilator one in rats, phenoxybenzamine could not completely suppress the NE-induced vasoconstriction in dogs. In pithed dogs, unlike pithed rats, i.v. Prop augmented neither sympathetic nerve stimulation- nor i.v. epinephrine (Epi)-induced pressor responses. Urethane anesthesia brought much higher concentrations in plasma Epi and NE in the dog than in the rat. In comparison with their respective values under the conscious state, SBP and HR of the dog were higher and those of the rat were lower under urethane anesthesia. As in urethane-anesthetized dogs, i.v. Prop elicited remarkable HR reduction accompanied by progressive hypotension in coronary-ligated rats with high sympathetic activity. Thus the reason for the absence of pressor response to beta-receptor blockage in the dog may be due to less functional significance of beta 2-adrenoceptor-mediated vasodilation in determining the peripheral vascular tone; and also, the possibility that there may be the involvement of an inverse influence of urethane on the cardiovascular regulatory system in terms of enhancing sympathetic nervous activity in the dog and a decreasing one in the rat can not be ruled out.

Adrenergic beta-Antagonists↗
PubMed1984

The effect of urethane on pituitary-adrenal function of female rats.

Urethane anaesthesia resulted in rapid and sustained increase in plasma corticosterone levels of adult female rats both in the (a.m.) AM and (p.m.) PM. Initial corticosterone levels of non-injected control rats showed marked AM-PM differences (i.e., 28.3 micrograms/dl and 52.6 micrograms/dl, respectively), but by 10 min post-injection, the morning corticosterone levels were increased (76.2 micrograms/dl) such that AM-PM differences were not observed. By 30 min post-injection, PM plasma corticosterone levels had increased significantly (88 micrograms/dl) but were not different from AM values for the remainder of the 2 h experiment. Saline injected controls showed the expected response to stress; plasma corticosterone levels were increased (P less than 0.01) at 10 min but were back to baseline by 45 min (9.0 micrograms/dl). Dexamethasone (100 micrograms/kg, sc) markedly suppressed both AM and PM urethane-stimulated corticosterone levels. However, diurnal differences in dexamethasone suppression were noted; whereas morning plasma corticosterone levels averaged 24.8 micrograms/dl over the five sampling times corresponding PM values averaged 54.3 micrograms/dl. Plasma corticosterone levels of non-anaesthetized, hypophysectomized ACTH-primed and injected rats were not different from those similarly treated and anaesthetized with urethane and urethane-induced increases in corticosterone were not abolished by hypothalamic isolation (HI). However, plasma corticosterone levels of HI rats were less than those of sham-operated controls (i.e., 58 micrograms/dl and 74 micrograms/dl, respectively). Collectively, these data indicate that urethane evokes a sustained increase in pituitary-adrenal activity, that the increased activity is dexamethasone sensitive and that a site of action for pituitary-adrenal activation is, at least in part, at the level of the hypothalamo-hypophyseal complex.

Adrenocorticotropic Hormone↗
PubMed1994

Comparison of lung tumorigenesis induced by urethan in athymic nude mice and euthymic littermates.

Athymic (nu/nu) and euthymic (nu/+) mice were intraperitoneally given doses of 0.25 to 1.5 mg/g body weight of urethan at the age of 14 to 16 days. Dose-response relationship and sequential changes in lung tumorigenesis induced by urethan in athymic mice were compared with those in euthymic littermates. The urethan dose-response relationship in lung tumorigenesis of the nu/nu mice was almost the same as that in the nu/+ mice. Incidence and multiplicity of the lung tumors were investigated sequentially 28 days to 12 months after urethan injection. They showed similar indexes in the two phenotypically different mice at varying periods after 0.5 mg/g body weight urethan treatment (incidences of 4.8 and 4.4 tumors/mouse and 96 and 97% for nu/nu and nu/+ mice, respectively, at 12 months after treatment). This means that the length of the latent period is similar in these phenotypically different mice. It may be concluded that the immunosurveillance mechanism mediated by T-cells does not function in the present model.

Animals↗
PubMed1975

Potentiation by urethane and inhibition by pentobarbitone of oxytocin release in vitro.

Isolated rat neural lobes were incubated in vitro in Locke's solution containing anaesthetic quantities of urethane, pentobarbitone or tribromoethanol. The oxytocin content of the incubation medium was estimated before, during and after stimulation of the tissue by raising the potassium chloride concentration from 5-6 to 56 mmol/l. Urethane (25 mmol/l) significantly potentiated oxytocin release (P less than 0-01) whereas tribromoethanol (0-5 mmol/l) had no obvious effect and pentobarbitone (0-4 mmol/l) significantly (P less than 0-01) inhibited its release. Reduction of the sodium chloride concentration in the medium potentiated the release of oxytocin in each case but did not alter its pattern. Urethane which increased secretion of oxytocin also increased calcium ion uptake by the neural lobes and pentobarbitone which decreased oxytocin release decreased calcium ion uptake. The results may explain why the blood concentration of the neurohypophysial hormones tends to be higher in rats anaesthetized with urethane than with tribromoethanol. Inhibition of hormone release by pentobarbitone suggests that this anaesthetic is unsuitable for use in studies of neurohypophysial hormone release. A partial explanation of the anaesthetic properties of urethane and pentobarbitone may also have been found if the release of neurotransmitter substances is influenced in a similar manner.

Animals↗
PubMed1985

Conditioned cortical slow potential responses in urethane anesthetized rats.

Cortical slow potential (SP) responses to tone or light stimuli preceding medial forebrain bundle (MFB) stimulation were recorded in urethane anesthetized rats. In the first study, rats were implanted with Ag-AgCl electrodes for recording frontal cortex SPs as well as monopolar electrodes for MFB stimulation. Following recovery, optimum stimulation parameters for SP conditioning were determined for each rat during self-stimulation sessions. These animals were then subjected to extensive associative conditioning in the unanesthetized state. Trials were presented at variable intervals and a 2-sec tone preceded a single 0.5 sec train of MFB stimulation. Negative SP responses developed with training and responses of similar waveform and amplitude were observed in the same animals under urethane anesthesia. Other rats were implanted with MFB stimulating electrodes and, after recovery, stimulation parameters were determined as above but the animals were not subjected to the conditioning procedure prior to urethane administration. Under urethane anesthesia, Ag-AgCl electrodes were placed on the dura over frontal cortex for recording SP responses during pseudoconditioning, conditioning, extinction and retraining trials, using either light or tone stimuli. Negative bilateral SP responses to the tone or light were minimal or nonexistent during pseudoconditioning, developed gradually with pairing, diminished markedly during extinction and returned to maximum amplitude with retraining. The SP responses also reflected discrimination between reinforced and nonreinforced tone and light stimuli as well as reversal conditioning. Furthermore, turning off a light could also serve as the conditioned stimulus for SP response generation. Cortical slow potential responses can be conditioned in urethane anesthetized rats. Therefore, it may be possible to apply additional neurophysiological techniques in these animals to investigate event-related slow potential mechanisms.

Anesthesia, General↗
PubMed1990

The effect of diethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and disposition in rats.

1. The disposition of diflunisal (DF) at 10 mg/kg i.v. was investigated over 4 h in bile-exteriorized male rats continuously anaesthetized with (a) diethyl ether inhalation (as required), (b) pentobarbitone sodium i.p. (55 mg/kg initially), (c) urethane i.p. (1500 mg/kg initially) or (d) urethane i.v. (750 mg/kg initially), and compared to that obtained in conscious rats. 2. Diethyl ether decreased the plasma clearance of DF to about 30% of control values, by inhibition of both glucuronidation and sulphation of DF. 3. Pentobarbitone anaesthesia caused only modest inhibition of DF elimination, with plasma clearance decreased to about 80% of control values. 4. Plasma profiles and biliary recovery of DF and its conjugates were little altered by urethane i.p. anaesthesia, but urinary recovery was low and variable because of the nearanuria produced by urethane via this administration route. 5. Urinary recovery of DF and its conjugates was satisfactory in rats given urethane i.v., but tissue distribution of DF was substantially decreased. 6. Pentobarbitone was considered to interfere least with DF disposition at the 10 mg/kg dose, and was selected as the most suitable anaesthetic agent for ongoing studies of disposition of DF and its conjugates in anaesthetized rats.

Anesthetics↗
PubMed1997

The inhibitory effect of vitamin E on arachidonic acid metabolism during the process of urethane-induced lung tumorigenesis in mice.

It is known that change in the arachidonic acid metabolism plays an important role in the development of tumors. This study was undertaken to understand the relationship of changes in lipoxygenase, cyclooxygenase and ornithine decarboxylase (ODC) to the inhibitory effect of vitamin E on urethane-induced lung tumorigenesis in mice. We analyzed the inhibitory effect of vitamin E on ornithine decarboxylase, cyclooxygenase and lipoxygenase activities at a promotion phase of lung tumorigenesis in mice. An increase in the ODC of urethane treated-mice and no significant change in the ODC of VE-treated mice were observed. An increase in the production of PGE2 and all HETES tested in the lungs of the urethane-treated mice was observed at week 8 after injection (promotion phase), showing a significant difference compared to the control group. Excessive vitamin E feeding during the initiation or promotion phases inhibited the increase in PGE2 and HETES produced by urethane treatment. These results suggest that the suppression of prostagrandin metabolism and ODC may be associated with the inhibitory effect of vitamin E against urethane-induced lung tumorigenesis.

Animals↗
PubMed1999

An investigation of male-mediated F1 effects in mice treated acutely and sub-chronically with urethane.

In order to investigate the alleged potential of paternally administered urethane to cause foetal abnormalities and heritable tumours, male CD-1 mice were treated with urethane, either acutely by intraperitoneal injection at doses of 1.25 and 1.75 g/kg bodyweight (bwt) or sub-chronically in the drinking water at 1.25 for 10 weeks, and 3.75 mg/ml for 9 weeks or vehicle for the control groups. They were mated to untreated females 1 week later. Uterine contents of half the pregnant females were examined just before full term, while the remaining females were allowed to deliver their litters. The resulting F1 offspring were observed for approximately 18 months and 12 months for acute and sub-chronic exposures respectively and subjected to necropsy examination. Some of the mice treated acutely with 1.75 g/kg bwt exhibited partial infertility but none of those treated with 1.25 g/kg bwt had an adverse effect on their reproductive ability. There was no genetic effect of acute urethane treatment on male germ cells as indicated by dominant lethality. After birth, there was an increase (P < 0.05) in post-implantation deaths possibly due to perinatal mortality. There was an increased incidence and earlier onset of liver tumours induced in F1 male offspring from F0 males treated with 1.75 g/kg bwt, (20.7% vs. 10.1%, P = 0.026) but not in the female offspring. F1 males from both treatment groups had mean bodyweights significantly higher than controls (P < 0.01). Some males from each dose group of the acute study were examined using the restriction site mutation assay involving analysis of exon sequences. No mutations were identified in testes, liver or spleen of DNA isolated from the urethane-treated animals. No reproductive or genetic effects were seen with sub-chronic treatment at either 1.25 or 3.75 mg/ml urethane nor was there any predisposition of F1 animals to tumours although observation times were shorter.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

The renin-angiotensin system and intraperitoneal toxicity: possible basis to urethane anaesthesia-induced reductions in renal clearance in the rat.

With the aim of examining the possible basis to i.p. urethane anaesthesia-induced reductions in renal clearance, this study has investigated: (a) the influence that some anaesthetic regimens may have on the renin-angiotensin system (RAS); and (b) the ability of these anaesthetic regimens to initiate intraperitoneal toxicity. In the rat, i.p. urethane anaesthesia, compared with pentobaritone i.p. and "Hypnorm/Hypnovel" i.p. anaesthesia, resulted in significantly lower mean arterial pressure (MAP) and elevations in plasma renin activity (PRA) in both surgically-prepared and surgically-intact animals. Urethane anaesthesia also produced intraperitoneal toxicity, which was characterized by a greater peritoneal fluid volume and peritoneal cavity total protein content. The elevated protein content in the peritoneal cavity resulted in part from plasma leakage from the vascular compartment, as demonstrated by i.v. Evans' blue dye studies. Intraperitoneal toxicity was absent following administration of urethane by either i.v. or oral routes. A reduction in systemic perfusion pressure and an elevation in renal vascular resistance, via activation of the RAS are likely to be responsible for i.p. urethane-induced reductions in renal clearance. Intraperitoneal toxicity is likely, only in part, to be responsible for such changes.

Anesthesia↗