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Gastric acid secretion by central injection of dynorphin A-(1-17), an endogenous ligand of kappa-opioid receptor, in urethane-anesthetized rats.

Gastric acid secretion has been proposed to be regulated by opioid receptors in the central nervous system (CNS). Previously, we reported that central injection of synthetic agonists of kappa-opioid receptors stimulated gastric acid secretion in rats, and the secretion by the agonists was inhibited by norbinaltorphimine (an antagonist of kappa-opioid receptor). In the present study, we investigated the effect of dynorphin A-(1-17), an endogenous ligand of kappa-opioid receptor on the gastric acid secretion in the perfused stomach of urethane-anesthetized rats. Injection of dynorphin A-(1-17) (0.1-1 microg per rat) into the lateral cerebroventricle (LV) stimulated the secretion in a dose-dependent manner. The effect of dynorphin A-(1-17) was almost completely inhibited by the LV injection of norbinaltorphimine (10 microg) and in vagotomized rats. Although some studies of dynorphin A-(1-17) after central injection showed non-opioid effects such as the involvement of N-methyl-D-aspartate (NMDA) receptor, the effect of dynorphin A-(1-17) was not inhibited by a selective antagonist of the NMDA receptor ((+/-)-3-(2-carboxypiperazin-4-yl)-1-propylphosphonic acid, 10 microg). The LV injection of naloxone benzoylhydrazone (a kappa3-opioid receptor agonist, 100 microg) also stimulated the secretion in norbinaltorphimine-sensitive manner. These findings showed that both an endogenous ligand dynorphin A-(1-17) and a synthetic kappa3-opioid receptor agonist stimulated gastric acid secretion via kappa-opioid receptors in the CNS of rats in vivo.

Anesthesia↗

Effects of urethane, alphaxolone/alphadolone, or halothane with or without neuromuscular blockade on survival during repeated episodes of global cerebral ischaemia in the rat.

The effect of 4 anaesthetic regimens on blood pressure and survival was investigated during repeated episodes of cerebral ischaemia in the rat induced by diathermy of the vertebral arteries and reversible occlusion of the carotid arteries. The best results were obtained with inspired halothane with neuromuscular blockade and artificial ventilation, followed in order by halothane, intravenous alphaxolone/alphadolone, and intraperitoneal urethane with spontaneous ventilation.

Anesthetics↗

Suppressive effects of cholecystokinin and bombesin on growth hormone and prolactin secretion in urethane-anesthetized rats.

The effects of cholecystokinin octapeptide (CCK) and bombesin on rat plasma growth hormone (GH) and prolactin (PRL) levels were investigated with the animals under urethane anesthesia. Intraventricular administration of both CCK (0.3 micrograms) and bombesin (2 micrograms) completely suppressed the GH secretion induced by FK 33-824, chlorpromazine (CPZ) or prostaglandin E2(PGE2). Both peptides also completely suppressed the PRL secretion induced by FK 33-824 or PGE2, and partially that induced by CPZ, but not that induced by domperidone. The intravenous administrations of CCK and bombesin had no or lesser potency in inhibiting the stimulated GH or PRL releases. These results indicate that the CCK and bombesin act much in the same manner to inhibit GH and PRL. These peptides may suppress the GH and PRL secretions via a hypothalamus-related action.

Anesthesia, General↗

Effects of pentazocine on coronary hemodynamics under pentobarbital or chloralose-urethane anesthesia in dogs.

The effect of pentazocine on the coronary hemodynamics was studied in anesthetized dogs. Under pentobarbital anesthesia pentazocine did not cause any significant changes in the coronary hemodynamics. Under chloralose-urethane anesthesia, however, it produced a statistically significant increase in heart rate, left coronary blood flow rate, myocardial oxygen consumption as well as myocardial oxygen extraction rate, but a decrease in coronary vascular resistance. These results indicate that the effects of pentazocine on the coronary hemodynamics are modified significantly by the drugs used for basal anesthesia.

Anesthesia, Intravenous↗

Plasma concentrations of prolactin and thyrotrophin during suckling in urethane-anaesthetized rats.

Plasma levels of prolactin and TSH were determined by radioimmunoassay in urethaneanaesthetized lactating rats during suckling. Oxytocin release was monitored by recording intramammary pressure. Application of ten pups, 3 h after administration of urethane (1-1 g/kg, i.p.), evoked a parallel rise in prolactin and TSH concentrations which reached a maximum during the 3rd hour of suckling and then declined. Peak hormone concentrations represented a 25-fold increase in prolactin and a ten-fold increase in TSH. Suckling also elicited a pulsatile (every 5-10 min) release of 0-5--1-0 mu. oxytocin. The gradual rise in prolactin and TSH occurred between the 1st and 20th oxytocin pulses. Intravenous injection of thyrotrophin-releasing hormone (TRH) into unsuckled, anaesthetized lactating rats resulted in a 7- to 30-fold increase in TSH concentration, whereas prolactin levels showed no substantial change. These results indicate that suckling releases TSH as well as prolactin in the urethaneanaesthetized rat. However, the absence of prolactin release after injections of TRH makes it unlikely that both endocrine responses are regulated solely by the actions of this one releasing hormone.

Anesthesia↗

Lack of modifying effects of eugenol on development of lung proliferative lesions induced by urethane in transgenic mice carrying the human prototype c-Ha-ras gene.

To investigate the modifying effects of eugenol (EUG), a component of cigarette smoke, on lung carcinogenesis, male and female transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) were given a single intraperitoneal injection of 250 mg/kg urethane (UR) or saline, followed by a diet containing 6,000 ppm EUG or basal diet for 26 weeks. Their non-transgenic CB6F1 littermates (non-Tg mice) were also treated in the same manner. In both male and female rasH2 mice, alveolar/bronchiolar hyperplasias, adenomas and carcinomas were observed in all UR-treated groups. However, there were no significant intergroup differences in the incidences and multiplicities of these lesions between the UR alone and UR + EUG groups. In non-Tg mice, alveolar/bronchiolar hyperplasias, adenomas or carcinomas were sporadically observed in UR-treated groups of both sexes, with no significant differences in the incidences and multiplicities between the UR alone and UR + EUG groups. There were no intergroup differences between them in the PCNA-positive ratios of adenomas or carcinomas and the areas of adenomas or carcinomas to the whole lung area examined. The present results suggest that the EUG treatment does not exert modifying effects on lung carcinogenesis induced by UR in both male and female rasH2 mice and non-Tg mice.

Adenoma↗

Immediate ascites conversion of mammary tumors induced in NYLR/Nya mice by 7,12-dimethylbenz-[a] anthracene and urethane feeding and by forced breeding.

Intragastric feeding of dimethylbenz-[a]anthracene in corn oil together with urethane in the drinking water and forced breeding were successful in rapidly inducing (2-4 months) mammary tumors (adenoacanthomas) in inbred NYLR/Nya mice, which have a low incidence of spontaneous breast tumors and of other tumors. The tumors could be quickly and permanently transformed to an ascites form by intraperitoneal inoculation of enzyme-dissociated cells and subsequent serial passage of free cells. Only 10 (3 in some cases) serial passages were required, thus conveniently providing multiple isogeneic carcinoma cell lines in this strain of mice. Some tumor cell lines proliferated strongly in the abdominal cavity even on the first passage.

9,10-Dimethyl-1,2-benzanthracene↗

Differentiation of human embryonic stem cells to hepatocytes using deleted variant of HGF and poly-amino-urethane-coated nonwoven polytetrafluoroethylene fabric.

Human embryonic stem (hES) cells have recently been studied as an attractive source for the development of a bioartificial liver (BAL). Here we evaluate the differentiation capacity of hES cells into hepatocytes. hES cells were subjected to suspension culture for 5 days, and then cultured onto poly-amino-urethane (PAU)-coated, nonwoven polytetrafluoroethylene (PTFE) fabric in the presence of fibroblast growth factor-2 (bFGF) (100 ng/ml) for 3 days, then with deleted variant of hepatocyte growth factor (dHGF) (100 ng/ml) and 1% dimethyl sulfoxide (DMSO) for 8 days, and finally with dexamethasone (10(-7) M) for 3 days. The hES cells showed gene expression of albumin in a time-dependent manner of the hepatic differentiation process. The resultant hES-derived hepatocytes metabolized the loaded ammonia and lidocaine at 7.8% and 23.6%, respectively. A million of such hepatocytes produced albumin and urea at 351.2 ng and urea at 7.0 microg. Scanning electron microscopy showed good attachment of the cells on the surface of the PTFE fabric and well-developed glycogen rosettes and Gap junction. In the present work we have demonstrated the efficient differentiation of hES cells to functional hepatocytes. The findings are useful to develop a BAL.

Actins↗

Ether, carbonate and urethane deoxynucleoside derivatives as prodrugs.

3'-Deoxythymidine and its 3'-azido derivative, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine and 2',3'-dideoxyadenosine have been acylated to form carbonates and urethanes in chemoselective reactions. The nucleosides have been N- and/or O-alkylated by alpha-chloroethyl or chloromethyl alkyl carbonates to form alpha-alkyloxycarbonyloxyethyl or alkyloxycarbonyloxymethyl derivatives. The products are lipophilic in order to facilitate transport through biological membranes and are designed to be cleaved by esterases with liberation of the bioactive nucleoside. Initial esterase cleavage of the alkylated derivatives produces hemiacetals or -aminals which subsequently dissociate to the active nucleoside.

Antiviral Agents↗

Activation of tachykinin system in the pedunculopontine tegmental nucleus suppresses hippocampal theta rhythm in urethane-anesthetized rats.

The pedunculopontine tegmental nucleus (PPN) is one of the reticular generators of the hippocampal theta rhythm. The PPN neuronal circuitry related to theta generation involves its cholinergic, GABA-ergic and glutamatergic components. Here we provide data indicating that the PPN tachykinin system may also be a part of this circuitry. In the experimental model of the tail-pinch elicited hippocampal theta in urethane-anesthetized rats (implanted with bilateral recording electrodes in the stratum moleculare of the upper blade of the dentate gyrus and with injection cannula unilaterally inserted into the PPN) it was found that intra-PPN microinjection of Substance P (SP) and [d-Pro2, d-Phe7, d-Trp9]-Substance P (DPDPDT) caused suppression of the theta and enhancement of the delta activity in the hippocampal EEG. Accordingly, there was approximately a 50% (SP)-70% (DPDPDT) decline of the peak power in the theta frequency range and a decrease by 0.4 Hz in the corresponding peak frequency (DPDPDT only) in both hippocampi. The circuitry through which SP exerts its effect in the PPN can be only hypothetical at present. We suggest SP-evoked activation (either direct or indirect through the glutamatergic inputs) of the GABA interneurons which may tonically inhibit PPN outputs to the other theta-relevant structures.

Anesthesia, Intravenous↗

Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat.

Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral models and that vary with respect to their primary biological target: 1) the nootropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-activated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the acetylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognition-enhancing drugs produced dose-dependent increases in hippocampal theta rhythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthetized rat. These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.

Anesthesia↗

Videographic assessment of the embolic characteristics of three polymeric compounds: ethylene vinyl alcohol, cellulose acetate, and liquid urethane.

BACKGROUND AND PURPOSE: Aneurysms have been clinically and experimentally treated with various surgical and endovascular methods, including endovascular polymer instillation. Additional tools may help to identify advantages and disadvantages of polymeric aneurysm treatment. We assessed the value of high-resolution videography to compare in vitro embolization characteristics of ethylene vinyl alcohol copolymer (VIN), cellulose acetate polymer (ACE), and urethane copolymer (UCO). METHODS: In a "neck-up" glass aneurysm model, solutions of 8% and 12% VIN, 8% and 12% ACE, and 8% UCO were introduced through a microcatheter into a xanthan gum solution at three flow rates: full physiological (62 cm/s), half physiological, and flow arrest. Each formulation was then introduced into a "neck-down" aneurysm model at flow arrest, for a total of 20 experiments. Results were tabulated for six different categories: outflow tail formation, inflow-zone polymer-mass deformation, inflow-zone migration, detachment tail formation, adherent mass pullout, and conjectural net effect. RESULTS: Of the 20 experiments, nine had unacceptable results because of potential clinical complications. The results were unacceptable in four of eight VIN experiments, four of eight ACE experiments, and one of four UCO experiments. VIN performance was more dependent on flow arrest than the more viscous ACE. The growth of the ACE solutions was most circumferential, with balloonlike growth characteristics, little inflow-zone effects, and fewer outflow tails than seen with VIN. All compounds had the potential for partial catheter adhesion and catheter-adhesing tails. UCO had the highest percentage of favorable results and the lowest percentage of unfavorable results. CONCLUSION: Videographic analysis allows detailed assessment of the dynamic embolization characteristics of polymers, revealing potential advantages of compounds such as UCO.

Cellulose↗

Ultrastructure of spontaneous and urethan-induced thymomas in buffalo rats.

Normal thymuses from Buffalo and Long-Evans rats of various ages, and spontaneous and urethan-induced thymomas in Buffalo rats, were examined by electron microscopy. Histological variabilities among thymomas of the lymphoid, mixed, and epithelial cell types were a reflection of the number of lymphoid cells within the network composed of neoplastic epithelial reticular cells. In the cytoplasm of these cells, development of tonofilaments and membrane-bound bodies and inverse development of the rough-surfaced endoplasmic reticulum were recognized in the sequential process from the lymphoid cell type to the epithelial cell type. An important role of the development of the rough-surfaced endoplasmic reticulum for thymic function was suggested. Phagocytic activity of the neoplastic epithelial reticular cells was revealed, and some of the membrane-bound bodies in these cells, especially those with moniliform structures, were regarded as remnants of damaged lymphocytes. Evidence for neoplastic epithelial reticular cell-lymphoid cell transformation could not be established from study of the thymoma tissue. No virus-like structures were observed in these thymomas.

Animals↗

On the influence of chloramphenicol on the induction of lung adenomas by urethane in mice.

It has been shown by a number of authors that the antibiotic chloramphenicol (CP), produced in the USSE under the name of levomycetin, had considerably inhibited the growth of liver tumors, induced by various carcinogenic compounds [3,7,8,21]. Moreover, it has been found by ourselves and other authors that CP greatly reduces the toxic effect of carcinogenic polycyclic hydrocarbons on cultures of embryonic fibroblasts of mice and the adrenals of rats [5,9,20,23]. As the full extent of the antiblastomogenic activity of CP has so far not been studied, it was important to elucidate its influence on other groups of chemical carcinogens. In experiments described in the present paper we have investigated the influence of CP on the incidence of lung adenomas in mice after administration of urethane.

Adenoma↗

Fentanyl-fluanisone-midazolam combination results in more stable hemodynamics than does urethane alpha-chloralose and 2,2,2-tribromoethanol in mice.

Near-physiologic hemodynamic conditions for several hours were needed to study cardiovascular physiology in a murine model. We compared two commonly used anesthetic treatments, urethane alpha-chloralose (U-alphaCh; 968 mg U and 65 mg alphaCh/kg) and 2,2,2-tribromoethanol (TBE; 435 mg/kg) and fentanyl fluanisone midazolam (FFM; 3.313 mg fentanyl, 104.8 mg fluanisone, and 52.42 mg midazolam/kg) with respect to mean arterial blood pressure (MAP) and heart rate (HR) for 100 min at similar levels of surgical anesthesia. Assessed every 10 to 15 min, the U-alphaCh+TBE group maintained a significantly (P < 0.001) lower mean MAP (49 4 mmHg) than did the FFM group (78 5 mmHg). Mean HR in the U-alphaCh+TBE group significantly (P < 0.001) increased from 308 34 bpm at the beginning to 477 43 bpm at the end of the experiment. In comparison, the FFM group showed a stable HR of 431 37 bpm. The MAP and HR of the U-alphaCh+TBE group were extremely unstable, with sudden and unpredictable changes in MAP when examined at 1-min intervals. The results of our study show that U-alphaCh+TBE anesthesia should not be used in murine models in which stable, near-physiologic hemodynamics are needed for cardiovascular studies.

Anesthesia↗

[Use of polyester urethane (Neuro-Patch) as a dural substitute. Prospective study of 70 cases].

Between October 1995 and March 1998, 70 patients were treated with a microporous polyester urethane dura substitute (Neuro-Patch), after brain or spinal surgery. These patients were assessed clinically and radiologicaly 10 days, 6 weeks and 1 year after surgery. Radiological evaluation used CT scan or MRI. All dura substitutes were fixed by continuous suture to the surrounding dura-mater. We studied the handling properties, the incidence of infection and of CSF leakage. Eleven patients underwent craniotomy again. This gave us the opportunity to examine the adhesion to the brain tissue and the integration of the dura substitute. Six sheets underwent histological examination. Our results show good handling properties of the material; 3 infections; 6 out of 9 radiological CSF leakage occurred from infratentorial surgery. During reoperation, no adhesion to the brain tissue or injury to the brain while detaching the dura substitute was noticed. An excellent histological integration was observed: pores of the Neuro-Patch were colonized by fibroblasts synthesizing collagen, and there was no immune or inflammatory reaction, with an actual 4 to 6 years follow-up. A Neuro-Patch can therefore be recommended as a dura substitute to repair spinal or cranial dural defects.

Adolescent↗

[Tumour inhibitory N-(bis--(2-chlorethyl)-aminomethyl)-urethanes (author's transl)].

The synthesis of N-[bis-(2-chlorethyl)-aminomethyl]-urethanes (I-VI) and N,N'-di[bis-(2-chlorethyl)-aminomethyl]-urea (VII) and their evaluation on the Yoshida sarcoma of the rat and on the sarcoma 180 of the mouse are described. The antitumor activity of I-VI is based on a reaction mechanism analogous to that of aromatic N-lost-derivatives.

Animals↗