Unilateral Vagotomy Research Articles

Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury.

Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a α7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion.

Right and left vagus nerves regulate breathing by multiplicative interaction

Although it has been recognized for more than a century, we still do not know how the two vagus nerves interact to produce Hering–Breuer reflex. In the current study, we tested the hypothesis that the vagus nerves interact via a multiplicative effect. We examined the Hering–Breuer reflex before and after unilateral (first) and then bilateral (second) vagotomies in the mouse. The lung is mostly innervated homolaterally. Since the right and left lung formed 68.2 and 31.8% of total lung weight, if the interaction is mediated by an additive mechanism, unilateral vagotomy would remove the reflex effects by 68.2 and 31.8%, respectively. Instead, unilateral vagotomy removed 85.4±6.0% (>68.2%) or 52.8±3.7% (>31.8%) of the reflex effects on respiratory rate (n=9, P<0.05); and removed 79.1±4.5% (>68.2%) or 59.3±9.1% (>31.8%) of the effect on expiratory pause induced by lung inflation (n=12, P<0.05). Since the first vagotomy removes more reflex effect than the second vagotomy, we conclude that the two vagus nerves exert their Hering–Breuer reflex effects by a multiplicative effect.

Abstract 1167: Inhibition of WNT/ß-catenin signaling-related glutamine metabolism but not the Warburg effect in denervation-induced suppression of gastric tumorigenesis

Abstract Background/aim: Cholinergic nerves have been shown to regulate gastric WNT/ß-catenin signaling in leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive stem cells and have recently been implicated in gastric tumorigenesis. Denervation by local vagotomy or botulinum neurotoxin type A injection or the muscarinic acetylcholine receptor 3 antagonist limit gastric cancer growth. The aim of this study was to further unravel the metabolic pathways underlying the vagotomy-induced suppression of gastric tumorigenesis. Methods: Unilateral subdiaphragmatic truncal vagotomy (VT) was performed in wild-type (WT) and the INS-GAS mice, a genetic mouse model of spontaneous gastric cancer. Metabolic profiling and gene expression profiling in gastric tissues at 6 months post-surgery were performed using liquid chromatography/mass spectrometry, gas chromatography/mass spectrometry, high resolution magic angle spinning NMR spectroscopy, and microarray gene expression (Illumina). Results: VT-induced suppression of tumorigenesis was manifested by reduced proliferation rate and increased apoptotic and autophagic signaling pathways, leading to reduced tumor size and prolonged survival. Principal component analysis showed four distinct clusters among 343 metabolic compounds: WT without VT, INS-GAS without VT, WT with VT and INS-GAS with VT. In the gastric tumor, the metabolic pathways that regulate stem cell homeostasis were downregulated after VT. Glutaminolytic pathway, including glutamine, glutamate, glycine and glutathione-S-S-glutathione, was down-regulated. The tricarboxylic acid cycle (TCA), including citrate, cis-aconitate, acetyle-CoA, threonine and glycine, was also down-regulated. However, glycolytic pathway, including glucose, glucose 6-phosphate, fructose 6-phosphate and lactate, was not significantly down-regulated. Signaling pathways that regulate glutamine metabolism, such as WNT/ß-catenin signaling, WNT target genes Cyclin D1, Axin2, Myc, Lgr5 and Cd44, p53 signaling, and mTOR signaling were down-regulated. The central carbon metabolism in cancer (“The Warburg effect” signaling) and lactate production were unchanged after VT. In addition, the choline metabolism, the lipid-derived eicosanoids and prostaglandins were reduced after VT. Conclusions: The denervation-induced suppression of gastric tumorigenesis was associated with the inhibition of WNT/ß-catenin signaling-related glutamine metabolism but not the Warburg effect. We suggest that glutamine and choline phospholipid metabolisms can be used for metabolism-based tumor detection with MRS and/or positron emission tomography (PET) for gastric cancer diagnosis and that blocking these metabolic functions can be a therapeutic approach for gastric cancer treatment. Citation Format: Gøran Andersen, Riyas Vettukattil, Yoku Hayakawa, Jon Erik Grønbech, Timothy C. Wang, Duan Chen, Chun Mei Zhao. Inhibition of WNT/ß-catenin signaling-related glutamine metabolism but not the Warburg effect in denervation-induced suppression of gastric tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1167. doi:10.1158/1538-7445.AM2015-1167

Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model.

Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome and type 1 diabetes. The alpha-7 nicotinic acetylcholine receptor (α7nAChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. α7nAChR expression, focus scores, and salivary flow were evaluated in salivary glands (SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. α7nAChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes.

Effects of Unilateral Cervical Vagotomy on Murine Dendritic Cells

The cholinergic anti-inflammatory pathway has been demonstrated to be an important mechanism that modulates several inflammatory diseases. This modulation occurs upon activation of the vagus nerve, which modulates splenic macrophages and lymphocytes through the predominant neurotransmitter, Acetylcholine (ACh). We hypothesized that this modulation could also take place in dendritic cells, as these cells represent a link between the innate and adaptive immune responses. Bone Marrow-Derived Dendritic Cells (BMDCs) were generated from mice subjected to a unilateral cervical vagotomy and the phenotypes and functions of the BMDCs were evaluated. No significant effects were found in BMDCs from vagotomized mice compared to cells from the control group. The specific immune response was evaluated with the Delayed-Type Hypersensitivity (DTH) skin test using Keyhole Limpet Hemocyanin (KLH) as an antigen and the peak of the response in the vagotomized animals was delayed compared to the control group. It is possible that the Dendritic Cells (DCs) can be modulated by the vagus nerve in other specific sites or under challenging conditions, but our work suggests that immune cells could be modulated by the components of another cholinergic anti-inflammatory pathway or by another neuro-immune pathway interaction.

Systemic Blood Flow Relations in Conscious South American Rattlesnakes

Estimating total systemic blood flow based on measurements from a single aortic arch is common practice in cardiovascular stud- ies on reptiles to avoid heavy instrumentation and consequent stress responses. This practice requires the validation of a specific correction factor that expresses the relationship between the measured blood flow and the blood flow to be estimated. Misleading estimations may occur when correction factors are used in different conditions from those they were originally measured. Despite recognized as a problem, such misleading estimations are common in physiology. In the present study, we derived values for correction factors to estimate systemic blood flow in the South American rattlesnake, Crotalus durissus, following recovery from anesthesia, using serial measurements of blood flow in the three main systemic arteries, left or distal right aortic arches and the carotid artery. Blood flow recorded in the left aortic arch provided the most reliable and less variable correction factors. Different from previously published, blood flow distribution in the systemic circulation varied with temperature. We suggest the use of the specific correction factors present in this paper for different experimental protocols and temperatures. Furthermore, we can affirm that unilateral left vagotomy, which effectively ablated control of right-left shunts, does not affect systemic blood flow distribution, so the same correction factors can be used.

The effect of L-carnosine on the circadian resetting of clock genes in the heart of rats.

It is reported that the circadian timing system may be included in the mechanism by which L-carnosine (Car) affects multiple physiological alterations including blood glucose, cardiovascular functions etc. However, it is not clear whether Car would affect the circadian rhythm of clock genes in the heart and what is the possible mechanism underlying. To clarify these issues, we compared the effects of Car on the expression of circadian genes in the heart of normal and vagotomized rats under control and jet lag conditions. The normal and vagotomized (va) male Wistar rats were divided into three groups respectively. The control and va-Control groups (fed with regular chow) were sampled before the reversal of LD cycle and feeding schedule (day 0). The normal and va-Normal resetting groups (fed with regular chow) as well as the Car and va-Car resetting groups (fed with Car-containing diet) were sampled on day 3 and day 5 after the experimental jet lag. Car-feeding obviously enhanced the resetting rates of clock genes (Bmal1, Dec1, Cry1) in the heart of normal rats after the experimental jet lag. The unilateral surgical vagotomy didn't alter the diurnal expression patterns and resetting rates of the examined clock genes in normal diet feeding rats. In contrast, it abolished the Car-induced rapid resetting of the clock genes in the heart. Therefore, Car feeding plays a positive role in the circadian resynchronization of the heart clock, which is underlied by the autonomic nervous system.

P.2.a.019 Lipopolysaccharide administration alters brain neurotransmission in prenatally stressed female rats

Extracellular ATP can influence cells via activation of P2X purinoceptors, the distribution of which can be altered in the central and peripheral nervous systems following injury or tissue damage. Here we have investigated the effect of a unilateral section of the cervical vagus nerve on the distribution of P2X1, P2X2, P2X3, P2X4 and P2X7 receptor subunit immunoreactivity (R-IR) in the dorsal vagal motor nucleus (DVN) and the nucleus ambiguus (NA) in the medulla oblongata. As early as 2 days, and followed up to 14 days, there was a dramatic ipsilateral increase in P2X1, P2X2 and P2X4R-IR in the cell soma of vagal efferent neurones in the DVN following the nerve section, but not the NA. There were no changes in P2X3 and P2X7R-IR in either nuclei. To test for possible functional consequences of increased P2X receptor levels, whole-cell patch-clamp recordings were made from DVN cells in brainstem slices 4 days following unilateral vagotomy. Application of ATP revealed large cell-to-cell variance in the current amplitude in neurones from both sectioned and control DVN. However, when ATP responses were compared to those elicited by the nicotinic acetylcholine receptor agonist carbachol, the mean ratio of the peak ATP-evoked current to the peak carbachol-evoked current was significantly larger in DVN neurones ipsilateral to the section. Thus the increase in P2XR levels in DVN cells ipsilateral to a nerve section are likely to reflect an increase in expression of functional P2XRs on the cell surface.

P.2.a.020 Hippocampal P2X7 receptor expression is modulated by stress and antidepressant treatment in the learned helplessness model

Extracellular ATP can influence cells via activation of P2X purinoceptors, the distribution of which can be altered in the central and peripheral nervous systems following injury or tissue damage. Here we have investigated the effect of a unilateral section of the cervical vagus nerve on the distribution of P2X1, P2X2, P2X3, P2X4 and P2X7 receptor subunit immunoreactivity (R-IR) in the dorsal vagal motor nucleus (DVN) and the nucleus ambiguus (NA) in the medulla oblongata. As early as 2 days, and followed up to 14 days, there was a dramatic ipsilateral increase in P2X1, P2X2 and P2X4R-IR in the cell soma of vagal efferent neurones in the DVN following the nerve section, but not the NA. There were no changes in P2X3 and P2X7R-IR in either nuclei. To test for possible functional consequences of increased P2X receptor levels, whole-cell patch-clamp recordings were made from DVN cells in brainstem slices 4 days following unilateral vagotomy. Application of ATP revealed large cell-to-cell variance in the current amplitude in neurones from both sectioned and control DVN. However, when ATP responses were compared to those elicited by the nicotinic acetylcholine receptor agonist carbachol, the mean ratio of the peak ATP-evoked current to the peak carbachol-evoked current was significantly larger in DVN neurones ipsilateral to the section. Thus the increase in P2XR levels in DVN cells ipsilateral to a nerve section are likely to reflect an increase in expression of functional P2XRs on the cell surface.

Vagus nerve stimulation: a new bioelectronics approach to treat rheumatoid arthritis?

There has been a marked improvement in the treatment of rheumatoid arthritis (RA), but most patients do not achieve disease remission. Therefore, there is still a need for new treatments. By screening an adenoviral short hairpin RNA library, we discovered that knockdown of the nicotinic acetylcholine receptor type 7 (α7nAChR) in RA fibroblast-like synoviocytes results in an increased production of mediators of inflammation and degradation. The α7nAChR is intimately involved in the cholinergic anti-inflammatory pathway (CAP). This led us to study the effects of α7nAChR activation in an animal model of RA, and we could show that this resulted in reduced arthritis activity. Accordingly, stimulation of the CAP by vagus nerve stimulation improved experimental arthritis. Conversely, we found aggravation of arthritis activity after unilateral cervical vagotomy as well as in α7nAChR-knockout mice. Together, these data provided the basis for exploration of vagus nerve stimulation in RA patients as a novel anti-inflammatory approach.

Loss of the ability to control right-to-left shunt does not influence the metabolic responses to temperature change or long-term fasting in the South American Rattlesnake Crotalus durissus.

Abstract In the undivided ventricle of noncrocodilian reptiles, the blood perfusing the systemic circulation is a controlled combination of oxygenated pulmonary blood, flowing from left to right across the heart, and relatively deoxygenated systemic blood, flowing from right to left. A clear inverse correlation has been experimentally established between metabolic demand and the magnitude of right-to-left cardiac shunt in several reptile groups. Unilateral left vagotomy renders the single effective pulmonary artery of the South American rattlesnake (Crotalus durissus) unable to adjust the magnitude of blood flow to the lung. This provides a unique model for investigation of the long-term consequences of abolition of the cardiac shunt in a squamate reptile. Rattlesnakes-vagotomized on the left or right side or sham operated-were exposed to long-term food deprivation or temperature change. Loss of control of the cardiac shunt following selective vagotomy did not change the progressive decrease in body mass or the onset of identifiable fasting stages. Resting metabolic rate and the increase in oxygen uptake measured during spontaneous or forced activity were also unchanged. The responses to reductions in temperature (from 30° to 20° or 15°C) in adult snakes or juvenile snakes were similarly unaffected by vagal transection. These data support rejection of the hypothesis that adjustment of the cardiac shunt is central to the control metabolic rate in squamate reptiles.

Mo1918 Mesna Ameliorates Acute Radiation Injury to the Anus

Background/aim: Innervation plays an important role in the regulation of epithelial homeostasis as well as tumorigenesis. Botulinum neurotoxin type A (Botox) is known to block both afferent and efferent nerve fibers by binding to SNARE proteins. The aim of this trial was to evaluate the effectiveness and underlying mechanism of local injection of Botox in the treatment of gastric cancer. Methods: 268 genetically-manipulated INS-GAS male and female mice with spontaneous gastric cancer were subjected to Botox injection or subdiaphragmatic unilateral vagotomy (UVT), with or without chemotherapy (5-FU, oxaliplatin, or 5-FU + oxaliplatin). Botox was injected subserosally along the greater curvature on the anterior side of the stomach and the injection was repeated every 2nd month. Chemotherapy was given by intraperitoneal injection once per week for 4 weeks in a two-cycle course with a 1-week rest. Clinical endpoints included tumor size, histopathological score, and survival. Gastric organoid cultures with or without Botox, neurons, or a muscarinic receptor agonist or antagonist were used. Results: Botox treatment was given to INS-GAS mice at 6 months of age when gastric cancer started to develop. Six months later, tumor size, cell proliferation rate, scores of inflammation, epithelial defects, atrophy, hyperplasia, dysplasia and metaplasia were markedly reduced in comparison with the uninjected posterior area of the stomach. When Botox treatment was given at 14 months of age in combination with 5-FU+oxaliplatin, tumor size was significantly reduced as early as 2 months after starting treatment, particularly in the area of Botox injection or in the surgically denervated stomach following UVT. The combination of either Botox or UVT with chemotherapy led to a significant increase in survival compared to chemotherapy alone. In vitro studies showed that neurons stimulated gastric organoid growth when compared to gastric organoids cultured in the absence of neurons, and that the addition of either Botox or scopolamine inhibited this stimulatory effect, whereas pilocarpine increased organoid growth. Furthermore, pilocarpine upregulated expression of stem cell markers and Wnt target genes, such as Lgr5, CD44, and Sox9, and both pilocarpine and neurons could substitute for Wnt3a in gastric organoid cultures that were otherwise strictly dependent on the addition of Wnt ligands. Conclusions: This preclinical trial demonstrates the efficacy of local Botox injection with or without chemotherapy in the treatment of gastric cancer. The therapeutic effect is likely mediated by acetylcholinemediated Wnt signaling in gastric stem cells. We may further suggest that greater consideration should be given to novel denervation approaches in combination with other therapies for gastric cancer and likely other solid malignancies.

Mo1917 Preclinical Trial of Botulinum Toxin Type a Injection in the Treatment of Gastric Cancer

Background/aim: Innervation plays an important role in the regulation of epithelial homeostasis as well as tumorigenesis. Botulinum neurotoxin type A (Botox) is known to block both afferent and efferent nerve fibers by binding to SNARE proteins. The aim of this trial was to evaluate the effectiveness and underlying mechanism of local injection of Botox in the treatment of gastric cancer. Methods: 268 genetically-manipulated INS-GAS male and female mice with spontaneous gastric cancer were subjected to Botox injection or subdiaphragmatic unilateral vagotomy (UVT), with or without chemotherapy (5-FU, oxaliplatin, or 5-FU + oxaliplatin). Botox was injected subserosally along the greater curvature on the anterior side of the stomach and the injection was repeated every 2nd month. Chemotherapy was given by intraperitoneal injection once per week for 4 weeks in a two-cycle course with a 1-week rest. Clinical endpoints included tumor size, histopathological score, and survival. Gastric organoid cultures with or without Botox, neurons, or a muscarinic receptor agonist or antagonist were used. Results: Botox treatment was given to INS-GAS mice at 6 months of age when gastric cancer started to develop. Six months later, tumor size, cell proliferation rate, scores of inflammation, epithelial defects, atrophy, hyperplasia, dysplasia and metaplasia were markedly reduced in comparison with the uninjected posterior area of the stomach. When Botox treatment was given at 14 months of age in combination with 5-FU+oxaliplatin, tumor size was significantly reduced as early as 2 months after starting treatment, particularly in the area of Botox injection or in the surgically denervated stomach following UVT. The combination of either Botox or UVT with chemotherapy led to a significant increase in survival compared to chemotherapy alone. In vitro studies showed that neurons stimulated gastric organoid growth when compared to gastric organoids cultured in the absence of neurons, and that the addition of either Botox or scopolamine inhibited this stimulatory effect, whereas pilocarpine increased organoid growth. Furthermore, pilocarpine upregulated expression of stem cell markers and Wnt target genes, such as Lgr5, CD44, and Sox9, and both pilocarpine and neurons could substitute for Wnt3a in gastric organoid cultures that were otherwise strictly dependent on the addition of Wnt ligands. Conclusions: This preclinical trial demonstrates the efficacy of local Botox injection with or without chemotherapy in the treatment of gastric cancer. The therapeutic effect is likely mediated by acetylcholinemediated Wnt signaling in gastric stem cells. We may further suggest that greater consideration should be given to novel denervation approaches in combination with other therapies for gastric cancer and likely other solid malignancies.

Modification of energy balance induced by the food contaminant T-2 toxin: A multimodal gut-to-brain connection

T-2 toxin is one of the most toxic Fusarium-derived trichothecenes found on cereals and constitutes a widespread contaminant of agricultural commodities as well as commercial foods. Low doses toxicity is characterized by reduced weight gain. To date, the mechanisms by which this mycotoxin profoundly modifies feeding behavior remain poorly understood and more broadly the effects of T-2 toxin on the central nervous system (CNS) have received limited attention. Through an extensive characterization of sickness-like behavior induced by T-2 toxin, we showed that its per os (p.o.) administration affects not only feeding behavior but also energy expenditure, glycaemia, body temperature and locomotor activity. Using c-Fos expression mapping, we identified the neuronal structures activated in response to T-2 toxin and observed that the pattern of neuronal populations activated by this toxin resembled that induced by inflammatory signals. Interestingly, part of neuronal pathways activated by the toxin were NUCB-2/nesfatin-1 expressing neurons. Unexpectedly, while T-2 toxin induced a strong peripheral inflammation, the brain exhibited limited inflammatory response at a time point when anorexia was ongoing. Unilateral vagotomy partly reduced T-2 toxin-induced brainstem neuronal activation. On the other hand, intracerebroventricular (icv) T-2 toxin injection resulted in a rapid (<1h) reduction in food intake. Thus, we hypothesized that T-2 toxin could signal to the brain through neuronal and/or humoral pathways. The present work provides the first demonstration that T-2 toxin modifies feeding behavior by interfering with central neuronal networks devoted to central energy balance. Our results, with a particular attention to peripheral inflammation, strongly suggest that inflammatory mediators partake in the T-2 toxin-induced anorexia and other symptoms. In view of the broad human and breeding animal exposure to T-2 toxin, this new mechanism may lead to reconsider the impact of the consumption of this toxin on human health.

52. Effect of unilateral cervical vagotomy on the phenotype and function of dendritic cells generated from bone marrow precursor cells

The vagus nerve plays an important role in the regulation of homeostasis, and its efferent pathway emit signals able to control immune function, acting on the inflammatory response of lymphocytes and macrophages via the inflammatory reflex. Our hypothesis is that this route may also alter the function of dendritic cells, since these cells are essential for the formation of an adaptive immune response, are sensitive to an increase in proinflammatory cytokines and have cholinergic receptors. Therefore, dendritic cells generated from bone marrow precursor cells of mice subjected to unilateral cervical vagotomy were analyzed for the phenotypic markers CD11c and MHC-II and the co-stimulatory molecules CD80 and CD86, as well as its phagocytic function and antigen presentation to lymphocytes from OT-II mice. The analysis of phenotype and phagocytic function revealed no significant changes between the groups of partially vagotomized animals and control, and data obtained in the OT-II lymphocyte proliferation assay showed that dendritic cells generated from the bone marrow of partially vagotomized animals promote a response similar to non-vagotomized animals. Therefore, the results to date refute the initial hypothesis that the partial vagotomy can alter the phenotype and function of dendritic cells generated from bone marrow precursor cells.

Unilateral or bilateral vagotomy induces ovulation in both ovaries of rats with polycystic ovarian syndrome

BackgroundInjecting estradiol valerate (EV) to pre-pubertal or adult female rat results in effects similar to those observed in women with polycystic ovarian syndrome (PCOS). One of the mechanisms involved in PCOS development is the hyperactivity of the sympathetic nervous system. In EV-induced PCOS rats, the unilateral sectioning of the superior ovarian nerve (SON) restores ovulation of the innervated ovary. This suggests that, in addition to the sympathetic innervation, other neural mechanisms are involved in the development/maintenance of PCOS. The aims of present study were analyze if the vagus nerve is one of the neural pathways participating in PCOS development.MethodsTen-day old rats were injected with EV dissolved in corn oil. At 24-days of age sham-surgery, unilateral, or bilateral sectioning of the vagus nerve (vagotomy) was performed on these rats. The animals were sacrificed at 90–92 days of age, when they presented vaginal estrous preceded by a pro-estrus smear.ResultsIn EV-induced PCOS rats, unilateral or bilateral vagotomy restored ovulation in both ovaries. Follicle-stimulating hormone (FSH) levels in PCOS rats with unilateral or bilateral vagotomy were lower than in control rats.ConclusionsThis result suggests that in EV-induced PCOS rats the vagus nerve is a neural pathway participating in maintaining PCOS. The vagus nerve innervates the ovaries directly and indirectly through its synapsis in the celiac-superior-mesenteric ganglion, where the somas of neurons originating in the SON are located. Then, it is possible that vagotomy effects in EV-induced PCOS rats may be explained as a lack of communication between the central nervous system and the ovaries.

Sa2017 Blocking Peripheral Serotonin Synthesis by Telotristat Etiprate Reduces the Severity of Both Chemical- and Infection-Induced Intestinal Inflammation

G A A b st ra ct s was recorded at termination. Blood was collected for determination of serum gastrin. The histological changes in the stomachs were examined. The presence of dysplasia and carcinoma on the anterior and posterior side of the stomachs were compared, and the oxyntic mucosal thickness and neuroendocrine (chromogranin A positive) cell density were calculated. Results: Ten of fifteen animals operated by anterior vagotomy and 11 of 16 sham-operated developed hypergastrinemia. Vagotomy did not affect intragastric pH or serum gastrin. There was no difference between innervated and denervated oxyntic mucosa in dysplasia and carcinoma development. However, vagotomy resulted in lower stomach weight in hypergastrinemic animals (2.8 ± 0.26 g vs. 3.7 ± 0.39 g, p=0.027) and reduced oxyntic mucosal thickness on the anterior side (0.83 ± 0.06 mm vs. 1.13 ± 0.1 mm, p ,0.01). Vagotomy also resulted in a reduction in volume density of chromogranin A positive cells in the oxyntic mucosa (12.1 ± 1.8 % vs. 18.8 ± 3.0 %, p=0.04). Conclusions: Unilateral truncal vagotomy reduced the trophic effects of hypergastrinemia on the ECL cell and oxyntic mucosa, but did not prevent gastric carcinogenesis in female Japanese cotton rats. The effects of vagotomy on gastric carcinogenesis in animal models are conflicting and further studies in patients should be done to clarify the clinically significant effects of vagotomy.

Sa2014 Unilateral Truncal Vagotomy Reduces Stomach Weight, Oxyntic Mucosal Thickness and Neuroendocrine Cell Density but Does Not Prevent Gastric Carcinoma Development in Hypergastrinemic Female Japanese Cotton Rats

Sa2014 Unilateral Truncal Vagotomy Reduces Stomach Weight, Oxyntic Mucosal Thickness and Neuroendocrine Cell Density but Does Not Prevent Gastric Carcinoma Development in Hypergastrinemic Female Japanese Cotton Rats

Sa2015 Signaling in Bile Acid-Induced DNA Damage in Barrett's Esophageal Adenocarcinoma Cells

G A A b st ra ct s was recorded at termination. Blood was collected for determination of serum gastrin. The histological changes in the stomachs were examined. The presence of dysplasia and carcinoma on the anterior and posterior side of the stomachs were compared, and the oxyntic mucosal thickness and neuroendocrine (chromogranin A positive) cell density were calculated. Results: Ten of fifteen animals operated by anterior vagotomy and 11 of 16 sham-operated developed hypergastrinemia. Vagotomy did not affect intragastric pH or serum gastrin. There was no difference between innervated and denervated oxyntic mucosa in dysplasia and carcinoma development. However, vagotomy resulted in lower stomach weight in hypergastrinemic animals (2.8 ± 0.26 g vs. 3.7 ± 0.39 g, p=0.027) and reduced oxyntic mucosal thickness on the anterior side (0.83 ± 0.06 mm vs. 1.13 ± 0.1 mm, p ,0.01). Vagotomy also resulted in a reduction in volume density of chromogranin A positive cells in the oxyntic mucosa (12.1 ± 1.8 % vs. 18.8 ± 3.0 %, p=0.04). Conclusions: Unilateral truncal vagotomy reduced the trophic effects of hypergastrinemia on the ECL cell and oxyntic mucosa, but did not prevent gastric carcinogenesis in female Japanese cotton rats. The effects of vagotomy on gastric carcinogenesis in animal models are conflicting and further studies in patients should be done to clarify the clinically significant effects of vagotomy.

The effects of unilateral truncal vagotomy on gastric carcinogenesis in hypergastrinemic Japanese female cotton rats

The stomach is innervated by the vagal nerve. Several studies have demonstrated that the vagal nerve has a trophic effect on the rat oxyntic mucosa and that the trophic effect of hypergastrinemia is dependent on intact vagal innervation. The effect of vagal denervation on gastric carcinogenesis has been examined in Mastomys natalensis and hypergastrinemic transgenic INS-GAS mice, with no effect of unilateral vagotomy in Mastomys but an anti-carcinogenic effect in INS-GAS mice.A proportion of female Japanese cotton rats develop spontaneous hypergastrinemia and ECL cell derived gastric carcinomas. In the current study we have examined the effects of unilateral anterior subdiaphragmatic vagotomy on gastric carcinogenesis. Female Japanese cotton rats were operated with unilateral anterior vagotomy or sham-operation at age 2months and were terminated at age 10months. Ten of fifteen animals operated by anterior vagotomy and 11 of 16 sham-operated developed hypergastrinemia. Vagotomy did not affect intragastric pH or serum gastrin. When comparing the anterior and posterior sides of the stomachs, vagotomy did not affect the occurrence of dysplasia or carcinoma development in the oxyntic mucosa. However, vagotomy resulted in lower stomach weight and reduced oxyntic mucosal thickness on the anterior side. Vagotomy also resulted in a reduction in volume density of chromogranin A positive cells in the oxyntic mucosa.In conclusion, vagotomy reduced the trophic effects of hypergastrinemia on the ECL cell and oxyntic mucosa, but did not prevent gastric carcinogenesis in female Japanese cotton rats. The effects of vagotomy on gastric carcinogenesis in animal models are conflicting and further studies in patients should be done to clarify the clinically significant effects of vagotomy.