Gastric Motor Dysfunction Research Articles

Gastrointestinal dysmotility is associated with proton pump inhibitor refractory esophagitis in patients with systemic sclerosis.

Patients with systemic sclerosis present with severe gastroesophageal reflux disease, often refractory to proton-pump inhibitors (PPI) treatment. The aim of the present study was to identify factors associated with PPI-refractory esophagitis. We performed a cross-sectional study in a single-center cohort of patients diagnosed with systemic sclerosis. We included patients who underwent an esophagogastroduodenoscopy while on PPI treatment. Patients with PPI-refractory erosive esophagitis were compared with those with endoscopically normal esophageal mucosa. A total of 69 patients were included, from these, 23 patients (33%) had PPI-refractory esophagitis (Grade A, n = 11; Grade B, n = 7; Grade C, n = 2; Grade D, n = 3) and 46 (67%) had an endoscopically normal esophageal mucosa. On univariate analysis, patients with PPI-refractory esophagitis were more frequently diffuse SSc subset (43% vs 17%; p= 0.041). Evaluating gastrointestinal motility tests, neither absent esophageal contractility (39% vs 25%, p= 0.292) nor hypotensive lower esophageal sphincter (47% vs 44%, p= 0.980) were significantly associated with PPI-refractory esophagitis. Gastrointestinal dysmotility, defined as abnormal gastric emptying and/or small bowel dilated loops, was significantly associated with PPI-refractory esophagitis (66 vs 8%, p = <0.001). On a multivariate regression model to evaluate the association between motility test results adjusted for the diffuse subset, gastrointestinal dysmotility (β = 0.751, p= 0.010) was independently associated with PPI-refractory esophagitis, while absent esophageal contractility (β = 0.044, p= 0.886) or a hypotensive LES were not (β=-0.131, p= 0.663). Our findings suggest that gastric and small intestinal motor dysfunction may be an important contributor to the development of PPI-refractory esophagitis in patients with systemic sclerosis.

Effect of sex on chronic stress induced alterations in hindbrain catecholaminergic system and autonomic dysfunction resulting in gastrointestinal dysmotility

It has been reported that the clinical symptoms of functional dyspepsia (FD) exacerbate upon stress while the gender-related factors have been incompletely understood. This study aims to investigate the role of sex in chronic heterotypic stress (CHS)-induced autonomic and gastric motor dysfunction. For CHS, the rats were exposed to the combination of different stressors for 7 consecutive days. Subsequently, electrocardiography was recorded in anesthetized rats to evaluate heart rate variability (HRV) for the determination of autonomic outflow and sympathovagal balance. Solid gastric emptying (GE) was measured in control and CHS-loaded male and female rats. The immunoreactivities of catecholaminergic cell marker tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), corticotropin releasing factor (CRF), and estrogen receptor (ER-α/β) were evaluated in medullary and pontine brainstem sections by immunohistochemistry. Compared with the controls, CHS significantly delayed GE in males but not in females. There was no significant sex-related difference in parasympathetic indicator HF under either control or CHS conditions. Sympathetic indicator LF was significantly higher in control females compared to the males. The higher sympathetic output in females was found to be attenuated upon CHS; in contrast, the elevated sympathetic output was detected in CHS-loaded males. No sex- or stress-related effect was observed on ChAT immunoreactivity in the dorsal motor nucleus of N.vagus (DMV). In males, greater number of TH-ir cells was observed in the caudal locus coeruleus (LC), while they were more densely detected in the rostral LC of females. Regardless of sex, CHS elevated immunoreactivity of TH throughout the LC. Under basal conditions, greater number of TH-ir cells was detected in the rostral ventrolateral medulla (RVLM) of females. In contrast, CHS remarkably increased the number of TH-ir cells in the RVLM of males which was found to be decreased in females. There was no sex-related alteration in TH immunoreactivity in the nucleus tractus solitarius (NTS) of control rats, while CHS affected both sexes in a similar manner. Compared with females, CRF immunoreactivity was prominently observed in control males, while both of which were stimulated by CHS. ER-α/β was found to be co-expressed with TH in the NTS and LC which exhibit no alteration related to either sex or stress status. These results indicate a sexual dimorphism in the catecholaminergic and the CRF system in brainstem which might be involved in the CHS-induced autonomic and visceral dysfunction occurred in males.

Perinatal High Fat Diet Exposure Reduces KCC2 Expression and Alters GABAergic Signaling in the Dorsal Motor Nucleus of the Vagus

Perinatal high fat diet (pHFD) exposure alters the development of vagal neurocircuits controlling gastrointestinal (GI) functions resulting in gastric motor dysfunction. GABAergic synaptic inhibition of vagal efferent motoneurons within the dorsal motor nucleus of the vagus (DMV) is critical in the brain’s ability to modulate gastric motility. This inhibition is maintained by KCC2, a Cl− transporter, who determines intracellular chloride concentration. The current study was designed to test the hypothesis that pHFD reduces KCC2 levels in DMV neurons, subsequently decreasing GABAergic inhibition and delaying gastric emptying rates. Pregnant Sprague-Dawley rats were fed either a control or high fat (14% vs 60% kcal from fat, respectively) diet from embryonic day 13, and offspring were used starting postnatal day 28. In vitro electrophysiological recordings were made from adult DMV neurons in brainstem slices. To assess the GABA-mediated inhibition, cell-attached recordings were made to preserve the internal Cl− concentration, and firing rate was quantified before and after application of bicuculline (BIC; 30μM), a GABAA antagonist. To determine the Cl− reversal potential, perforated patch clamp recordings were performed and the response to picospritz application of the GABAA agonist muscimol (100μM) was measured. KCC2 expression was quantified using pharmacology in the in vitro slice preparation, as well as immunofluorescence in brainstem cross-sections. Gastric emptying rates were quantified using the in vivo13C octanoic acid breath test technique. KCC2 transfection and induced expression in the DMV of pHFD rats was achieved using an adeno-associated viral vector. BIC increased firing rate in control DMV neurons (143.1% of baseline), but failed to increase DMV firing rate in DMV neurons from pHFD rats (96.27% of baseline; p=0.0103 using unpaired t-test). When control DMV neurons were treated with VU0240551 (VU; 10μM), a KCC2 blocker, BIC application led to a decrease in the firing rate (3.118 Hz to 1.606 Hz; p=0.0375 via paired t-test), demonstrating that antagonizing KCC2 attenuates GABAergic inhibition at this synapse. In control DMV neurons, the Cl− reversal potential was calculated to be -64.6mV. There was a depolarizing shift in Cl− reversal potential observed in pHFD neurons (-43.0mV; p=0.0007 using unpaired t-test). Application of VU shifted the chloride reversal from -64.6mV to -57.3mV in control neurons (p=0.0416 using a paired t-test). VU application had a reduced impact on pHFD neurons, shifting the reversal from -46.7mV to -45.0mV (p=0.1689 using a paired t-test), suggesting KCC2 downregulation. In fact, compared to control rats, there was a significant reduction in KCC2 expression in the pHFD DMV (2.237% area fluorescence in pHFD vs. 5.335%; p=0.0147 using unpaired t-test). When KCC2 expression was virally induced in young adult pHFD rats, GABA became inhibitory (163.7% of baseline firing rate after BIC application vs. 93.25% in pHFD + empty vector (EV); p=0.0019 using unpaired t-test), the Cl− reversal potential was normalized (-63.0mV vs. -49.7mV in pHFD + EV; p=0.0012 using an unpaired t-test), and gastric emptying rates were accelerated (58.7min vs 72.1min in pHFD + EV). Taken together, these results suggest that the loss of KCC2 function is a driver of the gastric pathophysiology seen in the pHFD rats, and that normalizing KCC2 levels can rescue the cellular and gastric phenotype. DK 111667. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach

Restricted gastric motor functions contribute to aging-associated undernutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC; gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg intraperitoneally twice a day for 3 weeks). Gastric ICC were analyzed by Western blotting and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

Zhizhu Kuanzhong, a traditional Chinese medicine, alleviates gastric hypersensitivity and motor dysfunction on a rat model of functional dyspepsia.

Ethnopharmacological relevance: Zhizhu Kuanzhong (ZZKZ) is a traditional Chinese medicine modified from classic formula Zhizhu decoction in "Synopsis of Golden Chamber" (Han Dynasty in the 3rd century) and the Zhizhu pill in "Differentiation on Endogenous" in Jin Dynasty (1,115-1,234). ZZKZ contains four botanical drugs, including Citrus × Aurantium L [Rutaceae; Aurantii Fructus Immaturus], Atractylodes Macrocephala Koidz. [Compositae; Rhizoma Atractylodis Macrocephalae], Bupleurum Chinense DC [Apiaceae; Radix Bupleuri Chinensis], and Crataegus Pinnatifida Bunge [Rosaceae; Fructus Crataegi Pinnatifidae], which have been widely used in clinical therapy for functional dyspepsia (FD). Aim of the study: This study aimed to evaluate the pharmacological effects and mechanisms of action of ZZKZ on gastric hypersensitivity and motor dysfunction in a rat model of FD. Materials and methods: FD was induced in Sprague-Dawley rats by neonatal gastric irritation with 0.1% iodoacetamide. The FD rats were treated with ZZKZ (0.5g/kg, 1.0g/kg, or 1.5g/kg respectively) by gavage for 7days, while domperidone (3mg/kg) acted as treatment control. Body weight gain, food intake, gastric emptying, and intestinal propulsion were also measured. Ex vivo gastric smooth muscle activity recordings and greater splanchnic afferent (GSN) firing recordings were employed to evaluate gastric motility and sensation. Particularly, the role of 5-HT in the action of ZZKZ in improving gastric dysmotility and hypersensitivity was explored. Results: ZZKZ promoted weight gain, food intake, gastric emptying, and intestinal propulsion in FD rats. ZZKZ promoted spontaneous and ACh-induced contractions of gastric smooth muscle strips in FD rats, alleviated spontaneous activity, and chemical (acid perfusion) and mechanical (intragastric distension) stimulated GSN firing in FD rats. ZZKZ ameliorated gastric smooth muscle contraction and GSN firing induced by 5-HT in FD rats. ZZKZ stimulated the release of serum 5-HT, with reduced 5-HT3 receptor and increased 5-HT4 receptor mRNA expression in the guts of FD rats. Conclusion: This study demonstrated that ZZKZ improves FD-related gastric hypersensitivity and motor dysfunction and should be an effective compound for relieving FD symptoms. The gastric 5-HT system with lower 5-HT3 activity and increased 5-HT4 distribution is involved in the mechanisms of ZZKZ underlying the treatment of FD.

Gastric motor dysfunction coincides with the onset of obesity in rats fed with high-fat diet.

Exposure to a high-fat diet (HFD) has been reported to impair central autonomic and enteric neurocircuitries, however, the relevant mechanisms and their time course are inadequately clarified. This study aimed to investigate the effects of HFD consumption through the period of adolescence on gastric motor functions in adulthood. Male Sprague-Dawley rats consumed a regular diet or HFD (60% kcal by fat) from 4 to 12 weeks of age. Body weight and food intake were monitored weekly. In adult rats, gastric emptying (GE) was measured. Additionally, using in-vitro organ bath, contractile and relaxant responses of antral and fundic strips were assessed with bethanechol and sodium nitroprusside (SNP), respectively. The expressions of choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were detected by immunofluorescence, whereas, the number of myenteric neurons were evaluated by staining with cuprolinic blue and enteric neuronal marker PGP 9.5. In adulthood, the HFD did not alter food intake, while significantly increasing the body weight. In HFD-fed adult rats, increased visceral fat mass was accompanied by delayed GE. Moreover, bethanechol- and SNP-induced responses were attenuated in antral and fundic tissues. HFD remarkably decreased the number of myenteric neurons and NOS immunoreactivity both in fundus and antrum. HFD remarkably decreased ChAT expression, while increasing the immunoreactivity for VIP in antrum. In conclusion, consumption of HFD between early adolescence and adulthood results in obesity and impairment of gastric motor functions. Particularly, HFD-induced gastric dysmotility appears to be predominantly dependent on the modifications in the non-adrenergic non-cholinergic inhibitory neurotransmission.

Gastroparesis in the Hospital Setting.

Gastroparesis (GP) is commonly seen in hospitalized patients. Refractory vomiting and related dehydration, electrolyte abnormalities, and malnutrition are indications for hospital admission. In addition, tube feeding intolerance is a common sign of gastric dysmotility in critically ill patients. The diagnosis and management of GP in the hospital setting can be quite challenging. Diagnostic tests are often deferred because of patient intolerance of the oral meal for standard scintigraphy or severity of the primary disease. The diagnosis of GP is often established on the basis of clinical scenario and risk factors for gastric motor dysfunction. Medical therapy in GP is directed toward controlling nausea and vomiting by prokinetic and antinausea medications and correcting nutrition risks or treating malnutrition with nutrition therapy. Enteral nutrition is the preferred nutrition intervention for patients with GP. Delayed gastric emptying in critically ill patients has a negative impact on the timely delivery of enteral feeding and meeting the energy and protein goals. Measures to improve gastric tolerance or provide feeding beyond the stomach are often needed, since early enteral nutrition has been an important target of therapy for critically ill patients. This review will address the current understanding of the mechanisms of GP and feeding intolerance in critical illness, diagnostic workup, drug therapies, and interventions to improve the provision of enteral nutrition in hospital settings when gastric dysmotility is present or suspected.

Functional dyspepsia and the role of digestive enzymes supplement in its therapy

Functional dyspepsia represents a heterogeneous group of gastrointestinal disorders marked by the presence of upper abdominal pain or discomfort. Reported prevalence of dyspepsia in the world varies from 11-30%. Basic Pathophysiology of functional dyspeptic symptoms is unclear and is considered to occur due to a combination of visceral hypersensitivity, gastric motor dysfunction and psychological factors. Strategies such as acid suppression, prokinetics and H. pylori eradication have been used with some success. Transient deficiency in digestive enzymes is one of the contributors for functional dyspepsia. The primary digestive enzymes are proteases, amylases and lipases. A commonly used therapeutic approach in its treatment is the use of oral enzymes supplementation therapy. Commercially, digestive enzymes are obtained from plant, animal and microbial sources. This review summarizes the pathophysiology of functional dyspepsia, different pharmacological approaches and focuses on the safety and efficacy of digestive enzymes in managing dyspepsia. Keywords including functional dyspepsia, digestive enzymes, lipase, diastase, papain, pepsin, trypsin and chymotrypsin were searched in databases such as Google, Google Scholar, PubMed, pharmacopoeia and textbooks.

The Role of Central Orexin‐A in Restraint Stress‐induced Gastric Dysmotility in Rats

Stress exposure stimulates the production of corticotropin‐releasing factor (CRF) in hypothalamic paraventricular nucleus (PVN) which in turn influences gastrointestinal (GI) motor functions by altering autonomic outflow in brain. In rodents, acute restraint stress (ARS) has been shown to delay gastric emptying (GE) by impairing the postprandial coordination of of antro‐pyloric contractions through a CRF‐dependent pathway. Besides its well‐defined orexigenic function, the hypothalamic neuropeptide orexin‐A (OXA) is also known to alter GI motor functions through central autonomic pathways. OXA‐producing cells reside mainly in lateral hypothalamic area (LHA), while its receptor OX1R is found in PVN. Accumulating evidence indicate that OXA‐containing neurons send intra‐hypothalamic projections to the CRF‐producing cells in PVN. Furthermore, central administration of OXA has been shown to enhance CRF‐induced neuroendocrine functions suggesting that central OXA may contribute to the CRF‐mediated impairment of GI motor functions under stressed conditions. The aim of the present study was to investigate the involvement of orexin‐A in CRF‐induced gastric motor dysfunction under stressed conditions. Central (icv) drug administrations were performed through an injection cannula stereotaxically placed into the lateral ventricle. Solid GE was measured following an overnight fasting in non‐stressed (NS) and ARS‐loaded rats following central pretreatment of CRF and OXA antagonists α‐helical‐CRF9,41 (10 nmol, 5 μl) and SB‐334867 (100 nmol, 5 μl), respectively. For recording of gastric motility, two miniature strain gages were implanted onto the serosal surface of antrum and pylorus. Postprandial antro‐pyloric contractions were monitored in conscious and freely‐moving rats simultaneously with microdialysis. To perform microdialysis, a probe with high molecular cut‐off membrane was placed into the PVN. The intra‐PVN microinjection of vehicle or selective SB‐334867 (10 nmol, 100 nL) was performed prior to the perfusion of the probe with artificial cerebro‐spinal fluid (aCSF) containing high KCl (100 mmol/L). CRF concentrations in microdialysis samples were quantified by enzyme immunoassay. Compared with NS rats, ARS significantly (p&lt;0.01) delayed GE. The ARS‐induced delayed GE was partially attenuated both by pretreatment of SB‐334867 (p&lt;0.05) and α‐helical‐CRF9,41 (p&lt;0.05), whereas it was completely restored (p&lt;0.01) when both antagonists were administered together. Perfusion with high KCl‐containing aCSF significantly increased the CRF level in microdialysates which was significantly attenuated by intra‐PVN microinjection of SB‐334867. Perfusion of KCl impaired the coordination of postprandial antro‐pyloric contractions. Compared with vehicle‐injected rats, KCL‐induced alterations were remarkably abolished by SB‐334867. These results suggest that central OXA plays a role in stress‐induced alterations in gastric motor functions through OX1R. Therefore, OX1R antagonism appears to be a candidate for the treatment of the stress‐related gastric motor dysfunctions.

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model.

BackgroundFunctional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal‐enhancing action for FD treatment.MethodsSolid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) ‐induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, rikkunshito, or an α 2‐adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free‐moving condition.Key ResultsExogenous acylated ghrelin supplementation restored UCN1‐induced delayed GE. Alpha2‐AR antagonist and rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of rikkunshito on delayed GE was blocked by co‐administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or rikkunshito.Conclusions & InferencesThe UCN1‐induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by rikkunshito may be effective in treating functional GI disorders.

The Usefulness of Water-drinking Ultrasonography Combined Test for Evaluating Patients with Functional Dyspepsia.

The major causes of functional dyspepsia (FD) are motility dysfunction and visceral hypersensitivity. Despite the large number of diagnostic tests, there are no convenient methods for evaluation of gastric functions. Therefore, this study was conducted to assess the relationship between the degree of dyspepsia and gastric accommodation, emptying, and sensitivity. A total of 120 FD patients that met the Rome III criteria and 30 healthy volunteers were included in this cross-sectional study. The mean cross-sectional area of the fornix was measured to investigate fundic accommodation and gastric emptying during and after water intake. During the test, abdominal symptoms were evaluated using the 4-point Likert scale. The water-drinking ultrasonography combined test revealed impairment of gastric accommodation in FD after 1,000 mL of water intake, delayed emptying after 5 min of water intake and statistically significant hyperesthesia after 400 mL of water intake in the FD group compared with healthy controls (p <œœ 0.05). Postprandial distress syndrome (PDS) and overlap syndrome were independently associated with gut motor disturbances instead of epigastric pain syndrome (EPS) (p <œœ 0.01). The results of the present study suggest that the water-drinking ultrasonography combined test could be used for diagnosis of gastric motor and sensory dysfunction, particularly in PDS and EPS-PDS patients. This test is easy, well tolerated by the patient and can be widely applied in clinical practice.

Complicated and Uncomplicated Peptic Ulcer Disease: Altered Symptom Response to a Nutrient Challenge Linked to Gastric Motor Dysfunction

Background: Bleeding peptic ulcer (BPU) frequently occurs in the absence of preceding dyspeptic symptoms. We have observed that patients with BPU had a diminished symptom response to nutrient challenge test compared to uncomplicated peptic ulcer disease (uPUD). We postulated that more symptoms are manifest in patients with uPUD than BPU because there are greater derangements in gastric motor function. Aim: To assess gastric emptying in patients with BPU, uPUD and healthy controls (HC). Methods: We studied 17 patients with BPU, 10 with uPUD, and 15 HC. After an 8-hour fast, subjects ingested 200 ml of an enteral feeding solution, containing 5 MBq ^99mTc-rhenium sulphide colloid, every 5 min up to a cumulative volume of 800 ml. Gastric emptying was measured by scintigraphy for the total, proximal and distal stomach. Results: Patients with uPUD had significantly higher gastric retention in the proximal and total stomach at 100 min than HC and BPU, while BPU had similar percent retention to HC. Patients with uPUD had significantly higher cumulative symptom response to the nutrient challenge than did HC and BPU, while BPU had similar symptom responses to HC. Conclusions: Patients with uPUD have significantly delayed gastric emptying compared to HC and BPU. Data suggest that in addition to alterations of visceral sensory function, altered gastric motor function occurs during a nutrient challenge in uPUD but not BPU. Gastric motor function may contribute to the manifestation of dyspeptic symptoms in PUD.

Transmural Pressure Loading Enhances Gastric Mucosal Cell Proliferation

Although increased intraluminal pressure in the stomach due to gastric outlet obstruction or functional gastric motor dysfunction, including gastroparesis, may affect gastric mucosal integrity, the direct effect of mechanical pressure on gastric mucosal cells has not yet been fully investigated. The aims of this study were to determine whether exposure to transmural pressure would affect the proliferation of gastric mucosal cells and to elucidate the intracellular signaling pathways involved. Cellular proliferation and DNA synthesis were evaluated in rat gastric epithelial cells exposed to high transmural pressures. The levels of activation of 3 MAP kinases, ERK, JNK, and p38, were assessed, and the induction of immediate early gene expression was examined. The activation of nuclear factor activator protein-1 (AP-1) was evaluated by an electrophoretic mobility shift assay. Exposure to high transmural pressure significantly increased DNA synthesis within 24 h, with the most marked increase observed after exposure to a pressure of 80 mmHg, and this increase was inhibited by the MEK1 inhibitor PD98059. Early activation of ERK kinase, but not of JNK or p38 kinase, was detected after pressure loading. Early induction of the c-fos and c-myc genes and activation of the AP-1 transcription factor were also demonstrated within 3 h of exposure to 80 mmHg of pressure. Gastric mucosal cell proliferation induced by exposure to high transmural pressure may be related to early activation of ERK, the induction of c-fos and c-myc, and the activation of AP-1.

Effect of the herbal preparation, STW 5, in a stress-induced model of functional dyspepsia

Psychological factors, especially stress, are known to play an important role in functional gastrointestinal diseases (1, 2). Based on the good correlation between stress and functional dyspepsia (FD), many animal models for FD have been developed where animals are subjected to psychological stress either during the neonatal period or in adulthood. This stress was found to induce gastric motor dysfunction resembling symptoms of FD. In one model, maternal separation (3) was performed on weanling rats starting from postnatal day 2 for 3h each day for 3 weeks. Rats were then allowed to mature to an adult age. The other model was that of restraint stress (RS) (4, 5). Adult animals were restrained for 90min/day for 1 week. The animals of both models were eventually sacrificed, the stomach fundus was isolated and its sensitivity in vitro to carbachol, potassium chloride, serotonin and adrenaline was tested. Blood samples were taken to assess levels of ghrelin, corticosterone releasing factor (CRF) and corticosterone. The sensitivity of fundus strips from restrained rats towards the agents tested, partly representing autonomic responsiveness, was more depressed than those from maternally separated ones. Levels of ghrelin, CRF and corticosterone were also more elevated in the RS model. That model was therefore chosen to test the efficacy of STW 5 in restoring the deranged parameters. A group of animals received STW 5 orally once daily starting treatment 1 week before exposing them to RS and continuing treatment for a further week during subjection to RS. STW 5 was effective in normalizing the depressed stomach fundus responses exhibited by animals subjected to RS and to normalize to a large extent the deranged blood levels of ghrelin, CRF and corticosterone. The findings lend further evidence to the role of the brain-gut axis in FD and gives supportive evidence for the first time for the clinical usefulness of STW 5 in this condition.

Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs

BACKGROUND Acotiamide hydrochloride (acotiamide), a novel selective acetylcholinesterase (AChE) inhibitor, has proven significantly effective in treating functional dyspepsia (FD) in clinical trials, particularly in alleviating meal-related symptoms. In the present study, we examined the gastrointestinal prokinetic effects of acotiamide administered orally or intraduodenally in conscious dogs and investigated in vivo and ex vivo anti-AChE activity of acotiamide to clarify its mechanism of prokinetic action. Gastrointestinal motility was measured in conscious dogs with chronically implanted force transducers. Oral administration of acotiamide stimulated postprandial gastroduodenal and colonic motor activities. Measurement of gastrointestinal motility showed that acotiamide, like itopride and mosapride, enhanced gastric antral motility. Further, acotiamide markedly improved clonidine (an α(2) -adrenoceptor agonist)-induced hypomotility in a dog model of gastric motor dysfunction. The postprandial gastric antral motility enhanced by acotiamide was completely abolished on treatment with the muscarinic receptor antagonist atropine. Results of an in vivo experiment on anti-AChE activity showed clearly increased acetylcholine-induced gastric motility on intraduodenal administration of acotiamide, just as observed with the AChE inhibitor neostigmine. Further, in ex vivo experiment, intraduodenal administration of acotiamide significantly inhibited AChE activity in canine gastric antrum. Our findings revealed that acotiamide administered through the alimentary tract exerts gastroprokinetic action via cholinergic pathways by inhibiting AChE activity. These results may also confirm the mechanism of action in clinical efficacy of acotiamide on FD.

Reduced expression of choline acetyltransferase in vagal motoneurons and gastric motor dysfunction in a 6-OHDA rat model of Parkinson's disease

Parkinson's disease (PD) has been characterized by dopaminergic neuron degeneration in the substantia nigra (SN) accompanied by pathology of the dorsal motor nucleus of the vagus (DMV). PD patients have often experienced gastrointestinal dysfunctions, such as gastroparesis. However, the mechanism underlying these symptoms in PD patients is not clear. In the present study, we investigated alterations of cholinergic and catecholaminergic neurons in the DMV and gastric motor function in rats microinjected with 6-hydroxydopamine (6-OHDA) bilaterally into the SN (referred to as 6-OHDA rats) and explored possible mechanisms. A strain gauge force transducer was used to record gastric motility in vivo. Expression of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) was evaluated by immunofluorescence and western blot analysis. Acetylcholine (Ach) content was measured using ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS) analysis. After treatment with 6-OHDA for 6 weeks, 6-OHDA rats exhibited decreased ChAT and enhanced TH expression in the DMV and decreased Ach content in the gastric muscular layer. Delayed gastric emptying and impaired gastric motility in vivo were observed in 6-OHDA rats. The results of the present study indicated that decreased ChAT and enhanced TH expression in the DMV may be correlated with the development of delayed gastric emptying and impaired gastric motility, which may be partly due to the decreased Ach release from the vagus.

W1924 Hypothalamic Oxytocin is Involved to Restore Gastric Motor Dysfunction Following Chronic Stress in Rats

patterns of rat terminal ileum hypertrophied by chronic obstruction. Methods: The motor responses to electrical stimulation (ES) (3Hz, 30V, 1msec, trains of 20” every 120”) and to distension (80mmH2O) were studied in the absence and in the presence of various pharmacological agents in 4 cm-long segments from sham-operated (SO) and hypertrophic (H) rats, horizontally mounted and connected to a pressure transducer and constantly intraluminally perfused (4). Female Wistar rats were used according to Guiding Principles in the Care and Use of Animals. Results: Data are expressed as mean±SEM (Student's ttest vs basal values)in the Table. InH tissues, ES lowered the intraluminal pressure (*P<0.001) and evoked higher amplitude TTX-sensitive peaks compared to SO segments (P=0.06). In all H tissues, distension produced rhythmic, anally propagating and propulsive contractions. Only non-propulsive motor patterns emerged in SO tissues. Atropine 1μM and guanethidine 4μM reversed the accommodation produced by ES in H tissues, decreased the amplitude of ES-contractions to 12.0mmHgxsec in SO (P<0.01) and 6.7mmHgxsec in H (P<0.01) and abolished stretch-induced motility. Exposure to L-NAME 300μM and protease αchymotrypsin 10UI/mL cancelled ES motor activity in both types of tissues and peristaltic movements in H ones. No effects were produced on peristalsis by 5HT2a receptor antagonist ketanserin 1μM or by 5HT3 blocker ondansetron 1μM, applied either on the mucosal or on the serosal side of H ileum.Conclusions: Rat H ileum showed an increased accommodation to ES compared to SO ileum and a unique ability to develop distension-induced peristalsis, primarily controlled by cholinergic and peptidergic transmission and consistent with the heightened sensitivity to excitatory and inhibitory mediators displayed by isolated H smooth muscles. 1. Gabella G. Anat Embryol 1990. 2. Ekblad E et al. Gut 1998. 3. Bertoni S et al. Neurogastroenterol Motil 2008. 4. Tonini M et al. Eur J Pharmacol 1981.

Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin‐induced diabetes

Interstitial cells of Cajal (ICC) are associated with afferent innervation and peristalsis of the stomach suggestive of a key role in the pathophysiology of gastroparesis. We studied changes in the density and ultrastructure of ICC and enteric nerves in the streptozotocin-induced diabetes mellitus (STZ-DM) in Wistar rats using immunohistochemistry and electron microscopy. Gastric emptying was studied in vivo by single-photon emission computed tomography. In the STZ-DM antrum, a marked reduction was observed in the density of the intramuscular ICC (ICC-IM) and ICC located at the submucosal border of the circular muscle layer of the antrum (ICC-SM). The surviving ICC showed lamellar bodies and partial vacuolation of the cytoplasm content, loss of connections between ICC-IM and nerves; it appeared that injured ICC-IM developed into fibroblast-like ICC. ICC associated with Auerbach's plexus (ICC-AP) in the antrum and ICC in the fundus were not affected significantly except for a loss of connections with nerve structures. Marked reduction in nerve tissue (Protein Gene Product-9.5 positivity) was also restricted to the muscle layers including nitrergic nerves (neuronal nitric oxide synthase positivity). In vivo assessed gastric emptying was markedly reduced in STZ-DM rats. Our data demonstrate in the STZ-DM rat stomach a decreased density of ICC limited to the antrum and to ICC-IM and ICC-SM, and structural degeneration in ICC-IM and associated nerves with a special emphasis on loss of synaptic connections, accompanied by a decrease in gastric emptying. Hence, in this model of gastroparetic diabetes, regional injury to subsets of ICC and nerves are associated with gastric motor dysfunction.

Correlations Among Electrogastrogram, Gastric Dysmotility, and Duodenal Dysmotility in Patients With Functional Dyspepsia

The aim of this study was to assess gastric slow waves, antral and duodenal motility simultaneously, and determine the correlation among all these measures in patients with functional dyspepsia. Thirty-one patients with functional dyspepsia were assessed for severity of upper gastrointestinal symptoms with the electrogastrography (EGG) and antroduodenal manometry. The EGG and manometry were recorded for 3 to 4 hours in the fasting state and for 2 hours after a solid meal. Computerized spectral analysis methods were used to compute various EGG parameters. The EGG was abnormal in 71.0% of patients. The abnormalities included normal slow waves lower than 70% in the fasting state (51.6% of patients) and in the fed state (48.4% of patients), a decrease in dominant power in 28.9% of patients. Antral motility was abnormal in 80.6% of patients and duodenal motility was abnormal in 74.2% of patients. For the EGG and antral motility, 19 of 31 patients had both abnormal EGG and abnormal antral motility; 2 of 31 patients had both normal EGG and normal antral motility. For the EGG and duodenal motility, these values were 16/31 and 2/31, respectively. By both EGG and antroduodenal manometry, abnormal gastric motor function was found in 93.5% of patients. However, quantitative one-to-one correlation between any of the EGG parameters and the antroduodenal dysmotility was not noted. The patients showed high symptom scores particularly to upper abdominal pain, nausea, and belch. No one-to-one correlation was noted between the symptom scores and any of the EGG or motility parameters. More than two-thirds of patients with functional dyspepsia have abnormalities in the EGG and antral/duodenal motility. The sensitivity of these 2 different methods is essentially the same. EGG and antroduodenal manometry can complement each other in demonstrating gastric motor dysfunction in patients with functional dyspepsia.

Regulative effects of essential oil from Atractylodes lancea on delayed gastric emptying in stress-induced rats

Gastric motor dysfunction induced by psychological stress results in many symptoms of functional dyspepsia (FD). There are a number of herbal medicines that are reported to improve gastrointestinal motor. However, the mechanisms of considerable herbal medicines are not explicit. In the present study, the effects of an essential oil (EO) extracted from Atractylodes lancea on delayed gastric emptying, gastrointestinal hormone and hypothalamic corticotropin-releasing factor (CRF) abnormalities induced by restraint stress in rats were investigated and the mechanism of the EO is also explored. Oral administration of EO for 7 days did not affect normal gastric emptying, but accelerated delayed gastric emptying induced by restraint stress in rats. The EO significantly increased the levels of motilin (MTL) and gastrin (GAS) and decreased the levels of somatostatin (SS) and CRF. The EO did not modify gastric emptying in vagotomized rats that underwent restraint stress, but antagonized delayed gastric emptying induced by intracisternal injection of CRF. These results suggest that the regulative effects of the EO on delayed gastric emptying are preformed mainly via inhibition of the release of central CRF and activation of vagal pathway, which are also involved in the release of gastrointestinal hormones such as MTL, GAS and SS.