Increase In Gastric Motility Research Articles

Нестероидные противовоспалительные препараты: повреждающее действие на слизистую оболочку желудка и способы защиты от их ульцерогенного влияния

Non-steroidal anti-inflammatory drugs (NSAIDs) are used for various diseases to relieve pain and reduce inflammation. However, the use of NSAIDs can lead to adverse side effects on the kidneys, heart, gastrointestinal tract (GIT) and the central nervous system, which complicates the use of NSAIDs in medicine. The review analyses literature on the anti-inflammatory action of NSAIDs and their adverse side effects. A special focus is given to the side effects of NSAIDs on the gastrointestinal tract. Taking NSAIDs can lead to pathological changes in the GIT: dyspeptic symptoms, gastropathy, gastrointestinal mucosal damage, including erosion and ulcers, which can be accompanied by serious complications such as gastrointestinal bleeding and perforations. The main mechanisms of the damaging effect of NSAIDs on the gastric mucosa include a slowdown in the blood flow rate in the stomach microvessels, which leads to an increase in their permeability, as well as an increase in gastric motility, a decrease in the secretion of mucus and bicarbonates in the stomach, a change in lipid peroxidation with the formation of free radicals that destroy the structure of cell membranes. Nonselective NSAIDs, including the well-known and popular indomethacin and aspirin, have a pronounced deleterious effect on the GIT. The selective NSAIDs are safer regarding the gastrointestinal side effects compared with nonselective ones, however, they can lead to serious cardiac problems. To mitigate the ulcerogenic effect of NSAIDs, antacids and proton pump inhibitors are used. They reduce the secretion of hydrochloric acid in the stomach. Another solution are drugs associated with membrane phospholipids. These drugs contain nitric oxide and hydrogen sulfide. Taking NSAIDs increases the level of glucocorticoid hormones in the blood, which compensate for the absence of prostaglandins and have a gastroprotective effect. Physical exercise stimulates the body’s natural defenses and protects the gastric mucosa from the negative effects of NSAIDs. In this regard, it is crucial for physiology to conduct more studies focusing on the mechanisms of NSAID-induced deleterious influence on the GIT, gastroprotective mechanisms and the development of evidence-based approaches to reduce the adverse effects of NSAIDs.

Randomized Controlled Clinical Trial on Value of Domperidone in Functional Abdominal Pain in Children.

The aim of the study was to evaluate the therapeutic effect of domperidone on children with abdominal pain predominant functional gastrointestinal disorders (AP-FGIDs). One hundred children (aged 5-12 years) fulfilling Rome III criteria for AP-FGIDs were randomized into 8 weeks of domperidone or placebo treatment. Primary outcomes defined were cure and patient-reported general improvement. Secondary outcomes were reduction in the severity of abdominal pain and increase in gastric motility. Patients were followed up for 6 months. Eighty-nine (42 in placebo group, 47 in domperidone group) completed the trial at 8 weeks. Seventy-nine completed the 6-month follow-up. When primary outcomes were assessed at 8 weeks, 37 (74%) in the domperidone group and 25 (50%) in the placebo group showed patient-reported general improvement (P = 0.013), whereas no significant difference was observed in cure (22 [44%] vs 14 [28%] P = 0.09). At 6-month follow-up 30 (60%) in the domperidone group and 19 (38%) in the placebo group reported cure (P = 0.028), whereas 44 (88%) in the domperidone group and 33 (66%) in the placebo group showed patient-reported general improvement (P = 0.009). When assessing secondary outcomes at 8 weeks, the domperidone group reported significant reduction in the severity of abdominal pain (54.1% vs 24.7%, P = 0.008) and an increase in the antral motility index (27.5% vs 7.2%, P = 0.029). None of the patients reported intervention-related adverse effects. Domperidone may be a safe and effective therapeutic modality to achieve a lasting remission of symptoms in children with AP-FGIDs.

Perinatal high fat diet increases inhibition of dorsal motor nucleus of the vagus neurons regulating gastric functions.

Previous studies suggest an increased inhibition of dorsal motor nucleus of the vagus (DMV) neurons following exposure to a perinatal high fat diet (PNHFD); the underlying neural mechanisms, however, remain unknown. This study assessed the effects of PNHFD on inhibitory synaptic inputs to DMV neurons and the vagally dependent control of gastric tone and motility. Whole-cell patch clamp recordings were made from DMV neurons in thin brainstem slices from Sprague-Dawley rats fed either a control diet or HFD (14 or 60%kcal from fat, respectively) from embryonic day 13 onwards; gastric tone and motility were recorded in in vivo anesthetized rats. The non-selective GABAA antagonist, BIC (10μmolL-1 ), induced comparable inward currents in PNHFD and control DMV neurons, but a larger current in PNHFD neurons at higher concentrations (50μmolL-1 ). Differences were not apparent in neuronal responses to the phasic GABAA antagonist, gabazine (GBZ), the extrasynaptic GABAA agonist, THIP, the GABA transport blocker, nipecotic acid, or the gliotoxin, fluoroacetate, suggesting that PNHFD altered inhibitory transmission but not GABAA receptor density or function, GABA uptake or glial modulation of synaptic strength. Similarly, the increase in gastric motility and tone following brainstem microinjection of low doses of BIC (1-10pmoles) and GBZ (0.01-0.1pmoles) were unchanged in PNHFD rats while higher doses of BIC (25pmoles) induced a significantly larger increase in gastric tone compared to control. These studies suggest that exposure to PNHFD increases the tonic inhibition of DMV neurons, possibly contributing to dysregulated vagal control of gastric functions.

Evaluation of gastric motility of Phyllanthus emblica and Asparagus racemosus in cold stress induced gastric damage

Background: Gastric emptying is known to be delayed in gastritis and gastric ulcer. Phyllanthus emblica and Asparagus racemosus are known to be gastroporotective. The objective if the study is to evaluate the effects of Phyllanthus emblica and Asparagus racemosus on gastric motility per se and by using the cold stress model of gastric damage. Methods: 84 wistar rats were used and divided into 7 groups. Different extracts of Phyllanthus emblica was administered to rats. Other groups received distilled water (control), Asparagus racemosus and ranitidine. All rats were given a test meal of methyl cellulose (1.5%) mixed with phenol red (50 mg/100 ml) orally and gastric emptying was measured 20 minutes later. Results: Gastric emptying was found to be 58.00±8.36 in normal rats (group I). None of the study drugs had any per se effect on gastric motility. Cold stress significantly reduced the gastric emptying 35.33±5.46 (p<0.05). Phyllanthus emblica and Asparagus racemosus showed increase in gastric motility 82.66±6.43 (phyllanthus emblica hot water extract) and 68.50±4.54 respectively which was statistically significant (p<0.01). Ranitidine also showed statistically significant increase in gastric motility 70.00±5.40 (p<0.01). Conclusions: Phyllanthus emblica and Asparagus racemosa have gastric motility enhancing effect and this could be one of the mechanisms of decrease in gastric erosions.

Hindbrain glucoprivation effects on gastric vagal reflex circuits and gastric motility in the rat are suppressed by the astrocyte inhibitor fluorocitrate.

Fasting and hypoglycemia elicit powerful gastrointestinal contractions. Whereas the relationship between utilizable nutrient and gastric motility is well recognized, the explanation of this phenomenon has remained incomplete. A relatively recent controversial report suggested that astrocytes in the dorsal hindbrain may be the principal detectors of glucoprivic stimuli. Our own studies also show that a subset of astrocytes in the solitary nucleus (NST) is activated by low glucose. It is very likely that information about glucopenia may directly impact gastric control because the hindbrain is also the location of the vago-vagal reflex circuitry regulating gastric motility. Our in vivo single unit neurophysiological recordings in intact rats show fourth ventricular application of 2-deoxyglucose (2-DG) inhibits NST neurons and activates dorsal motor nucleus (DMN) neurons involved in the gastric accommodation reflex. Additionally, as shown in earlier studies, either systemic insulin or central 2-DG causes an increase in gastric motility. These effects on motility were blocked by fourth ventricle pretreatment with the astrocyte inactivator fluorocitrate. Fluorocitrate administered alone has no effect on gastric-NST or -DMN neuron responsiveness, or on gastric motility. These results suggest that glucoprivation-induced increases in gastric motility are dependent on intact hindbrain astrocytes.

Perinatal high fat diet dysregulates GABAergic signaling to vagal efferent motoneurons regulating gastric motility

Parasympathetic innervation to the stomach is supplied by dorsal motor nucleus of the vagus (DMV) neurons. Studies have demonstrated that ongoing GABAergic inputs to DMV neurons play a major role in regulating vagal efferent output. The aim of this study was to investigate whether perinatal HFD affects the GABAergic regulation of vagal efferent output to the stomach. Male Sprague Dawley rats were fed a HFD (60%kcal from fat) from E13 until experimentation at 12 weeks of age. Miniaturized strain gauges sutured to the ventral surface of the gastric corpus were used to record gastric motility. The GABAA receptor antagonist, bicuculline methiodide (BMI; 60nl) was microinjected into the dorsal vagal complex and the resulting increase in gastric motility was measured at 3 time points after injection (1.5, 4 and 6.5min) and averaged. Responses were expressed relative to the maximal increase in motility in response to i.v. injection of the non‐selective muscarinic agonist, bethanecol (353pmol; 1ml), which itself was unaffected by diet (9.08±1.20g in control vs 9.27±1.03g in HFD; P&gt;;0.05).In control rats, BMI induced a dose‐dependent increase in gastric motility (3.1±0.6%, 4.8±1.1% and 5.7±1.7% at 25, 50 and 100pmol, n=8,8,4, respectively, P&lt;0.05 for each). In contrast, following HFD, the BMI‐induced increase in gastric motility was significantly attenuated (0.004±0.0001%, 1.2±0.3% and 1.25±0.3% at 25, 50 and 100pmol, n= 4,5,4, respectively, P&lt;0.05 vs control). These data suggest that exposure to a HFD during the perinatal period alters GABAergic activity within brainstem neural circuits controlling gastric functions, which may contribute to the dysregulation of homeostatic reflexes, including appetite and metabolic regulation.Supported by NSF IOS 1148978

Glucose and the vagus: sensory cells savour sweet substances

Glucose and the vagus: sensory cells savour sweet substances

Vagal Nerve Regulation Is Essential for the Increase in Gastric Motility in Response to Mild Exercise

It has been shown that mild to moderate exercise can accelerate gastric emptying in humans. However, understanding of the underlying mechanism is hampered by the lack of appropriate animal models. To investigate the effects of mild exercise on gastric motility, we developed an animal model, in which strain gauge transducers were surgically planted on the antral surfaces of female Sprague-Dawley rats. We continuously recorded the contractions of gastric circular muscle in unrestrained conscious rats, divided into four groups: sham-operated exercise, sham-operated sedentary, vagotomized exercise, and vagotomized sedentary. The rats were trained for 3 weeks, and gastric motility was monitored before and after exercise. Although exercise accelerates gastric antral contraction in sham-operated rats, this effect was absent in the vagotomized exercise group, indicating the involvement of the vagal nerve in the exercise-mediated increase in gastric motility. Among the four groups, daily food intake was highest in the sham-operated exercise group. In contrast, the vagotomized exercise group exhibited the smallest body weight gain. Severe gastric retention was observed in vagotomized rats, suggesting a role of the vagal nerve in facilitating food movement and digestion in the stomach. Moreover, at the end of the 3-week exercise, there were no differences in plasma levels of growth hormone, peptid YY, and ghrelin among the four groups. These results indicate that in response to a mild physical exercise challenge, the vagal nerve stimulates gastric motility and enhances the ability of the stomach to process food. Our findings highlight the significance of neuronal control of stomach function.

Effects of metoclopramide on gastric motility measured by short-term bio-impedance

To analyze the accuracy of short-term bio-impedance as a means of measuring gastric motility. We evaluated differences in the short-term electrical bio-impedance signal from the gastric region in the following conditions: (1) fasting state, (2) after the administration of metoclopramide (a drug that induces an increase in gastric motility) and (3) after food ingestion in 23 healthy volunteers. We recorded the real component of the electrical impedance signal from the gastric region for 1000 s. We performed a Fast Fourier Transform (FFT) on this data and then compared the signal among the fasting, medicated, and postprandial conditions using the median of the area under the curve, the relative area under the curve and the main peak activity. The median of the area under the curve of the frequency range in the region between 2-8 cycles per minute (cpm) decreased from 4.7 cpm in the fasting condition to 4.0 cpm in the medicated state (t = 3.32, P = 0.004). This concurred with the decrease seen in the relative area under the FFT curve in the region from 4 to 8 cpm from 38.3% to 26.6% (t = 2.81, P = 0.012) and the increase in area in the region from 2 to 4 cpm from 22.4% to 27.7%, respectively (t = -2.5, P = 0.022). Finally the main peak position also decreased in the region from 2 to 8 cpm. Main peak activity in the fasting state was 4.72 cpm and declined to 3.45 cpm in the medicated state (t = 2.47, P = 0.025). There was a decrease from the fasting state to the postprandial state at 3.02 cpm (t = 4.0, P = 0.0013). Short-term electrical bio-impedance can assess gastric motility changes in individuals experiencing gastric stress by analyzing the area medians and relative areas under the FFT curve.

GABA signaling in the nucleus tractus solitarius sets the level of activity in dorsal motor nucleus of the vagus cholinergic neurons in the vagovagal circuit

It has been proposed that there is an "apparent monosynaptic" connection between gastric vagal afferent nerve terminals and inhibitory projection neurons in the nucleus tractus solitarius (NTS) and that two efferent parallel pathways from the dorsal motor nucleus of the vagus (DMV) influence peripheral organs associated with these reflexes (6). The purpose of our study was to verify the validity of these views as they relate to basal control of gastric motility. To test the validity of a direct connection of vagal afferent terminals (known to release l-glutamate) directly impacting second-order projection neurons, we evaluated the effect of GABA(A) receptor blockade in the area of the medial subnucleus of the tractus solitarius (mNTS) on gastric motility. Microinjection of bicuculline methiodide into the mNTS produced robust decreases in gastric motility (-1.6 +/- 0.2 mmHg, P < 0.05, n = 23), which were prevented by cervical vagotomy and by pretreatment with kynurenic acid microinjected into the mNTS. Kynurenic acid per se had no effect on gastric motility. However, after GABA(A) receptor blockade in the mNTS, kynurenic acid produced a robust increase in gastric motility. To test for the contribution of two parallel efferent DMV pathways, we assessed the effect of either intravenous atropine methylbromide or N(G)-nitro-l-arginine methyl ester on baseline motility and on decreases in gastric motility induced by GABA(A) receptor blockade in the mNTS. Only atropine methylbromide altered baseline motility and prevented the effects of GABA(A) receptor blockade on gastric motility. Our data demonstrate the presence of intra-NTS GABAergic signaling between the vagal afferent nerve terminals and inhibitory projection neurons in the NTS and that the cholinergic-cholinergic excitatory pathway comprises the functionally relevant efferent arm of the vagovagal circuit.

Mechanisms underlying the gastroprotective action of glucocorticoids released in response to ulcerogenic stress factors.

Our previous results demonstrate the gastroprotective but not ulcerogenic action of glucocorticoids released in response to ulcerogenic stress factors. The present study was undertaken to investigate the possible mechanisms underlying the gastroprotective action of glucocorticoids in rat stomachs. The effects of deficiency of glucocorticoid production, with or without corticosterone supplementation, on blood flow velocity in gastric microvessels, microvascular permeability, mucus production, motility as well as gastric lesions were studied 3 to 4 h after the onset of ulcerogenic stimuli: water-restraint stress or indomethacin administration. The contribution of glucocorticoids in the healing process of gastric injury was also evaluated. The deficiency in glucocorticoid production significantly potentiated the functional disorders induced by ulcerogenic stimuli, such as a decrease in blood flow velocity and mucus production and an increase in gastric motility and in microvascular permeability, which resulted in aggravation of the formation of gastric lesions as well as impairment of their healing. The changes observed were prevented by supplementation of corticosterone at a dose mimicking a stress-induced corticosterone rise. We conclude that a gastroprotective action of glucocorticoids may be provided by multiple actions, including maintenance of the gastric mucosal blood flow and mucus production, attenuation of the enhanced gastric motility and microvascular permeability as well as beneficial influences on healing processes.

Functional mechanism underlying COX-2 expression following administration of indomethacin in rat stomachs: importance of gastric hypermotility.

The expression of COX-2 is up-regulated in the rat stomach after administration of indomethacin, and the inhibition of this enzyme may be a key to NSAID-induced gastric damage. The present study investigated the mechanism for COX-2 expression induced in the rat stomach by indomethacin, in relation with the ulcerogenic processes. The animals were given indomethacin or SC-560 p.o., and the gastric mucosa was examined 8 hr later. Indomethacin decreased the mucosal PGE2 content and produced gross damage with gastric hypermotility and the expression of COX-2 mRNA in the mucosa. Although SC-560 did not produce damage, this agent caused a decrease in the PGE2 content and an increase in gastric motility as well as the up-regulation of COX-2 expression, and provoked damage in the presence of rofecoxib. Gastric lesions induced by indomethacin were prevented by both atropine (even in the presence of exogenous HCl) and omeprazole, although the hypermotility response was inhibited only by atropine. The COX-2 expression induced by indomethacin or SC-560 was inhibited by atropine, even in the presence of exogenous HCl, while omeprazole had no effect. The mucosal PGE2 content was decreased by SC-560 at 2 hr but recovered 8 hr later, and this recovery of PGE2 was attenuated by both atropine and rofecoxib but not omeprazole. These results suggested that the COX-2 expression in the stomach following treatment with indomethacin is functionally associated with gastric hypermotility response induced by COX-1 inhibition. Luminal acid does not play a role in the up-regulation of COX-2 expression in the stomach following administration of indomethacin.

Functional mechanism for up-regulation of COX-2 induced by COX-1 inhibition in rat stomachs: Importance of gastric hypermotility

We have recently reported the expression of COX-2 mRNA in the rat stomach after administration of indomethacin or SC-560, a selective COX-1 inhibitor, and suggested that this may be a reason why inhibition of both COX-1 and COX-2 is required for gastric ulcerogenic action of NSAID. In the present study, we investigated the functional mechanism for COX2 expression in the rat stomach under COX-1 inhibition. Methods: Male SD rats were used after 18 h fasting. The animals were given indomethacin (30 mg/kg), SC-560 (30 mg/kg), rofecoxib (30 mg/kg) or SC-560 plus rofecoxib PO, and the gastric mucosa was examined 8 h later. Atropine (1 mg/kg) or omeprazole (60 mg/kg) was given SC 30 rain before indomethacin or 5C-560 plus rofecoxib. Gastric motility was determined by a balloon method. Mucosal PGE2 content was measured by EIA, while COX-2 mRNA was examined by RT-PCR. Results: lndomethacin decreased the mucosal PGE2 content and produced gross damage in the stomach with a marked gastric hypermotility. SC-560 alone caused a decrease in the PGE2 content and an increase in gastric motility but did not produce any damage in the stomach. However, SC-560 plus rofecoxib produced gastric hypermotility and gross lesions in the stomach, similar to indomethacin. Rofecoxib alone did not cause damage in the mucosa with no effect on gastric motility and PGE2 content. Gastric lesions induced by indomethacin were prevented by both atropine and omeprazole, although the hypermotility response was inhibited only by atropine. COX-2 mRNA was expressed in the gastric mucosa 4 h after indomethacin or SC-560 but not rofecoxib. The COX-2 expression induced by indomethacin was inhibited by atropine, even in the presence of exogenous HCI, while omeprazole had no effect. SC-560 markedly decreased the mucosal PGE2 content at 2 h after the administration, but this effect was significantly reverted 8 h later, in a rofecoxib or atropine but not omeprazole-senstive manner. Conclusion: These results confirmed the COX-2 expression in the stomach after administration of IM or SC-560, and further suggested that this process is associated with gastric hypermonhty response induced by COX-1 inhibition by these agents. Luminal acid does not play a role in the up-regulation of COX-2 in the, stomach under inhibition of COX-1.

Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats.

We investigated the mechanisms underlying the protective action of glucocorticoids against indomethacin-induced gastric lesions. One-week adrenalectomized rats with or without corticosterone replacement (4 mg/kg sc) were administered indomethacin (25 mg/kg sc), and gastric secretion (acid, pepsin, and mucus), motility, microvascular permeability, and blood glucose levels were examined. Indomethacin caused gastric lesions in sham-operated rats, with an increase in gastric motility and microvascular permeability as well as a decrease in mucus secretion. Adrenalectomy significantly worsened the lesions and potentiated these functional disorders. Glucose levels were lowered by indomethacin in sham-operated rats, and this response was enhanced by adrenalectomy. The changes observed in adrenalectomized rats were prevented by supplementations of corticosterone at a dose mimicking the indomethacin-induced rise in corticosterone, whereas the protective effect of corticosterone was attenuated by RU-38486, a glucocorticoid receptor antagonist. We conclude that the gastroprotective action of endogenous glucocorticoids may be provided by their support of glucose homeostasis and inhibitory effects on enhanced gastric motility and microvascular permeability as well as maintaining the production of mucus.

Involvement of serotonin and nitric oxide in endotoxin-induced gastric motility changes in conscious rats.

Severe bacterial infection causes gastrointestinal dysmotility by an unknown mechanism. We investigated the possible involvement of serotonin (5-HT) and nitric oxide (NO) in endotoxin-induced motility disturbance, using an in vivo rat model. Six days prior to the experiment, a force transducer was sutured to the gastric antrum of rats. Lipopolysaccharide induced strong repetitive contractions in the gastric antrum within 2 to 3 min in all rats tested. After 15 min of hypermotility, motility decreased and remained low for more than 60 min. The initial increase in motility was suppressed by atropine, FK1052, or SB204070, whereas it was not affected by granisetron. The subsequent decrease was inhibited by L-NAME and S-methylisothiourea sulfate. These results indicate that in conscious rats, lipopolysaccharide induces a transient increase in gastric motility followed by suppression. The increase might be mediated by 5-HT4 receptors, and the decrease by inducible NOS.

Body temperature dependency in baclofen-induced gastric acid secretion in rats: Relation to capsaicin-sensitive afferent neurons

Body temperature dependency in gastric functional responses to baclofen, a GABA B agonist, such as acid secretion, mucosal blood flow (GMBF) and motor activity, was examined in urethane-anesthetized rats under normal (37±1 °C) and hypothermic (31±1 °C) conditions. A rat stomach was mounted in an ex-vivo chamber, perfused with saline, and the acid secretion was measured using a pH-stat method, simultaneously with GMBF by a laser Doppler flowmeter. Gastric motility was measured using a miniature balloon as intraluminal pressure recordings. Intravenous administration of baclofen significantly increased acid secretion at the doses > 0.3 mg/kg under hypothermic conditions, yet it caused a significant stimulation only at doses >10 mg/kg under normothermic conditions. The increases in gastric motility and GMBF were similarly induced by baclofen, irrespective of whether the animals were subjected to normothermic or hypothermic conditions. These functional responses to baclofen under hypothermic conditions were totally attenuated by either bilateral vagotomy or atropine (3 mg/kg, s.c.). Baclofen at a lower dose (1 mg/kg i.v.) significantly increased the acid secretion even under normothermic conditions when the animals were subjected to chemical deafferenation of capsaicin-sensitive neurons or pretreatment with intracisternal injection of CGRP 8-37 (30 ng/rat). These results suggest that 1) gastric effects of baclofen are dependent on body temperature in stimulating acid secretion but not GMBF or motor activity, 2) the acid stimulatory action of baclofen is enhanced under hypothermic conditions, and 3) the suppression of baclofen-induced acid response under normothermic conditions may be related to capsaicin-sensitive afferent neuronal activity, probably mediated by central release of CGRP.

Prostaglandin E Inhibits Indomethacin-Induced Gastric Lesions through EP-1 Receptors

Backgrounds and Aims: We examined the effect of various prostaglandin E (PGE) analogs specific to EP receptor subtypes on indomethacin-induced gastric lesions in rats and investigated which EP receptor subtype is involved in the protective action of PGE₂ using EP-receptor knockout mice. Methods: Gastric lesions were induced by subcutaneous administration of indomethacin (35 mg/kg). Gastric motility was measured using a balloon method, while neutrophil chemotaxis determined using a Boyden chamber. Results: Indomethacin-induced gastric lesions were significantly prevented by PGE₂ as well as atropine, and the former effect was mimicked by sulprostone (EP₁/EP₃) and 17-phenyl PGE₂ (EP₁) and antagonized by an EP₁ antagonist, ONO-AE-829. Neither butaprost (EP₂), ONO-NT-012 (EP₃) nor 11-deoxy PGE₁ (EP₃/EP₄) showed any protection on the lesions. Indomethacin caused a marked increase in gastric motility; the response preceded the onset of lesions and was inhibited by atropine as well as PGE derivatives acting as EP₁ receptors. Neutrophil chemotaxis was inhibited by PGE₂, butaprost and slightly by 11-deoxy PGE₁, but not by either 17-phenyl PGE₂, ONO-NT-012 or atropine. In addition, indomethacin caused damage similarly in both wild-type and knockout mice lacking EP₁ or EP₃ receptors, yet the protective action of PGE₂ was observed in wild-type and EP₃ receptor knockout mice but totally disappeared in mice lacking EP₁ receptors. Conclusion: PGE₂ inhibits indomethacin-induced gastric lesions, through EP₁ receptors, and this effect may be functionally associated with inhibition of gastric motility but not of neutrophil activation/migration.

Induction of endogenous tumor necrosis factor-α: suppression of centrally stimulated gastric motility

Gastric stasis is frequently seen in conjunction with critical infectious illness, chronic inflammatory disorders, radiation sickness, and carcinogenesis. These conditions are associated with elevated circulating levels of the cytokine tumor necrosis factor-alpha (TNF-alpha). The present studies examined the relationship between endogenously produced TNF-alpha and the central neural mechanisms that augment gastric motility. Systemic lipopolysaccharide (LPS) was employed to induce TNF-alpha production in thiobutabarbital-anesthetized rats. Sixty minutes after intravenous LPS injection, gastric motility could not be stimulated by a potent centrally acting gastrokinetic stimulant, thyrotropin-releasing hormone (TRH). This failure to elicit gastric motility via central mechanisms coincided with high circulating levels of TNF-alpha. However, intravenous injections of bethanecol, a peripherally acting cholinergic agonist with direct gastrokinetic effects, were still able to elicit normal increases in gastric motility in the presence of TNF-alpha and LPS. Therefore, the inability to stimulate gastric motility via central TRH could not be attributed to the direct inhibitory effects of either LPS or TNF-alpha on the stomach. If the production of endogenous TNF-alpha was suppressed via the use of urethan as the anesthetic agent, then intravenous injections of LPS were no longer effective in suppressing gastric motility. Thus these effects on gastric motility are not directly attributable to LPS nor are they due to direct effects on the gastric smooth muscle. Our previous study demonstrated that microinjection of femtomole quantities of TNF-alpha in the brain stem dorsal vagal complex (DVC) can modulate gastric motility. This central TNF-alpha effect on gastric motility was dose dependent and required an intact vagal efferent pathway. The results from these two studies suggest that systemically produced TNF-alpha may gain access to the DVC to modulate gastric function.

Electrogastrographic power ratio in humans is not related to changes in antrum-skin distance but to antral motility.

It is not clear whether the power increase in electrogastrography (EGG) after meal or water ingestion reflects increases in gastric motility or gastric distension bringing the stomach closer to the electrodes on the abdominal skin surface. We recorded EGG and real-time ultrasonography simultaneously before and after 150-ml water ingestion in 17 healthy volunteers. We calculated gastric power, by spectral analysis of EGG by the maximum entropy method, for 400 s before and after water ingestion, and calculated their ratio (power ratio). We calculated, using sonography, the number of antral contractions before and after water ingestion, the motility index after water ingestion, the distance between the antrum and the abdominal skin surface before and after water ingestion, and the ratio of these distances (distance ratio). The number of contractions was positively correlated with gastric power before water ingestion, and the antrum-skin distance was negatively correlated with gastric power both before and after water ingestion. The motility index after water ingestion was positively correlated with both gastric power after water ingestion (Spearman's rank correlation r = 0.492; P = 0.0498) and the power ratio (r = 0.615; P = 0.0141). There was no correlation between the distance ratio and the power ratio. These results suggest that the power increase in EGG induced by water ingestion does not reflect the approach of the antrum to the abdominal surface, but rather, reflects antral motility after water ingestion.

Gastric mucosal blood flow in relation to stress-induced hypercontraction in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is a widely used animal model for essential hypertension, and is less susceptible to cold restraint stress in gastric ulcer formation. We previously reported that acid secretion is low in SHR due to sympathetic facilitation compared with normotensive Wistar-Kyoto rats (WKY). The purpose of this study was to evaluate the autonomic nervous function and the gastric mucosal blood flow related to gastric motility during cold restraint stress in SHR. Male SHR and WKY, 24-28 weeks old, were used in this study. Noradrenergic innervation, noradrenaline and dopamine contents in the muscle layer were significantly greater in SHR than in WKY, and tissue choline acetyltransferase activity was significantly lower in SHR. Gastric motility was markedly enhanced by cold restraint stress in WKY. By contrast, SHR maintained the rhythmic and low amplitude contractions regardless of hypothermia. Mucosal blood flow decreased markedly during hypothermia in WKY but was well sustained in SHR. In conclusion, the increase in gastric motility associated with cold restraint stress was suppressed in SHR by sympathetic facilitation in the muscle layer, and this may have contributed to the prevention of ulcer formation by maintaining mucosal blood flow in SHR.