Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats.

We evaluated the effects of cyclooxygenase-2 (COX-2) selective inhibitors, COX-1 selective inhibitor, or COX non-selective inhibitor on gastric emptying and intestinal transit of liquids, and evaluated the effect of a COX-2 selective inhibitor on gastric tonus (GT). Male Wistar rats were treated per os with saline (control), rofecoxib, celecoxib, ketorolac, rofecoxib + ketorolac, celecoxib + ketorolac, or indomethacin. After 1 h, rats were gavage-fed (1.5 mL) with the test meal (5% glucose solution with 0.05 g mL(-1) phenol red) and killed 10, 20 or 30 min later. Gastric, proximal, medial or distal small intestine dye recovery (GDR and IDR, respectively) were measured by spectrophotometry. The animals of the other group were treated with i.v. valdecoxib or saline, and GT was continuously observed for 120 min using a pletismomether system. Compared with the control group, treatment with COX-2 inhibitors, alone or with ketocolac, as well as with indomethacin increased GDR (P < 0.05) at 10-, 20- or 30-min postprandial intervals. Ketorolac alone did not change the GDR, but increased the proximal IDR (P < 0.05) at 10 min, and decreased medial IDR (P < 0.05) at 10 and 20 min. Valdecoxib increased (P < 0.01) GT 60, 80 and 100 min after administration. In conclusion, COX-2 inhibition delayed the gastric emptying of liquids and increased GT in rats.     

Hyperglycemia impairs antro-pyloric coordination and delays gastric emptying in conscious rats

Delayed gastric emptying has been shown in diabetes. Although it has been proposed that hyperglycemia, and not only autonomic neuropathy, contributes to the pathogenesis of delayed gastric emptying, the inhibitory mechanism of hyperglycemia on gastric emptying remains unclear. We studied the effects of hyperglycemia per se on gastric emptying and postprandial gastric motility in conscious rats. Liquid and solid gastric emptying were compared between saline-infused rats and D-glucose-infused rats. Two strain gauge transducers were implanted on the antrum and pylorus and the postprandial antro-pyloric coordination was compared between euglycemia and hyperglycemia. D-glucose infusion for 30 min increased blood glucose level from 5.4 +/- 0.5 to 13.0 +/- 1.3 mM and significantly delayed gastric emptying. Forty minutes after the feeding, contractions with low frequency (<3 cycles min(-1)) and high amplitude (>15 g) of the antrum were observed. This period reflects the emptying process of the gastric content and the coordination between the antrum and pylorus was frequently observed. D-glucose infusion significantly reduced feeding-induced antral contractions and abolished the number of episodes of antro-pyloric coordination. Sham feeding-induced gastric contractions were also significantly reduced by hyperglycemia. Postprandial antro-pyloric coordination was not observed in vagotomized rats, suggesting a mediation of vagus nerve. It is concluded that hyperglycemia impairs antral contractions and antro-pyloric coordination in rats. The inhibitory effect of hyperglycemia on gastric emptying is mediated, at least in part, via impaired vagal activity.     

Intracerebroventricular leptin inhibits gastric emptying of a solid nutrient meal in rats

The effects of leptin injected intracerebroventricularly (i.c.v.) or i.p. on food intake and gastric emptying of a solid nutrient meal were studied in fasted Long-Evan rats. Leptin (3 microg, i.c.v.) reduced the 5 h cumulative food intake by 39% and gastric transit by 50% while i.p. leptin (300 microg) resulted in a 35% decrease in food intake and no change in gastric transit after 5 h. Lower i.p. doses of leptin (30 or 3 microg) did not alter food intake. These results show that central, unlike peripheral, injection of leptin inhibits gastric transit of an ingested meal; such a central action of leptin may contribute to the greater potency of i.c.v. than i.p. leptin to suppress food intake.     

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long‐term l ‐dopa therapy. Neurohormonal aspects of the brain‐gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric‐derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD. © 2013 International Parkinson and Movement Disorder Society     

Influence of gastric acid on gastric emptying and gastric distension-induced pain response in rats - effects of famotidine and mosapride

Background Gastroduodenal acidification has been reported to aggravate upper abdominal discomfort and pain that are symptoms suffered by functional dyspepsia (FD) patients. Delayed gastric emptying and hypersensitivity to gastric distension (GD) contribute importantly to the pathophysiology of FD. Methods In the present study, we determined the influence of pentagastrin‐stimulated endogenous gastric acid on gastric emptying and GD‐induced pain responses using rat model systems. Moreover, we evaluated the effects of famotidine and mosapride on changes in gastric emptying and the GD‐induced pain response to gastric acid hypersecretion. Gastric emptying was measured by excretion of glass beads that had been intragastrically administered with a liquid nutrient, and gastric pain response was evaluated by observing whether a GD‐induced increase in mean blood pressure occurred. Key Results Pentagastrin (2 mg kg^?1, s.c.) which markedly and continuously stimulated gastric acid secretion, significantly delayed and enhanced respectively, gastric emptying and pain compared with saline‐injected groups. Oral famotidine (0.1–3 mg kg^?1) and mosapride (0.3–3 mg kg^?1) administration in a dose‐dependent manner accelerated the delay of gastric emptying. Furthermore, famotidine (0.3–3 mg kg^?1) significantly alleviated the aggravation of the GD‐induced pain response, but mosapride (10 mg kg^?1) did not. Conclusions & Inferences We established rat models to evaluate the effect of gastric acid hypersecretion on gastric emptying and the GD‐induced pain response. In these models, acid hypersecretion delayed gastric emptying and aggravated the pain response. Furthermore, we showed that famotidine ameliorated both delayed gastric emptying and gastric hypersensitivity, whereas mosapride only improved delayed gastric emptying.     

Assessment of symptoms during gastric emptying scintigraphy to correlate symptoms to delayed gastric emptying

Background Symptoms of gastroparesis based on patient recall correlate poorly with gastric emptying. The aim of this study is to determine if symptoms recorded during gastric emptying scintigraphy (GES) correlate with gastric emptying and with symptoms based on patient recall. Methods Patients undergoing GES completed the Patient Assessment of GI Symptoms (PAGI‐SYM) assessing symptoms over the prior 2 weeks and a questionnaire for which patients graded six symptoms during GES. A Symptom Severity Index (SSI) represented the mean of six symptoms at each time point. Key Results A total of 560 patients underwent GES for clinical evaluation of symptoms. Of 388 patients included in the study: 232 patients had normal GES (NGES), 156 delayed GES (DGES), and 11 rapid GES (RGES). Symptom severity index increased pre to postprandial for each group: NGES: 0.51 ± 0.07 to 0.92 ± 0.03, DGES: 0.60 ± 0.09 to 1.13 ± 0.05, and RGES: 0.56 ± 0.12 to 0.79 ± 0.13. Delayed gastric emptying scintigraphy patients had a higher postprandial SSI than NGES patients (1.13 ± 0.05 vs 0.92 ± 0.03, P < 0.05). Postprandial symptoms of stomach fullness (1.9 ± 0.12 vs 1.5 ± 0.09; P = 0.011), bloating (1.4 ± 0.11 vs 1.1 ± 0.09; P = 0.033), and abdominal pain (1.1 ± 0.08 vs 0.7 ± 0.12; P = 0.012) were higher in DGES than NGES. Symptom severity based on PAGI‐SYM for 2 weeks prior to GES correlated with symptoms during the test for nausea (NGES, r = 0.61; DGES, r = 0.70), stomach fullness (NGES, r = 0.47; DGES, r = 0.60), and bloating (NGES, r = 0.62, DGES, r = 0.66). Conclusions & Inferences Stomach fullness, bloating, and abdominal pain recorded during GES were higher in patients with delayed gastric emptying than in patients with normal gastric emptying. Symptoms recorded during GES correlated with those during daily life by patient recall.     

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Background Levodopa (l ‐dopa) is the most commonly used treatment for alleviating symptoms of Parkinson’s disease. However, l ‐dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents l ‐dopa action on gastric emptying and enhances circulating l ‐dopa in rats. Methods Gastric emptying of non‐nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) l ‐dopa, or intravenous (i.v.) ghrelin 10 min before orogastric l ‐dopa. Plasma l ‐dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 μg kg^?1) 10 min before i.p. l ‐dopa. Key Results Levodopa (5 and 15 mg kg^?1) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 μg kg^?1, i.v.) completely prevented l ‐dopa’s (15 mg kg^?1, orogastrically) inhibitory action on gastric emptying and enhanced plasma l ‐dopa and dopamine levels compared with vehicle 15 min after orogastric l ‐dopa. Levodopa (5 mg kg^?1) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg^?1, i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. Conclusions & Inferences Ghrelin counteracts l ‐dopa‐induced delayed gastric emptying but not Fos induction in the brain and enhances circulating l ‐dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson’s disease patients treated with l ‐dopa remain to be investigated.     

Comparisons of the effects of enterostatin on food intake and gastric emptying in rats

The effects of central and peripheral administration of enterostatin (ENT) on food intake and gastric emptying of a non-nutrient liquid meal have been studied in rats. Intraperitoneal and intragastric administration of ENT at a dose of 120 nmol suppressed the intake of a high-fat diet but failed to inhibit gastric emptying in Sprague-Dawley (SD) rats. Intracerebroventricular (i.c.v.) ENT (1 nmol) reduced intake of a high-fat diet in Osborne-Mendel (OM) and SD rats but not in S5B/Pl rats, whereas it decreased gastric emptying in S5B/Pl and SD rats but not in OM rats. The data suggest that although central ENT may reduce gastric emptying rate, this effect is not related to the inhibitory effect of ENT on food intake.     

The control of gastric emptying

The control of gastric emptying has been restudied. Methods used are described. It was found that in the alert unanesthetized monkey saline is emptied from the stomach at a rate that is volume-dependent; an exponential curve results since higher volumes provoke more rapid emptying and lower volumes slower emptying. For glucose test meals emptying is quite linear; also emptying is slower and progressively slower with progressive increases in glucose concentration. There is, however, an early rapid phase of gastric emptying that converts to a slower, more linear pattern. Calories rather than osmoles appear to control emptying. Glucose in the pyloris has an inhibitory effect in gastric emptying. A theory of control is discussed. The control of gastric emptying also relates to the control of feeding.     

Predictors of gastric emptying in Parkinson''s disease

Predictors of gastric emptying (GE) in patients with idiopathic Parkinson's disease (PD) of a solid and liquid meal are not well defined. For measurement of GE 80 patients with PD were randomly assigned to receive either a solid meal (250 kcal) containing 13C-octanoate (n = 40) or a liquid meal (315 kcal) with 13C-acetate (n = 40). All patient groups were off medication affecting motility and were matched for age, gender, body mass index, disease duration and severity, using Unified Parkinson's Disease Rating Scale (UPDRS). Gastric emptying was compared with a healthy control group (n = 40). Multiple regression analysis was used to determine predictors of gastric emptying. Exactly 88% and 38% of PD patients had delayed GE of solids and liquids respectively. Solid and liquid emptying was similar in women and men. There were no differences in GE in PD patients < 65 years of age when compared with patients > or = 65 years. Multiple regression analysis showed that motor handicaps such as rigour and action tremor are independent predictors of solid GE (r = 0.68, P < 0.001). The severity of motor impairment, but not any other neurological symptom, as assessed by UPDRS is associated with gastroparesis in PD and solid emptying is more likely to be delayed.     

Advances in the physiology of gastric emptying

There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits. The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP‐1 inhibit gastric emptying via the GIVMC, and in the inter‐digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.     

Time-course of recovery of gastric emptying and motility in rats with experimental spinal cord injury

Abstract  We have shown recently that spinal cord injury (SCI) decreases basal gastric contractions 3 days after injury. In the present study we used the [¹³C]-octanoic acid breath test and gastric strain gauges with the aim to investigate the time-course of recovery from postinjury gastric stasis in rats that underwent experimental SCI at the level of the third thoracic (T3) vertebra. Following verification of the [¹³C]-breath test sensitivity in uninjured rats, we conducted our experiments in rats that underwent T3- spinal contusion injury (T3-CI), T3-spinal transection (T3-TX) or laminectomy (control) surgery at 3 days, 1, 3 or 6 weeks postinjury. Our data show that compared to rats that underwent laminectomy, rats that received SCI showed a significant reduction in the cumulative per cent [¹³C] recovery. Although more marked in T3-TX rats, the delayed gastric emptying in T3-CI and T3-TX rats was comparable in the 3 days to 3 weeks period postinjury. At 6 weeks postinjury, the gastric emptying in T3-CI rats recovered to baseline values. Conversely animals in the T3-TX group still show a significantly reduced gastric emptying. Interestingly, the almost complete functional recovery observed in T3-CI rats using the [¹³C]-breath test was not reflected by analysis of spontaneous gastric contractions after SCI. These data indicate that T3-SCI produces a significant reduction in gastric emptying independent of injury severity (T3-CI vs T3-TX) that persists for at least 3 weeks after injury. However, 6 weeks postinjury T3-CI, but not T3-TX, rats begin to demonstrate functional recovery of gastric emptying.     

Validation of a stable isotope gastric emptying test for normal, accelerated or delayed gastric emptying

To validate a 13C-Spirulina platensis breath test for measurement of accelerated or delayed gastric emptying, we measured gastric emptying of egg containing 13C-S. platensis and 99mTc-sulphur colloid by breath 13 CO2 every 15 min over 3 h and scintigraphy every 15-30 min over 5 h in 57 healthy volunteers. Thirty-three received no treatment, 10 received erythromycin, and 14 atropine. A generalized linear regression model predicted half-emptying time by scintigraphy (t1/2S) from breath 13CO2 (t1/2B) data. Accuracy was assessed by standard deviation (SD) of differences between t1/2S and t1/2B and by receiver operating characteristic (ROC) curves. Regression models using breath samples at baseline, and 45, 90, 105 and 120 min, predicted t1/2B (mean +/- SD) at 118 +/- 59 min, similar to t1/2S (118 +/- 67 min). Correlation between t1/2B and t1/2S was significant (r=0.88; P < 0.0001). Differences between t1/2S and t1/2B were: 18-19.2 min for t1/2 < 70-150 min, and 68.3 min for t1/2 > 150 min. Breath test detected abnormal emptying with a sensitivity of 86% and specificity of 80%. Thus, the 13C-S. platensis test measures gastric emptying t1/2 for solids, which is accelerated or delayed to mimic a range of conditions from dumping syndrome to severe gastroparesis, with high sensitivity and specificity. Additional breath samples are needed to increase sensitivity in detecting accelerated gastric emptying.     

High-viscosity liquid meal accelerates gastric emptying

Adding pectin to an elemental formula increases its viscosity through gelatinization, thus presumably preventing gastro-oesophageal reflux and aspiration pneumonia. We investigated the influence of the viscosity of an elemental formula on gastric emptying. Eleven healthy volunteers underwent three tests at intervals of >1 week. After fasting for >8 h, each subject received a test meal (enteral nutrition solution, enteral solution plus pectin, or water). Then gastric emptying (continuous (13)C breath test), gastro-oesophageal intraluminal pressures, oesophageal pH, and blood levels of glucose, insulin and gastrin were all measured simultaneously. The gastric emptying coefficient was significantly increased by adding pectin to enteral nutrition (3.01 +/- 0.10 vs 2.78 +/- 0.10, mean +/- SE, P < 0.05). The antral motility index was also significantly higher with pectin than without at 45-60 min and 60-75 min after the test meal (526 +/- 237 vs 6.5 +/- 4.6 mmHg s(-1) and 448 +/- 173 vs 2.3 +/- 2.3 mmHg s(-1) respectively; P < 0.05). Plasma glucose was significantly higher with pectin than without it at 60 min after ingestion (141.5 +/- 6.03 vs 125.8 +/- 4.69 microM mL(-1), P < 0.05). In healthy individuals, pectin increased the viscosity of enteral nutrition and accelerated gastric emptying.     

Effect of meal volume on gastric emptying

Abstract While the volume of a liquid meal has been identified as the principal accelerator of gastric emptying of liquids, the relationship between meal volume and gastric emptying of solids has been controversial. With solid foods, the need to reduce solid foods into small particles (trituration) before passage might obscure the effect of meal volume on solid propulsion. To distinguish trituration from driving force as the rate-limiting factor for emptying, 75 (1.6 mm) nylon spheres were fed along with different amounts of steak meals (150, 300 and 600 g), or alternatively, 50, 100 or 200 (1.6 mm) nylon spheres were fed to six dogs with 300 g steak meals. To examine the effect of meal volume on gastric emptying, we studied the effect of different meal volumes on the speed of gastric emptying of liquids (150, 300, 600 and 1200 ml of phosphate buffer) and solids (150, 300 and 600 g of cooked beef steak) in five dogs with duodenal fistulas. Intestinal inhibition was eliminated by diverting all chyme through the fistulas. In the absence of intestinal feedback, we found that gastric emptying of steak and spheres were different in that steak emptying was independent of meal volume (g min^-1 was constant across 150–600 g) while sphere emptying was affected by the number of spheres in the stomach and that liquid emptying was dependent on the meal volume (ml min^-1 increased across 150–1200 ml). Thus, meal volume accelerated gastric emptying provided the process is not rate-limited by trituration.     

The neural pathway underlying social buffering of conditioned fear responses in male rats

In social animals, the presence of an affiliative conspecific alleviates acute stress responses, and this is termed social buffering. However, the neural mechanisms underlying social buffering have not been elucidated. We have reported that the main olfactory system mediates social buffering of conditioned fear responses in male rats, and this is accompanied by suppression of the lateral and central amygdala. Therefore, olfactory signals are probably transmitted from the main olfactory system to the amygdala. Because the lateral and central amygdala do not receive projections from the main olfactory bulb, the site that links the main olfactory bulb and amygdala was presumed to be located within the main olfactory system. To find the linkage site, we generated lesions within the main olfactory system, and found that a bilateral lesion in the posteromedial region of the olfactory peduncle (pmOP) blocked social buffering. Next, we determined that the pmOP receives direct projections from the main olfactory bulb. Finally, we demonstrated that the connection between the pmOP and ipsilateral amygdala is important for social buffering, and that the pmOP projects directly to the ipsilateral amygdala, including the lateral and central amygdala. On the basis of these results, we suggest that the pmOP links the main olfactory blub to the amygdala and enables social buffering of conditioned fear responses. These results provide the first comprehensive picture of the neural pathway underlying the social buffering phenomenon.