Effect of DA‐9701, a novel prokinetic agent,on stress‐induced delayed gastric emptying and hormonal changes in rats

Background DA‐9701 is a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber. This study aimed to evaluate the effect of DA‐9701 on stress‐induced delay in gastric emptying and changes in plasma adrenocorticotropic hormone and ghrelin levels in rats. Methods Changes in gastric emptying in response to different durations of stress were evaluated. Gastric emptying was compared between the following groups: (i) nonstressed vehicle‐ or DA‐9701‐treated group, (ii) nonstressed vehicle‐ or mosapride‐treated group, (iii) 2‐h stressed vehicle‐ or DA‐9701‐treated group, and (iv) 2‐h stressed vehicle‐ or mosapride‐treated group. Water immersion restraint stress was used as the stressor. DA‐9701 or mosapride at 3 mg kg^?1 was administered to the rats after subjecting them to 2‐h stress, and then gastric emptying was measured using the phenol red method. Key Results Gastric emptying was significantly delayed in the 2‐h stressed group compared with the nonstressed group. Mosapride administration resulted in significant recovery from the stress‐induced delay in gastric emptying. Gastric emptying in the rats that underwent 2‐h stress followed by DA‐9701 administration was not significantly different from that in the nonstressed group. The plasma adrenocorticotropic hormone and active ghrelin levels in the 2‐h stressed group were significantly higher than those in the nonstressed group. These increases were significantly inhibited by DA‐9701. Conclusions & Inferences The administration of DA‐9701 improved delayed gastric emptying and inhibited the hormonal changes induced by stress, suggesting that DA‐9701 can be used as a gastroprokinetic agent for the treatment of delayed gastric emptying, particularly that associated with stress.     

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.     

Comparative evaluation of DQ-2511, a novel gastroprokinetic agent,with cisapride in ameliorative action on experimentally induced delayed gastric emptying

We compared the main pharmacological effect of DQ-2511 (3-[[[2-(3,4-dimethoxyphenyl)-ethyl]carbamoyl]methyl]amino -N- methylbenzamide), a novel gastroprokinetic agent, with that of cisapride. Single oral administration of DQ-2511 (3–10 mg kg^?1) caused similar significant improvements to delays in gastric emptying of semi-solid meals evoked by chole-cystokinin-octapeptide (CCK₈: 5 μ kg^?1, i.v.) in monkeys, to that with cisapride (3 mg kg^?1). A 2-week oral treatment of unilaterally vagotomized rats with DQ-2511 (1–10 mg kg^?1) lessened delays in gastric emptying, whereas cisapride (0.3–10 mg kg^?1) had no effect under the same experimental protocols. In anesthetized rats, bolus intravenous injection of either compound (60 μg kg^?1) enhanced gastric motility determined by means of strain gauge force transducers. Electrophysiological investigations revealed that bolus injection of DQ-2511 (6–60 μ kg^?1) depressed the afferent discharge rate of the ventral gastric branch of the vagus nerve, while cisapride showed no effect. These results suggest that the mechanism of ameliorative action of DQ-2511 on delayed gastric emptying may differ from that of cisapride.     

Intestinal electrical stimulation improves delayed gastric emptying and vomiting induced by duodenal distension in dogs.

The aim of this study was to investigate the effects of short-pulse intestinal electrical stimulation (IES) on duodenal distention-induced delayed gastric emptying and vomiting in dogs and its possible mechanisms. The study was performed in 12 dogs with jejunal electrodes and a duodenal cannula in three separate experiments to investigate the effects of IES on duodenal distension (DD)-induced delayed gastric emptying and discomfort signs, vagal efferent activity, and jejunal tone. We found that: (i) IES significantly accelerated gastric emptying of liquid delayed by distension (18.05 +/- 4.06%vs. 7.18 +/- 1.99%, P = 0.036 at 60 min). (ii) IES significantly reduced vomiting and discomfort/pain induced by distension. The average signs score was 15.33 +/- 1.37 during distension which decreased to 6.50 +/- 0.91 (P = 0.0002) with IES. (iii) IES did not change vagal afferent activity, which was assessed by the spectral analysis of the heart rate variability. (iv) IES decreased jejunal tone. In conclusion, IES with parameters commonly used in gastric electrical stimulation for nausea and vomiting associated with gastroparesis improves DD-induced delayed gastric emptying and prevents DD-induced vomiting and discomfort signs. Further studies are warranted to investigate the therapeutic potential of IES for gastrointestinal symptoms associated with disturbances in motility and sensory function in small intestine.     

Relationship between symptom pattern, assessed by the PAGI-SYM© questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

Abstract The patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI‐SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI‐SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI‐SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson’s linear correlation, multiple regression analysis, chi‐square and Student’s t‐tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = ?0.27), bloating (r = ?0.23), heartburn/regurgitation (r = ?0.21), and upper abdominal pain (r = ?0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut‐off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI‐SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.     

Characterization of gastric volume responses and liquid emptying in functional dyspepsia and health by MRI or barostat and simultaneous 13C-acetate breath test

Abstract The assessment of gastric accommodation and emptying by different methodologies provides inconsistent results. We aimed to compare magnetic resonance imaging (MRI), barostat and ¹³C‐acetate breath test (BT) for the assessment of gastric volume responses and emptying in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent: (i) continuous BT with simultaneous MRI in the upright position after ingestion of isocaloric, 300 kcal, 200 and 800 mL meals, both labelled with 100 mg of ¹³C‐acetate; and (ii) BT with gastric barostat after ingestion of the 200 mL meal. MRI measured total gastric volume and gastric content volume (GCV) at baseline, after filling and during emptying. Meal emptying half‐times (T½) for MRI and BT were calculated (mean ± SD). We found: (i) Initial GCV was lower in FD than in HC (762 ± 22 vs 810 ± 52 mL, P < 0.04) after the 800 mL meal but not the 200 mL meal. T½_MRI was shorter for the 800 mL than the 200 mL meal (P < 0.001), but similar in HC and FD (200 mL: HC 117 ± 30 min vs FD 138 ± 42 min, ns; 800 mL: HC 71 ± 16 min vs FD 78 ± 27 min, ns). In contrast, T½_BT was similar between meals and groups (200 mL: HC 111 ± 11 min vs FD 116 ± 19 min; 800 mL: HC 114 ± 14 min vs FD: 113 ± 17 min). (ii) Barostat measurements showed similar postprandial volume increases between groups. We conclude that direct measurements by MRI provide a sensitive, non‐invasive assessment of gastric accommodation and emptying after a meal. In contrast to MRI, BT did not detect faster emptying of high‐volume compared to low‐volume liquid nutrient meals in HC or FD.     

Central administration of pan‐somatostatin agonist ODT8‐SST prevents abdominal surgery‐induced inhibition of circulating ghrelin,food intake and gastric emptying in rats

Background Activation of brain somatostatin receptors (sst_1–5) with the stable pan‐sst_1–5 somatostatin agonist, ODT8‐SST blocks acute stress and central corticotropin‐releasing factor (CRF)‐mediated activation of endocrine and adrenal sympathetic responses. Brain CRF signaling is involved in delaying gastric emptying (GE) immediately post surgery. We investigated whether activation of brain sst signaling pathways modulates surgical stress‐induced inhibition of gastric emptying and food intake. Methods Fasted rats were injected intracisternally (i.c.) with somatostatin agonists and underwent laparotomy and 1‐min cecal palpation. Gastric emptying of a non‐nutrient solution and circulating acyl and desacyl ghrelin levels were assessed 50 min post surgery. Food intake was monitored for 24 h. Key Results The abdominal surgery‐induced inhibition of GE (65%), food intake (73% at 2 h) and plasma acyl ghrelin levels (67%) was completely prevented by ODT8‐SST (1 μg per rat, i.c.). The selective sst₅ agonist, BIM‐23052 prevented surgery‐induced delayed GE, whereas selective sst₁, sst₂, or sst₄ agonists had no effect. However, the selective sst₂ agonist, S‐346‐011 (1 μg per rat, i.c.) counteracted the abdominal surgery‐induced inhibition of acyl ghrelin and food intake but not the delayed GE. The ghrelin receptor antagonist, [D‐Lys³]‐GHRP‐6 (0.93 mg kg^?1, intraperitoneal, i.p.) blocked i.p. ghrelin‐induced increased GE, while not influencing i.c. ODT8‐SST‐induced prevention of delayed GE and reduced food intake after surgery. Conclusions & Inferences ODT8‐SST acts in the brain to prevent surgery‐induced delayed GE likely via activating sst₅. ODT8‐SST and the sst₂ agonist prevent the abdominal surgery‐induced decrease in food intake and plasma acyl ghrelin indicating dissociation between brain somatostatin signaling involved in preventing surgery‐induced suppression of GE and feeding response.     

The pattern of brain c-fos mRNA induced by a component of fox odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), in rats, suggests both systemic and processive stress characteristics

Predators to rodents and their associated odors are increasingly chosen to study the neural mechanisms of stress and anxiety. Specifically, predatory odors are believed to elicit responses based on the perceived threat (psychological or processive), rather than to any direct systemic effects (pain, blood loss, infection, etc.) of the stimulus, which are mediated by distinct neural pathways. The hypothesis that a chemical component from fox feces, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), elicits stress responses by specific activation of processive neural pathways was tested. Different amounts of TMT (range: 0-600 micromol) or the control odor butyric acid (0-1200 micromol) were presented to male Sprague-Dawley rats for 30 min. Immediately after odor presentation, rats were sacrificed, blood levels of adrenocorticotropic hormone (ACTH) and corticosterone were measured, and brains were rapidly harvested to measure regional brain c-fos mRNA induction by in situ hybridization. Presentation of TMT (> or =75 micromol), but not butyric acid (up to 1200 micromol), significantly increased ACTH and corticosterone release. TMT presentation, especially with amounts (> or =75 micromol) producing endocrine activation, induced c-fos mRNA in several brain areas, including the olfactory bulb, lateral septal nucleus, septohypothalamic nucleus, anteromedial and oval nuclei of the bed nucleus of the stria terminalis, the central nucleus of the amygdala, the anteroventral, anterodorsal, and medial preoptic nuclei, the anterior, dorsomedial, lateral, supramammillary, dorsal premammillary and paraventricular hypothalamic nuclei, the external lateral parabrachial nucleus, the locus coeruleus, and the nucleus of the solitary tract. Interestingly, these brain regions represent a mix of regional c-fos mRNA induction pattern not reported previously with any other single stressor. These results suggest that TMT elicits stress responses through a relatively unique and complex mix of brain regions associated with both processive and systemic neural pathways, unlike those seen in response to cat odors.     

Endocrine,cognitive and hippocampal/cortical 5HT 1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats

Post traumatic stress disorder (PTSD) is characterised by hyperarousal, anxiety and amnesic symptoms. Deficits in explicit memory recall have been causally related to volume reductions of the hippocampus and prefrontal cortex. While stress-related glucocorticoid secretion appears involved in this apparent atrophy, there is also evidence for low plasma cortisol in PTSD. Prior exposure to trauma is an important risk factor for PTSD, suggesting a role for sensitisation. Using Sprague-Dawley rats, we studied the effects of a time-dependent sensitisation (TDS) model of stress on spatial memory deficits, 1 week post-stress, using the Morris water maze. Basal and 7-day post-stress plasma corticosterone levels were also determined. Due to the putative role of serotonin in anxiety and stress, and in the treatment of PTSD, hippocampal 5HT(1A) and prefrontal cortex 5HT(2A) radioligand binding studies were performed. TDS stress evoked a marked deficit in spatial memory on day 7 post TDS stress, coupled with significantly depressed plasma corticosterone levels. Cognitive and endocrine changes at day 7 post stress were associated with a significant increase in receptor density (B(max)) and a significant decrease in receptor affinity (K(d)) for hippocampal 5HT(1A) receptors. The B(max) of prefrontal cortex 5HT(2A) receptors were unaffected, but K(d) was significantly increased. We conclude that TDS stress evokes cognitive and endocrine changes characteristic of PTSD. Moreover, TDS stress induces diverse adaptive 5HT receptor changes in critical brain areas involved in emotion and memory that may underlie the effect of stress on cognitive function.