An experimental model for the study of transient lower oesophageal sphincter relaxation and motor function of the proximal stomach in humans

A simple and reliable experimental model would be useful in human research on new drugs which target transient lower oesophageal sphincter (LOS) relaxation. The aim was to investigate the effect of repeated distensions on the rate of transient LOS relaxation, LOS pressure and motor function of the proximal stomach. Twelve healthy subjects were studied with a multilumen manometric assembly incorporating a sleeve sensor for the LOS and a bag positioned in the proximal stomach and connected to a barostat. Intrabag volume was set at 75% of the threshold for gastric discomfort and maintained for two 30-min distension periods separated by a 45-min washout with the bag deflated. The studies lasted 145 +/- 2 min. The rate of transient LOS relaxations was similar during the two distensions, 3.5;2-4 vs 3;2.5-4 (median;interquartile range) and so was LOS pressure. Baseline intrabag pressure, as a measure of gastric tone, and the number of pressure waves, as a measure of phasic contractions, were also similar, 11.3;9.3-12.3 mmHg vs 10.8;9.3-12.5 mmHg and 16;13-28 mmHg vs 19;15-29 mmHg, respectively. Our model allows to perform 1-day studies which can assess two experimental conditions on transient LOS relaxations and motor function of the proximal stomach within an acceptable time span.     

A model for evaluation of gastric sensitivity in awake rats

We developed a model for the evaluation of gastric sensitivity to distension in awake rats. A balloon made from a latex condom was chronically placed in the stomach and three stainless steel electrodes were implanted in the neck muscles. Isobaric distensions were performed with a barostat by step of 5 mmHg with 10 min inflation and 2 min deflation. Gastric pressure, integrated neck electromyogram (EMG) and gastric volume were continuously monitored on a potentiometric recorder. Gastric distension at 15 or 20 mmHg induced a typical posture associated with contractions of the neck muscles. Pain threshold was defined as the pressure inducing an increase of integrated neck EMG greater than 100%.
The mean pain threshold was 18.5 ± 0.7 mmHg and was not modified 2, 4 and 7 days after the first experiment. However, gastric volumes were significantly higher on the 4th and the 7th days. Morphine at the doses of 0.4 and 4 mg kg⁻¹ i.p. significantly increases the pain threshold. At the doses of 0.04 and 0.4 mg kg⁻¹, morphine significantly increased gastric volume for the distending pressure of 10 mmHg. Naloxone (2.5 mg kg⁻¹ i.p.) reversed the effects of morphine. In conclusion, our model permits simultaneous evaluation of pain threshold and gastric compliance associated with gastric distension in conscious rats.     

Influence of ghrelin on the gastric accommodation reflex and on meal-induced satiety in man

Abstract  Ghrelin increases gastric tone in the fasting state and enhances gastric emptying in gastroparesis. The aims of the study were to evaluate the effect of ghrelin on postprandial gastric tone and on meal-induced satiety in health. Ten healthy volunteers underwent a barostat study on two occasions. After determination of intra-abdominal pressure (minimal distending pressure, MDP), isobaric volume measurement was performed for 90 min at MDP + 2 mmHg. After 20 min, ghrelin (40 μg) or saline was administered i.v. over 30 min in a double-blind-randomized cross-over design, followed 10 min later by a liquid meal (200 mL, 300 kcal). Stepwise isobaric distentions (+2 mmHg per 2 min) were performed 60 min after the meal. Data (mean ± SEM) were compared using paired Student's t -test and anova . Separately, a satiety drinking test (15 mL min⁻¹ until satiety score 5) was performed on 10 subjects twice, after treatment with placebo or ghrelin. Ghrelin infusion significantly inhibited gastric accommodation (mean volume increase adjusted means 108.0 ± 50 vs 23.0 ± 49 mL, P  = 0.03, ancova with the premeal postinfusion volume as covariate) and reduced postprandial gastric volumes (197.2 ± 24.6 vs 353.5 ± 50.0 mL, P  = 0.01). Pressures inducing perception or discomfort during postprandial gastric distentions were not altered. During satiety testing, ghrelin did not alter nutrient volume ingested till maximal satiety (637.5 ± 70.9 vs 637.5 ± 56.2 mL, ns). Ghrelin administered during the meal significantly inhibits gastric accommodation in health, but this is not associated with early satiation.     

Different regional brain activity during physiological gastric distension compared to balloon distension: a H215O‐PET study

Background Stepwise gastric balloon distension progressively activates a ‘visceral pain neuromatrix’, ultimately inducing discomfort and pain. On the other hand, normal meal ingestion requires gastric volume expansion without induction of pain. The aim was to test the hypothesis that physiological gastric distension (liquid meal infusion) until maximal satiation elicits brain responses similar to balloon distension at discomfort threshold. Methods Brain H₂¹⁵O‐positron emission tomography (PET) was performed in two different groups of healthy volunteers (both n = 14) during continuous and stepwise infusion of a liquid meal through a nasogastric tube, until maximal satiation. Brain (de)activation patterns were compared with historical controls in which discomfort was elicited using gastric balloon distension. This latter reference group was acquired on the same scanner using the same acquisition protocol; all data were analyzed using statistical parametric mapping (SPM2). Within each group, brain activity at maximal distension was compared to baseline activity and between‐group comparisons were made. Key Results Intragastric volumes and satiation/gastric sensation scores at endpoint were similar in all groups. Continuous and stepwise nutrient infusion was associated with progressive deactivations in key areas of the ‘visceral pain neuromatrix’ that were activated during balloon distension. Additionally, stepwise infusion progressively activated prefrontal areas and showed deactivations in ‘default network’ brain regions also found to be deactivated during balloon distension. Conclusions & Inferences Compared to gastric balloon distension, physiological gastric distension using nutrient infusion elicits opposite brain responses in the ‘visceral pain neuromatrix’, but similar responses in other areas. We interpret this finding as a prerequisite for tolerance of normal meal volumes in health.     

Influence of continuous isobaric rectal distension on gastric emptying and small bowel transit in young healthy women

Patients with slow transit constipation frequently have delayed gastric emptying. In animals rectal distensions inhibit gastrointestinal motility. In healthy volunteers isovolumetric rectal distensions delay upper gut transit. The purpose of this study was to determine the effect of continuous isobaric rectal distension on gastric emptying and oro-cecal transit in young females. Using validated 13C octanoic and lactose-[13C] ureide breath tests gastric half-emptying time and oro-cecal transit time for a meal were measured in 12 volunteers. The tests were repeated in randomized order: during isobaric balloon distension and during sham distension. Isobaric rectal distension was applied using a polyethylene bag connected to a barostat. Intraballoon pressure was kept just below the threshold for the urge sensation. Mean gastric half-emptying time during rectal distension (92.3 +/-5.1 min) was significantly higher than during sham distension (78.8 +/- 4 min; P = 0.015). Mean oro-cecal transit time during rectal distension (391.3 +/-29.1 min) and sham distension (328.8 +/- 38.4 min) were not significantly different. In conclusion, these findings indicate that isobaric rectal distension inhibits gastric emptying, but not small bowel transit in young healthy women. Studies in patients with constipation are indicated.     

Elicitation of transient lower oesophageal sphincter relaxations in response to gastric distension and meal ingestion

The aim of this study was to compare the effect of graded gastric barostat distension and meal-induced fundic relaxation on the elicitation of transient lower oesophageal sphincter relaxation (TLOSR). In 15 healthy subjects, stepwise fundic distension and oesophageal manometry were performed simultaneously. Next, the effect of meal ingestion on proximal stomach volume and lower oesophageal sphincter function was studied. During stepwise barostat distension of the proximal stomach, a significant linear correlation between intragastric pressure (r = 0.91; P < 0.01) and the TLOSR rate during inflation and subsequent deflation (r = 0.96; P < 0.01) was found. A similar relationship was found for volume. In addition, after meal ingestion, the TLOSR rate increased significantly from 1.40 +/- 3 to 5.4 +/- 1.5 h-1 (P < 0.01) and 5.2 +/- 1.7 h-1 (P < 0.01), respectively, during the first and second 30-min postprandially. However, at similar calculated intragastric volumes, barostat distension led to a significantly higher TLOSR rate than the meal. Similarly, distension-induced increase in gastric wall tension, estimated from the measured bag pressure and volume using Laplace's law, was associated with significantly higher TLOSR rates (P < 0.01). In conclusion, the rate of TLOSRs in healthy volunteers is directly related to the degree of proximal gastric distension and pressure-controlled barostat distension is a more potent trigger of TLOSRs than a meal. The latter finding suggests that tension receptor activation is an important stimulus for TLOSRs.     

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.     

Cardiovascular effects and c-Fos expression in the rat hindbrain in response to innocuous stomach distension

The present work was planned to study the effects of non-noxious gastric distension on hemodynamic variables and on cardiovascular hindbrain areas detected by means of c-Fos immunoreactivity, to determine the afferent and central mechanisms involved. In anesthetized rats, innocuous stomach distension increased arterial blood pressure and heart rate and induced c-Fos immunoreactivity within nucleus tractus solitarii, nucleus ambiguus, ventrolateral medulla and lateral reticular nucleus. Bilateral vagotomy abolished the pressor response and c-Fos immunoreactivity in nucleus ambiguus and ventrolateral medulla. Also, c-Fos immunoreactivity was significantly decreased in nucleus tractus solitarii and lateral reticular nucleus. After bilateral splanchnicotomy the pressor and tachycardic responses caused by gastric distension were reduced. c-Fos immunoreactivity in nucleus tractus solitarii, lateral reticular nucleus and nucleus ambiguus was reduced in comparison to the intact rats. In ventrolateral medulla a preferential localization of c-Fos immunoreactivity was found within its caudal portion. It was shown that such gastric distension, known to activate low threshold mechanoreceptors, induced cardiovascular effects via both vagal and splanchnic afferents and involving their central convergence and interaction in modulating the baroreceptor buffer system.     

Oesophageal heat transfer properties indication of segmental blood flow changes during distension

Abstract  The pain perception to distension of the oesophagus can be explained by activation of receptors responding to mechanical deformation or to distension-induced ischaemia. The aim of this study was to develop a new method for detection of changes in segmental blood flow during distension based on measurement of heat transfer. A bag was distended in the distal oesophagus of six healthy subjects followed by cooling or heating of the bag fluid to 5 or 60 °C. After equilibrium, the temperature was allowed to change back to body temperature. The temperature was recorded together with intraluminal ultrasound imaging, allowing assessment of the heat transfer properties at different bag volumes. The heat transfer constants were higher after heating the bag than after cooling the bag (Tukey, P  < 0.05). The heat transfer constants after heating the bag decreased as function of bag volumes whereas the heat transfer during cooling was not affected by the bag volume ( F  = 0.9, P  = 0.4). The findings indicate that segmental blood flow can be assessed indirectly by calculating the heat transfer properties. Distension induced a drop in regional blood flow. Hence, ischaemia may contribute to distension-induced pain. Furthermore, heat increased segmental blood flow and cold decreased segmental blood flow. This method may in the future be used to explore the mechanisms behind oesophageal pain.     

Sensation evoked by esophageal distension in functional chest pain patients depends on mechanical stress rather than on ischemia

Background Functional chest pain is commonly reproduced by bag distension in the esophageal body. It is unknown whether such pain is primarily associated with mechanical stress and strain (force‐deformation) or with changes in mucosal perfusion. Methods Fourteen patients (6M, 8F, average age 55.9 years) underwent ramp bag distension before and after injection of 20 mg butylscopolamine bromide (BS) using a novel bag catheter incorporating endosonography and laser Doppler perfusion monitoring. Healthy subjects served as controls. Mucosal perfusion was evaluated and stress and strain were computed and related to the sensation. Key Results The symptom score increased with bag volume (P < 0.001). Volume as a function of pressure was higher in patients than in controls (P < 0.001), both before and during BS. The stress–strain relationship was exponential and indicated a stiffer esophageal wall in patients especially before BS (P < 0.01). The stress–strain curves indicate increased muscle tone in the functional chest pain patients. The perfusion decreased with increasing symptom score from visual analog scale 1–7 during BS. The decrease was on average 18.9% in patients and 19.7% in controls (P = ns). Multiple regression analysis from distensions during BS showed that the discomfort/pain sensations depended on stress and strain (P < 0.001) and with stress as the largest contributor. Perfusion did not contribute. Conclusions & Inferences Pain evoked by bag distension in patients with functional chest pain is stress‐dependent rather than dependent on mucosal perfusion. Furthermore, the esophagus of the patients was characterized by more pronounced muscle tone during the distensions.     

Influence of naloxone on rectal sensorimotor function in health

Abstract  Abnormal rectal motor physiology and visceral hypersensitivity are implicated in the pathogenesis of irritable bowel syndrome. Endogenous opioids are involved in both the regulation of gut motility and the processing of sensory information. Our aim was to study the effect of suppression of endogenous opioid function by naloxone on rectal sensorimotor function in health. Eighteen healthy subjects participated in a rectal barostat study. Sensorimotor function was evaluated during two consecutive stepwise distensions separated by 30 min of basal tone recording, and with perception scoring on a 0–6 graded scale. Naloxone was administered, after 15 min of basal tone measurements, as an intravenous bolus (0.4 mg), followed by continuous infusion (20 μg kg⁻¹ h⁻¹) in a placebo-controlled, single-blinded and randomized fashion. Naloxone did not alter rectal sensitivity. Comparison of visual analogue scale scores between naloxone and saline did not reveal altered intensities of pain or discomfort. Compared to the baseline distension, a significant adaptive increase in compliance occurred during the second distension after saline (7.8 ± 0.7 vs 11.0 ± 0.6 mL mmHg⁻¹, P  = 0.0016). This dynamic change in rectal compliance did not occur after naloxone administration (8.8 ± 0.7 vs 10.1 ± 0.8 mL mmHg⁻¹, ns). Low intensity tonic distension induced a rectal adaptive relaxation, which was absent after naloxone. Naloxone does not alter rectal sensitivity but abolishes rectal adaptation in response to repeated balloon distention. These observations suggest that the endogenous opioid system is involved in control of rectal tone rather than rectal sensitivity.     

Lower postprandial gastric volume response in diabetic patients with vagal neuropathy

Poor relaxation in the stomach after a meal may contribute to disturbed gastric emptying and abdominal discomfort in patients with diabetes mellitus. In this study we aimed to compare barostat-recorded postprandial volume responses in these patients to those in healthy controls, and to study the relationship between the proximal volume responses, antral filling and vagal neuropathy.
We compared 14 consecutively recruited patients with type 1 diabetes mellitus (DM) to 18 healthy controls (HC) with respect to meal-induced gastric volume response assessed by a barostat, antral area recorded by ultrasound, and vagal tone assessed by respiratory sinus arrhythmia (RSA).
Meal-induced volume repsponse of the proximal stomach (area under time–volume curve 0–30 min) was significantly (P = 0.04) lower in DM than in HC, 49.4 min.mL ± 60.7 vs. 114.9 min.mL ± 100.8. Antral area was significantly larger in DM than in HC, both fasting (4.3 cm² ± 1.9 vs. 3.0 cm² ± 0.9) and 10 min after ingestion of meat soup (11.8 cm² ± 3.4 vs. 8.8 cm² ± 2.9), P = 0.03 and P = 0.02, respectively. Vagal tone was significantly (P = 0.01) lower in DM than in HC, 3.7 beats min⁻¹ ± 2.3 vs. 6.1 beats min⁻¹ ± 2.2. No significant correlation was observed between the proximal volume responses and antral widening. Maximal gastric volume response correlated significantly with vagal tone (r = 0.77, P = 0.002). Conclusions: patients with diabetes mellitus type 1 have impaired meal-induced volume response, possibly as a consequence of reduced vagal tone.     

The effects of midazolam and ephedrine on post-exercise autonomic chronotropic control of the heart in normal subjects

Benzodiazepines may induce hypotension by inhibiting the pressor response. Ephedrine has adrenergic effects on the circulation. After exercise, changes in cardiovascular control impair orthostatic tolerance. The impaired pressure response can be compensated for by chronotropic control of the heart. We studied the effect of midazolam and ephedrine on post-exercise cardiac autonomic chronotropic control in six 21-year-old female volunteers, who received single doses of 15 mg midazolam, 50 mg ephedrine, or placebo orally according to a placebo-controlled, double-blind, crossover design. After exercise, the subjects assumed the supine position for rest, then a?10° head-down position followed by a 70° head-up position. Power spectral analysis of heart rate variability for 7 min and steady-state brachial arterial blood pressure were measured in each position. After administration of midazolam, three subjects had an abnormal fall in their arterial blood pressure (with one presyncope) as a response to head-up tilt. Changes in heart rate variability exceeded those seen during placebo treatment (p<0.01) and involved oscillations, suggesting activation of both sympathetic and parasympathetic dynamics. After ephedrine administration, arterial blood pressure increased during head-down tilt, but parasympathetic dynamics to the heart were dampened. Head-up tilt induced increased sympathetic stimulation of the heart and a sympathicotonic cardiovascular response (p<0.01). In conclusion, midazolam induced unexpectedly great changes in dynamic cardiac control during cardiovascular stimulation. Ephedrine increased tonic sympathetic activity and stabilized the neural circulatory control of the heart by immobilizing dynamic parasympathetic activation.     

Influence of abuse history on gastric sensorimotor function in functional dyspepsia

Abstract  Patients with functional gastrointestinal disorders have elevated rates of sexual or physical abuse, which may be associated with altered rectal sensorimotor function in irritable bowel syndrome. The aim was to study the association between abuse history and gastric sensorimotor function in functional dyspepsia (FD). We studied gastric sensorimotor function with barostat (sensitivity, compliance and accommodation) and gastric emptying test in 233 consecutive FD patients from a tertiary care centre (162 women, mean age 41.6 ± 0.9). Patients filled out self-report questionnaires on history of sexual and physical abuse during childhood or adulthood. Eighty-four patients (out of 198, 42.4%) reported an overall history of abuse [sexual and physical in respectively 30.0% (60/200) and 20.3% (42/207)]. FD patients reporting general as well as severe childhood sexual abuse have significantly lower discomfort thresholds during gastric distension [respectively 10.5 ± 0.4 vs 7.5 ± 1.0 mmHg above minimal distending pressure (MDP), P  = 0.014 and 10.5 ± 0.4 vs 6.6 ± 1.2 mmHg above MDP, P  = 0.007]. The corresponding intra-balloon volume was also significantly lower (respectively 579 ± 21 vs 422 ± 59 mL, P  = 0.013 and 579 ± 19 vs 423 ± 79 mL, P  = 0.033). Gastric accommodation was significantly more pronounced in patients reporting rape during adulthood (91 ± 12 vs 130 ± 40 mL, P  = 0.016). Abuse history was not associated with differences in gastric emptying. A history of abuse is associated with alterations in gastric sensorimotor function in FD. Particularly sexual abuse, rather than physical abuse, may influence gastric sensitivity and motor function.     

Gastric secretion but not nitric oxide is involved in pentagastrin-induced gastric relaxation in conscious dogs

Gastrin delays gastric emptying of liquids probably by reducing gastric tone. The mechanism responsible for the relaxatory effect induced by pentagastrin was unknown. The aim of this study was to investigate the effects of pentagastrin and the underlying mechanisms responsible for these effects. Could nitric oxide (NO) be involved as a mediator? Gastric tone was monitored with a flaccid bag introduced into the stomach via a gastric cannula and connected to a barostat. A series of pressure–volume curves with a 30-min interval were constructed by increasing intragastric pressure to a maximum of 14 mmHg (2-mmHg steps). Pentagastrin (4 μg kg^?1 s.c.) facilitated the volume increases induced by isobaric gastric distension. This effect could be completely blocked by pretreatment with cimetidine (10 mg kg^?1 s.c.) or by omeprazole (10 mg kg^?1 p.o.). The effect induced by pentagastrin could be mimicked by histamine (0.16 mg kg^?1 s.c.) and to a lesser extent by insulin (0.2 IU kg^?1 i.v.). Cimetidine and omeprazole had no intrinsic effect on gastric tone. With an opened cannula, allowing the gastric secretions to leave the stomach, no increased gastric relaxation could be observed either in the presence of pentagastrin or in the presence of histamine or insulin. Nitro-l-arginine (L-NNA, 5 mg kg^?1 i.v.) reduced the volume increases induced by distension. Unexpectedly, even in the presence of L-NNA, pentagastrin remained effective. In conclusion, pentagastrin induces a gastric relaxation via a mechanism which involves gastric secretion but not nitric oxide.     

Facilitation of gastric compliance and cardiovascular reaction by repeated isobaric distension of the rat stomach

Gastric distension causes cardiovascular reactions and enhances gastric compliance. Here, we investigated how these responses are related to each other, whether they change upon repeated distension and which neural mechanisms are involved. Mean arterial blood pressure (MAP) in phenobarbital-anaesthetized rats was recorded from a carotid artery and gastric compliance determined with an electronic barostat. Runs of intermittent gastric distension were generated by stepwise increments (5 mmHg) of intragastric (IG) pressure. While gastric compliance peaked at IG pressures of 20 mmHg, the change in MAP (predominantly hypotension) was largest at IG pressures beyond 30 mmHg. Repeated distension enhanced the MAP response to IG pressures beyond 35 mmHg, whereas gastric compliance was facilitated primarily at IG pressures below 20 mmHg. This facilitation of gastric compliance depended on the magnitude of the preceding distension. The MAP response to distension was enhanced by nitric oxide synthase inhibition, inhibited by subdiaphragmatic vagotomy but hardly affected by coeliac ganglionectomy. The facilitation of gastric compliance was changed by vagotomy in a complex manner but left unaltered by the other interventions. These findings show that isobaric gastric distension elicits both MAP and gastric compliance responses whose characteristics, mechanisms and sensitization properties differ profoundly.     

Pressor effect of water instilled via a gastrostomy tube in pure autonomic failure

BACKGROUND: The oral ingestion of water increases seated blood pressure in chronic autonomic failure although the mechanisms of this effect remain unclear. Recent studies in normal subjects suggest that oropharyngeal stimulation during swallowing may be of greater importance in causing a rise in blood pressure (BP) than the gastric effects of water. We therefore assessed the haemodynamic effects of water instilled directly into the stomach via a gastrostomy tube in pure autonomic failure (PAF). METHODS: The subject had longstanding (>20 years) PAF. A gastrostomy tube had been previously placed because of dysphagia. Distilled water (480 ml) was instilled in the seated position with BP and heart rate (HR) measured over the following 40 min while the subject remained seated. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were recorded intermittently every 3 min with a Dinamap automated syphgmomanometer and continuously using a Portapres device. Subsequent model flow analysis of the Portapres data provided beat-to-beat estimates of cardiac output, stroke volume, and total peripheral resistance (TPR). Subjective orthostatic symptoms were recorded before and after water. RESULTS: Seated SBP and DBP increased after water instillation with increases first noted between 5 and 8 min after the water had been instilled. The BP remained elevated until 35 min post water increase over baseline being +36.5 mm Hg SBP and +24.3 mm Hg DBP. HR, cardiac output, and stroke volume remained unchanged during the study. Total peripheral resistance (TPR) increased post water. These results are similar to those reported in a recent study involving oral ingestion of 480 ml of water in PAF subjects. CONCLUSIONS: Instilling water directly into the stomach in a patient with PAF resulted in similar haemodynamic responses to those seen when water is taken orally. Thus, oropharyngeal factors and swallowing do not appear to be essential in the generation of the water pressor effect in autonomic failure.     

Central regulation of gastric emptying of solid nutrient meals by corticotropin releasing factor

Central regulation of gastric emptying of a solid nutrient meal and spatial and temporal parameters of gastro-pyloro-duodenal contractions by corticotropin-releasing factor (CRF) were investigated in conscious dogs. Intracerebroventricular (ICV) infusion of CRF at 0.033 nmol kg⁻¹ min⁻¹ for 15 min in a volume of 0.2 mL significantly delayed the total gastric emptying time of the meal. ICV infusion of CRF also increased the mean frequency of proximal duodenal contractions and decreased the percentage of distally propagating contractions in the whole duodenum. The remaining parameters of pyloric and duodenal contractions were not affected. A prior ICV infusion of I-helical CRF_9–41 (0.166 nmol kg⁻¹ min⁻¹ for 15 min in a volume of 0.2 mL) blocked the central effects of CRF on gastric emptying time and the duodenal contractions. Central infusion of CRF had no significant effect on the lag phase of gastric emptying. Bilateral truncal vagotomy significantly delayed the gastric emptying time of the solid nutrient meal. However, after vagotomy, ICV infusion of CRF had no effect on gastric emptying time or the spatial and temporal parameters of gastro-pyloro-duodenal contractions. In conclusion, CRF, the mediator of stress response, delays the total gastric emptying time of solid nutrient meals. The delay in gastric emptying may not be due to a change in the spatial and temporal parameters of gastric or pyloric contractions, but mainly due to changes in the parameters of duodenal contractions. The central effects of CRF on gastric emptying and duodenal contractions may be mediated by the vagus nerves.     

A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia

Abstract  Impaired gastric accommodation, hypersensitivity to distension and delayed gastric emptying are major pathophysiological mechanisms in functional dyspepsia (FD). Acotiamide (Z-338) was well-tolerated in healthy volunteers. To determine the effect of three doses of Acotiamide on major pathophysiological mechanisms, symptoms, quality of life (QOL) and safety in functional dyspeptics. A phase IIa, randomized, double-blind, placebo-controlled study (14, 21 and 28 days, respectively, for run-in, study drug administration and follow-up). Gastric accommodation, sensitivity to distension and gastric emptying were assessed by barostat and ¹³C breath test, symptoms by daily diary cards and QOL by SF-36. A total of 71 patients were enrolled (62 evaluable). There was no effect on gastric emptying and sensitivity to distension. 300 mg was better than placebo for meal accommodation ( P  = 0.024). 100 mg was better than placebo at week 2 for upper abdominal bloating ( P  = 0.001) and overall symptom score ( P  = 0.022), and at week 3 for bloating ( P  = 0.008) and heartburn ( P  = 0.041). 100 mg was also better than placebo for QOL (physical function) ( P  = 0.003). Acotiamide was safe and well-tolerated in patients with FD. The involved mechanism could at least in part depend on an effect on meal-induced accommodation. 100 mg Acotiamide exhibited the potential to improve FD symptoms and QOL. Further studies are indicated.     

Oesophageal wall stretch: the stimulus for distension induced oesophageal sensation

Recently, we reported a novel ultrasound technique to assess the biomechanical properties of the oesophagus in humans. To investigate whether the oesophageal sensation induced by oesophageal distension correlates with wall tension, wall stress or wall strain, we studied 20 healthy subjects using a manometry catheter equipped with a high-compliance bag and a high-frequency intraluminal ultrasound probe. Oesophageal distensions were performed by injecting 1-20 mL water into the bag for 20-30 s. Subjects scored the nature (heartburn or chest pain) and severity of sensation in response to distension, before and after atropine (15 microg kg(-1), i.v.). Ultrasound images of oesophagus were digitized and measurements were made to calculate oesophageal wall tension, stress and strain during distensions. Subjects experienced mostly heartburn, not chest pain, in response to oesophageal distension. Oesophageal wall strain and bag pressures correlated best with the oesophageal sensation. Atropine reduced bag pressure but did not affect the distension induced heartburn and chest pain. We conclude that heartburn is a common sensation in response to oesophageal distension in normal subjects. A strong correlation between wall strain and oesophageal sensation suggests that the wall stretch is the stimulus for nociceptive mechanoreceptors of the oesophagus.