Role of cholecystokinin in the regulation of liquid gastric emptying and gastric motility in humans: studies with the CCK antagonist loxiglumide

Background—Exogenous cholecystokinin (CCK)inhibits antral motility and slows gastric emptying (GE) but the effectof endogenous CCK on the gastric motor mechanisms responsible for GEremains unclear.
Methods—The effect of the CCK-A antagonistloxiglumide (LOX) on GE and motility was studied using magneticresonance imaging in six healthy volunteers after ingestion of 500 mlIntralipid 10% (550 kcal). Subjects were studied in the supineposition on two occasions during intravenous infusion of LOX(66 µmol/kg/h for 10 min followed by 22 µmol/kg/h) or placebo. GEwas determined every 15 minutes using transaxial abdominal scans andmotility was studied by means of 120 coronal scans, 1.2 seconds apart. For each coronal image the proximal and distal (antral) diameters weremeasured at a fixed point in the stomach to determine contraction frequency (ACF) and amplitude (AMP).
Results—GE was faster during LOX infusion thanplacebo (t_1/2 31 (22) versus 115 (67) minutes, p<0.03).There was little variation in the diameter of the proximal stomach witheither LOX or placebo. In the distal stomach marked contractileactivity was observed during LOX (ACF 2.9 (0.2) versus 1.5 (2.9) duringplacebo, p<0.01). AMP also increased during LOX compared with placebo(56 (22)% versus 27 (16)%, p<0.001).
Conclusion—The increases in antral motility arelikely to contribute to the acceleration of GE and suggest that CCK mayregulate GE by acting on the distal stomach although an effect on theproximal stomach cannot be excluded.

Keywords:loxiglumide; magnetic resonance imaging; gastricemptying; gastric motility; antral contraction

     

Role of bile in regulation of gut motility

Abstract. Bile empties into the duodenum not only after a meal but also in the interdigestive state. In man, inter-digestive biliary emptying is related to fasting motor activity, the migrating motor complex (MMC), in the stomach and small bowel and generally occurs during phase 2 preceding a gastroduodenal phase 3 activity (activity front). It seems that the main regulatory peptide to initiate phase 3 is motilin. During a period with 13 phase 3 activities of MMC, 18 episodes of gall-bladder emptying and 19 motilin peaks were observed. Such a peak of plasma motilin usually took place 25 ± 11 min after onset of biliary emptying. In conclusion, data indicate that motilin is released to the circulation by the biliary output and induces phase 3 of MMC. The induced phase 3 propels bile acids along the gut to promote their absorption in the distal intestine. The choleretic action of recycling of bile acids may cause subsequent episodes of biliary emptying with motilin release by the action of the enterohepatic circulation of bile acids. In such a manner the MMC may be withheld as a recycling motility pattern.     

钾通道在D型钠尿肽抑制胃动力中的作用

目的:探讨钾通道在D型钠尿肽抑制豚鼠胃窦环形肌自发性收缩活动中的作用.方法:采用四道生理记录仪记录豚鼠胃窦环形肌自发性收缩活动;应用放射免疫法测定豚鼠胃窦环形肌组织和灌流液中环-磷酸鸟苷(cGMP)含量;运用全细胞模式的膜片钳技术记录豚鼠胃窦环形肌上钙敏感钾电流和延迟整流型钾电流.结果:DNP抑制豚鼠胃窦环形肌自发性收缩活动并呈现剂量依赖性.1、10、100及1000nmol/L的DNP抑制自发性收缩幅度分别为35%±6%、54%±6%、78%±13%及94%±6%.10 nmol/L鸟苷酸环化酶抑制剂LY83583使收缩幅度抑制减弱(42%±6%vs60%±4%.P<0.05);而用100 nm01/L的cGMP依赖的磷酸脂酶抑制剂zaparinast使DNP对胃窦环行肌自发性收缩的抑制效应增强(72%±7%vs58%±5%,P<0.05).DNP明显增加豚鼠胃窦环形肌组织和灌流液中的cGMP水平.10 nmol/LDNP增加豚鼠胃窦环形肌上钙敏感钾电流,在60mV时增加的幅值为62.31%±3.22%,抑制延迟整流型钾电流,在60 mV时抑制幅度为18%±2.3%.结论:DNP通过增加I<,K(ca)>和cGMP途径实现对豚鼠胃窦环形肌的舒张作用.I<,K(v)>不参与此过程,但在维持豚鼠胃窦环形肌细胞的静息膜电位中起重要作用.     

Role of the hypophysis in regulation of pancreatic and gastric somatostatin

Since hypophysectomy and GH deficiency are associated with decreases in hypothalamic content and release of SRIF, it was of interest to determine whether these hormonal alterations also affect peripheral tissue levels of SRIF. Hypophysectomized (hypox) rats were studied at various times after surgery and compared with age-matched controls. Pancreatic, gastric, and hypothalamic SRIF levels were measured by RIA and expressed as nanograms per mg protein or nanograms per organ. Decreased levels of hypothalamic SRIF were observed in hypox animals at all time periods after surgery. In contrast, pancreatic SRIF concentrations increased within 1 week of hypophysectomy, and the tissue content increased as much as 3-fold after 20 weeks. Measurement of the SRIF content of isolated rat islets of Langerhans revealed a 67% increased content/islet in hypox rats compared with controls. The gastric SRIF concentration was not changed early, but subsequently, the total organ content was significantly decreased compared with that in controls. The changes in stomach and pancreas SRIF contents became more marked with duration of pituitary deficiency. Studies in genetically dwarfed Snell mice, lacking primarily GH but also other anterior pituitary hormones, were similar to the findings noted in hypox rats; the SRIF concentration was significantly increased in the pancreas and decreased in the stomach and hypothalamus. It is probable that deficiencies in other hormones as well as GH are involved in producing the changes in pancreatic SRIF in hypox and dwarfed animals. This contention was supported in that replacement of T3 (5 micrograms/kg . day) reduced pancreatic SRIF concentration by 30%, while GH plus T3 produced a significantly greater (60%) decrease in pancreatic SRIF in hypox rats.     

Bilateral adrenalectomy worsens gastric mucosal lesions induced by indomethacin in the rat. Role of enhanced gastric motility

The mechanism by which bilateral adrenalectomy worsens indomethacin-induced gastric lesions was investigated in rats. In sham-operated rats subcutaneously administered indomethacin produced gastric lesions at doses of 10 mg/kg body wt or greater, in association with lowering of blood glucose levels. In a parallel study, indomethacin induced gastric hypermotility at the same dose levels but had no effect on acid output or mucosal blood flow even at 25 mg/kg body wt. Adrenalectomy (2 wk) itself significantly reduced the blood glucose levels (approximately 50%) and markedly potentiated the ulcerogenic and motility responses caused by indomethacin; the ED50 values dropped to approximately 10 times lower than those in sham-operated rats. Both acid output and mucosal blood flow were significantly reduced by adrenalectomy, but these values were increased after indomethacin treatment (3 mg/kg body wt). The ulcerogenic and motility responses caused by indomethacin were significantly reduced by acute infusion of glucose (25% wt/wt, 1.2 ml/h) intravenously in both sham-operated and adrenalectomized rats, and by subcutaneous administration of hydrocortisone acetate (10 mg/kg body wt for 2 wk) in the latter group. When the motility and the ulcer score were determined in the same animals, a highly significant relationship was found between these two factors in both sham-operated and adrenalectomized rats. These results suggest that (a) the increased gastric motility may be a key element in the pathogenesis of indomethacin-induced lesions and in the mechanism for aggravation of the lesions and in the mechanism for aggravation of the lesions by adrenalectomy, and (b) abrasion of adrenal glands by inducing hypoglycemia may sensitize the system to indomethacin and increase gastric motility.     

Effects of ghrelin on gastric distension sensitive neurons and gastric motility in the lateral septum and arcuate nucleus regulation

Background

Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) and a peptide hormone that promotes food intake and gastric motility. Our aims are to explore the effects of ghrelin on gastric distension (GD) sensitive neurons in the lateral septum, and the possible regulation of gastric motility by ghrelin through the hypothalamic arcuate nucleus (ARC).

Methods

Single-unit discharges were recorded, extracellularly, and the gastric motility was monitored by the administration of ghrelin in the lateral septum. The projection of nerve fiber and expression of ghrelin were observed by retrograde tracer and fluo-immunohistochemistry staining. The expression of GHS-R and ghrelin was determined by real-time polymerase chain reaction and western blotting analysis.

Results

There were GD neurons in the lateral septum. The administration of ghrelin could excite both GD-excitatory (GD-E) and GD-inhibitory (GD-I) neurons in the lateral septum. Gastric motility was significantly enhanced by the administration of ghrelin in the lateral septum in a dose-dependent manner. Pretreatment with [d-Lys-3]-GHRP-6, however, could completely abolish the ghrelin-induced effects. Electrical stimulation of the ARC could significantly excite the response of GD neurons to ghrelin, increase ghrelin protein expression in the lateral septum and promote gastric motility. Nevertheless, these effects could be mitigated by pretreatment of [d-Lys-3]-GHRP-6. Electrical lesion of the lateral septum resulted in decreased gastric motility. The GHS-R and Ghrelin/FG-double labeled neurons were observed in the lateral septum and ARC, respectively.

Conclusions

It is suggested that the lateral septum may receive afferent information from the gastrointestinal tract and promote gastric motility. Ghrelin plays an important role in promoting gastric motility in the lateral septum. The ARC may be involved in the regulation of the lateral septum’s influence on gastric motility.     

Importance of gastric motility in the pathogenesis of indomethacin-induced gastric lesions in rats

Effects of indomethacin on gastric motility and secretion, and levels of endogenous prostaglandins (PGs) were investigated in rats, in attempts to elucidate the factors involved in the pathogenesis of indomethacin-induced macroscopic gastric lesions. Subcutaneous administration of indomethacin had no effect on the gastric mucosa at doses of 1 and 5 mg/kg, but induced visible lesions dose dependently at over 10 mg/kg within 4 hr. At 25 mg/kg, there were apparent nonhemorrhagic lesions within 1 hr, and these lesions became hemorrhagic with time. Acid secretion was not affected by this agent at either dose level, but pepsin or acid-induced HCO₃ ^– secretion was significantly increased or decreased, respectively, at a dose less than 5 mg/kg, which did not induce any lesion. Gastric motility, however, was dose dependently increased after administration of indomethacin, and its effect was significant at 10 mg/kg or greater. Time-course changes in the motility were in parallel with those of the lesion formation. PGE₂ and 6-keto PGF₁ levels in the corpus mucosa were reduced around 80–90% for more than 4 hr from 30 min after administration of 5 mg/kg or more of indomethacin. When all the above changes caused by indomethacin were plotted for the various doses, a significant correlation (r=0.958, P<0.01) was found between the lesion index and the changes in motility, but not in other factors, including PG levels. These results indicate that gastric motility may be an important factor in the pathogenetic mechanism of indomethacin-induced gastric lesions in rats. A deficiency of endogenous PGs may be a prerequisite for later extension of the lesions.     

Role of vasoactive intestinal peptide and nitric oxide in the modulation of electroacupucture on gastric motility in stressed rats

INTRODUCTION In recent years, along with the extensive research into enteric nerve system (ENS), increasing evidence shows that peptidergic neurotransmitters are the key factors regulating the gastric motility. Our previous research[1-3] showed that electroacupucture (EA) at acupoints of the Stomach Meridian of Foot-Yangmin may regulate gastric movement, increase blood flow in the microvessels in the gastric mucosa, and exert a protective effect on gastric mucosa. Nitric oxide (NO) an…     

Relationship between gastric mucosal hemodynamics and gastric motility

Continuous measurement of gastric mucosal hemodynamics (the index of mucosal hemoglobin concentration, the index of oxygen saturation and blood flow) in rats showed oscillatory changes. The mechanism of the oscillations was investigated using a probe specially designed for simultaneous measurement of hemodynamics and intragastric pressure. A hemodynamics-measuring probe for either reflectance spectrophotometry or laser-Doppler flowmetry was tied to a pressure microtransducer, inserted through an incision in the forestomach, and brought into gentle contact with the corpus mucosa. Synchronous oscillatory changes (4-6 cycles/min) in hemodynamics and motility were observed in the resting state (mean blood pressure: 120 mmHg). During moderate hemorrhagic hypotension (mean: 81 mmHg), oscillations in the hemodynamics increased in both amplitude and frequency, while motility remained constant. Oscillations in the hemodynamics were also affected by fluctuations in blood pressure and by topical application of norepinephrine to the corpus serosa. In water-immersion restraint rats, changes in the oscillations in the hemodynamics and motility were virtually synchronous; frequency decreased and amplitude increased. These findings suggest that oscillatory changes in gastric mucosal hemodynamics are regulated not only by gastric motility but also by arteriolar vasomotion of the gastric wall.     

Relationship between gastric mucosal hemodynamics and gastric motility

Continuous measurement of gastric mucosal hemodynamics (the index of mucosal hemoglobin concentration, the index of oxygen saturation and blood flow) in rats showed oscillatory changes. The mechanism of the oscillations was investigated using a probe specially designed for simultaneous measurement of hemodynamics and intragastric pressure. A hemodynamics-measuring probe for either reflectance spectrophotometry or laser-Doppler flowmetry was tied to a pressure microtransducer, inserted through an incision in the forestomach, and brought into gentle contact with the corpus mucosa. Synchronous oscillatory changes (4-6 cycles/min) in hemodynamics and motility were observed in the resting state (mean blood pressure: 120 mmHg). During moderate hemorrhagic hypotension (mean: 81 mmHg), oscillations in the hemodynamics increased in both amplitude and frequency, while motility remained constant. Oscillations in the hemodynamics were also affected by fluctuations in blood pressure and by topical application of norepinephrine to the corpus serosa. In water-immersion restraint rats, changes in the oscillations in the hemodynamics and motility were virtually synchronous; frequency decreased and amplitude increased. These findings suggest that oscillatory changes in gastric mucosal hemodynamics are regulated not only by gastric motility but also by arteriolar vasomotion of the gastric wall.     

Effect of gastric acid suppressants on human gastric motility

Background—The effect of histamine H₂receptor antagonists on gastric emptying is controversial.
Aims—To determine the effects of ranitidine,famotidine, and omeprazole on gastric motility and emptying.
Patients and methods—Fifteen normal subjectsunderwent simultaneous antroduodenal manometry, electrogastrography(EGG), and gastric emptying with dynamic antral scintigraphy (DAS).After 30 minutes of fasting manometry and EGG recording, subjectsreceived either intravenous saline, ranitidine, or famotidine, followed by another 30 minutes recording and then three hours of postprandial recording after ingestion of a radiolabelled meal. Images were obtainedevery 10-15 minutes for three hours to measure gastric emptying andassess antral contractility. Similar testing was performed afteromeprazole 20 mg daily for one week.
Results—Fasting antral phase III migrating motorcomplexes (MMCs) were more common after ranitidine (9/15 subjects,60%), famotidine (12/15, 80%), and omeprazole (8/12, 67%) comparedwith placebo (4/14, 29%; p<0.05). Postprandially, ranitidine,famotidine, and omeprazole slowed gastric emptying, increased theamplitude of DAS contractions, increased the EGG power, and increasedthe antral manometric motility index.
Conclusions—Suppression of gastric acid secretionwith therapeutic doses of gastric acid suppressants is associated withdelayed gastric emptying but increased antral motility.

Keywords:gastric motility; gastric emptying; histamineH₂ receptor antagonists; proton pump inhibitors; gastricacid secretion; scintigraphy

     

Neural mechanism of acupuncture-modulated gastric motility

AIM： To investigate the acupuncture-modulated gastric motility and its underlying neural mechanism. METHODS： Intragastric pressure and/or waves of gastric contraction in rats were recorded by intrapyloric balloon and changes of gastric motility induced by acupuncture stimulation were compared with the background activity before any stimulation, Gastrovagal or splanchnic-sympathetic nerves were recorded or cut respectively for investigating the involvement of autonomic nerve pathways, Spinalization experiment was also performed. RESULTS： Acupuncture-stimulation by exciting Aδ and/ or C afferent fibers, could only modulate gastric motility. Acupuncture-stimulation on fore- and hind-limbs evoked a moderate gastric motility followed by increased vagus discharges with unchanged sympathetic activity, while the same stimulus to the acupoints in abdomen resulted in reversed effects on gastric motility and autonomic nervous activities. The inhibitory gastric response was completely abolished by splanchnic denervation, but the facilitative gastric response to stimulation of acupoints in limbs was not influenced, which was opposite to the effect when vagotomy was performed. The similar depressive effects were produced by the stimulation at the acupoints homo-segmental to the gastric innervation in the animals with or without spinalization. However, the facilitation induced by the stimulation at the acupoints hetero-segmental to the gastric innervation was not observed in the spinalized animals. CONCLUSION： Facilitative effects of stimulating hetero-segmental acupoints are involved in the intact preparation of vagal nerves and spinal cord, while the inhibitory response induced by stimulating homosegmental acupoints is involved in the intact preparation of sympathetic nerves. Only the acupuncture-stimulation with intensity over the threshold of Aδ and/or C afferent fibers can markedly modulate gastrointestinal motility.     

Antral motility in patients with gastric ulcer

Summary Quantitative analysis of antral motility in patients with gastric ulcer revealed a significant decrease in rhythmic propulsive Type II contractions. After healing of the ulcer, the motility patterns returned to normal. When the antrum was distended, the motor response in ulcer patients was similar to that of healthy volunteers.Supported in part by Research Grant AM-06908 from the National Institutes of Health, U. S. Public Health Service.