Unique distribution of interstitial cells of Cajal in the feline pylorus

The feline gastrointestinal (GI) tract is an important model for GI physiology but no immunohistochemical assessment of interstitial cells of Cajal (ICC) has been performed because of the lack of suitable antibodies. The aim of the present study was to investigate the various types of ICC and associated nerve structures in the pyloric sphincter region, by using immunohistochemistry and electron microscopy to complement functional studies. In the sphincter, ICC associated with Auerbach’s plexus (ICC-AP) were markedly decreased within a region of 6–8 mm in length, thereby forming an interruption in this network of ICC-AP, which is otherwise continuous from corpus to distal ileum. In contrast, intramuscular ICC (ICC-IM) were abundant within the pylorus, especially at the inner edge of the circular muscle adjacent to the submucosa. Similar distribution patterns of nerves positive for vesicular acetylcholine transporter (VAChT), nitric oxide synthase (NOS) and substance P (SP) were encountered. Quantification showed a significantly higher number of ICC-IM and the various types of nerves in the pylorus compared with the circular muscle layers in the adjacent antrum and duodenum. Electron-microscopic studies demonstrated that ICC-IM were closely associated with enteric nerves through synapse-like junctions and with smooth muscle cells through gap junctions. Thus, for the first time, immunohistochemical studies have been successful in documenting the unique distribution of ICC in the feline pylorus. A lack of ICC-AP guarantees the distinct properties of antral and duodenal pacemaker activities. ICC-IM are associated with enteric nerves, which are concentrated in the inner portion of the circular muscle layer, being part of a unique innervation pattern of the sphincter. This study was supported by operating grants from the Canadian Institutes of Health Research (to J.D.H. and N.E.D.) and from the Canadian Association of Gastroenterology (to L.W.C.L.).     

Role of vagus nerve in postprandial antropyloric coordination in conscious dogs

It is generally believed that gastric emptying of solids is regulated by a coordinated motor pattern between the antrum and pylorus. We studied the role of the vagus nerve in mediating postprandial coordination between the antrum and pylorus. Force transducers were implanted on the serosal surface of the body, antrum, pylorus, and duodenum in seven dogs. Dogs were given either a solid or a liquid meal, and gastroduodenal motility was recorded over 10 h. Gastric emptying was evaluated with radiopaque markers mixed with a solid meal. Dogs were treated with hexamethonium, N(G)-nitro-l-arginine methyl ester (l-NAME), or transient vagal nerve blockade by cooling. A postprandial motility pattern showed three distinct phases: early, intermediate, and late. In the late phase, profound pyloric relaxations predominantly synchronized with giant antral contractions that were defined as postprandial antropyloric coordination. A gastric emptying study revealed that the time at which gastric contents entered into the duodenum occurred concomitantly with antropyloric coordination. Treatment by vagal blockade or hexamethonium significantly reduced postprandial antral contractions and pyloric relaxations of the late phase. l-NAME changed pyloric motor patterns from relaxation dominant to contraction dominant. Solid gastric emptying was significantly attenuated by treatment with hexamethonium, l-NAME, and vagal blockade. Postprandial antropyloric coordination was not seen after feeding a liquid meal. It is concluded that postprandial antropyloric coordination plays an important role to regulate gastric emptying of a solid food. Postprandial antropyloric coordination is regulated by the vagus nerve and nitrergic neurons in conscious dogs.     

Relative contributions of "pressure pump" and "peristaltic pump" to gastric emptying

The relative contributions to gastric emptying from common cavity antroduodenal pressure difference ("pressure pump") vs. propagating high-pressure waves in the distal antrum ("peristaltic pump") were analyzed in humans by high-resolution manometry concurrently with time-resolved three-dimensional magnetic resonance imaging during intraduodenal nutrient infusion at 2 kcal/min. Gastric volume, space-time pressure, and contraction wave histories in the antropyloroduodenal region were measured in seven healthy subjects. The subjects fell into two distinct groups with an order of magnitude difference in levels of antral pressure activity. However, there was no significant difference in average rate of gastric emptying between the two groups. Antral pressure history was separated into "propagating high-pressure events" (HPE), "nonpropagating HPEs," and "quiescent periods." Quiescent periods dominated, and average pressure during quiescent periods remained unchanged with decreasing gastric volume, suggesting that common cavity pressure levels were maintained by increasing wall muscle tone with decreasing volume. When propagating HPEs moved to within 2-3 cm of the pylorus, pyloric resistance was found statistically to increase with decreasing distance between peristaltic waves and the pylorus. We conclude that transpyloric flow tends to be blocked when antral contraction waves are within a "zone of influence" proximal to the pylorus, suggesting physiological coordination between pyloric and antral contractile activity. We further conclude that gastric emptying of nutrient liquids is primarily through the "pressure pump" mechanism controlled by pyloric opening during periods of relative quiescence in antral contractile wave activity.     

On the mechanism of gastroduodenal motility inhibition under psychogenic stress in rabbits

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) in antral and pyloric parts of the stomach and in two sites of proximal duodenum was studied under stress induced by fastening rabbit to a table in supine position. The stressor impact induced inhibition of contractile activity in antrum and pylorus. The duodenal contractile activity after initial complete suppression overshot its initial level. Blockade of beta1/beta2-adrenoceptor with propranolol and blockade of alpha2-adrenoceptor with yohimbine did not influence qualitatively the pattern of the stressor responses of antrum and pylorus, and of the postpyloric part of duodenum. In conditions of unselective blockade of alpha-adrenoceptor with dihydroergotoxin there was no initial complete inhibition of duodenal contractile activity, and its strengthening was more expressed than in the control experiments. The received data indicate that the stressor inhibition of antral and pyloric contractile activity possibly results from activation of non-adrenergic inhibitory neurons of the enteric nervous system. The initial short-term suppression of duodenal motility resulted from its "adrenergic" inhibition which can also be a factor limiting the manifestation of stimulating effect of the humoral agent on the duodenal motility. In the period after release of the animal, index of antral and pyloric contractile activity did not significantly differ from its initial level; after beta1/beta2-adrenoceptor blockade in antral and after alpha2-adrenoceptor blockade or nonselective alpha-blockade in antral and pyloric parts of the stomach, there was decrease of contractile activity compared with its initial level; after alpha2- or beta1/beta2-adrenoceptor blockade there was no poststressor exceeding of the initial level of the duodenal contractile activity, observed in the control experiments.     

Gastric control of duodenal electric activity--the function of the gastroduodenal junction.

An investigation was made into the links between electric activity of antral and of duodeno-jejunal musculature in different functional conditions. The function of the gastroduodenal junction in this linking mechanism was analysed. The following observations were made: (a) in the absence of gastric stimulation, the slow electric activities of stomach and duodenum appear to be completely independent; (b) the gastroduodenal junction evidences no electric activity of its own but is affected by that of the two adjacent structures; (c) chemical stimulation of the gastric mucosa causes activation of the electric and mechanical activity of the stomach and analogous activation of duodenal musculature; this effect is mediated by the gastroduodenal junction; (d) very probably, the transmission of gastric activation to the duodenum is myogenic for it ceases after surgical transection but not after cooling or after ligature. The possible functional role of the pyloric junction in the complex gastroduodenal mechanism is discussed.     

The mechanism of the duodenal motility strengthening under psychogenic stress in rabbits

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) of two sites of duodenum and of antral and pyloric parts of the stomach was studied under stress induced by fastening a rabbit to a table in supine position. In both sites of duodenum, the stress impact induced a short-time inhibition of contractile activity which was followed by its strengthening that exceeded the initial level. Meanwhile in antrum and pylorus, the whole period of stress impact was characterized by suppression of contractile activity, the latter being more pronounced in the antrum. The strengthening of the duodenal contractile activity was preserved after muscarinic ornicotinic cholinoceptor blockade. It was concluded that the contractile response of duodenum seemed to be of humoral origin.     

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility.     

A stomach road or "Magenstrasse" for gastric emptying

Gastric muscle contractions grind and mix solid/liquid meal within the stomach, and move it into the bowels at a controlled rate. Contractions are of two types: slow volume-reducing contractions of the proximal stomach (the fundus), and peristaltic contraction waves in the distal stomach (the antrum). Fundic squeeze maintains gastro-duodenal pressure difference to drive gastric emptying. Emptying is generally assumed to proceed from the antrum to the fundus, so that ingested drugs can take hours to enter the small intestines and activate. Antral contraction waves (ACW), in contrast, generate fluid motions that break down and mix gastric content. Using a computer model of the human stomach, we discover a new function of these contraction waves apart from grinding and mixing. In coordination with fundic contraction, antral contraction waves move liquid content from the fundus along a very narrow path to the duodenum through the center of the antrum. Using physiological data, we show that this gastric emptying "Magenstrasse" (stomach road) can funnel liquid gastric content from the farthest reaches of the fundus directly to the intestines within 10 min. Consequently, whereas drugs (tablets, capsules, liquid) released off the Magenstrasse may require hours to enter the duodenum, at low concentration, when released on the Magenstrasse the drug can enter the duodenum and activate within 10 min-at high concentration. This discovery might explain observed high variability in drug initiation time, and may have important implications to both drug delivery and digestion, as well as to other wall-driven emptying of elastic containers.     

Emptying of the abomasum in adult ruminants

In the adult ruminant, abomasal emptying is a permanent phenomenon depending upon meal volume. Intradian rhythm involving the motor pattern of the duodenum and circadian rhythm of unknown origin modulate the transpyloric flow rate. The fundic tone, antro-duodenal coordination and pyloric resistance regulate gastric outflow. The break-like function of the pyloric resistance involves chyme viscosity. Transpyloric flow rate is controlled by a hierarchy of extrinsic and intrinsic mechanisms triggered at the duodenal level. The vagus permanently inhibits the motility of the abomasum. A similar relationship is observed between the pyloric sphincter and duodenal motility. Removal of the pyloric ring leads to an increased food intake.     

The innervation of the human antro-pyloric region: organization and composition.

Although the composition of the gastric innervation has been determined in animal models, relatively little known about the innervation of the human antro-pyloric region. We used immunocytochemical techniques to establish the localization and co-expression of neuropeptides and nitric oxide in the human antrum and upper duodenum. Our results demonstrate the existence of a clearly defined submucosal plexus in the antral region that is absent in rats and guinea pigs. The abundant innervation of the lamina propria contains 3 major nerve populations: VIP- and NOS-, SP- and CGRP-, and GRP-immunoreactive. For the first time, NOS-containing nerve fibers were observed throughout the length of the antral glands. Within the antrum somatostatin was confined to endocrine cells, however, at the pyloric sphincter both enteric plexi contained immunoreactive neurons and nerve fibres. Within the pyloric sphincter CGRP- and SP-immunoreactive fibres were significantly increased, correlating with the presence of large ganglia in the submucosal plexus. In conclusion, the organization and composition of the innervation of human antro-pylorus differed substantially from that reported in other mammals. The presence of an abundant mucosal innervation paralled by a well-defined submucosal plexus indicates that the functional regulation of the gastric-pyloric region will be distinct from that of smaller animal models.     

The Influence of Antral Ulcers on Intramural Gastric Nerve Projections Supplying the Pyloric Sphincter in the Pig (Sus scrofa domestica)—Neuronal Tracing Studies

BackgroundGastric ulcerations in the region of antrum pylori represent a serious medical problem in humans and animals. Such localization of ulcers can influence the intrinsic descending nerve supply to the pyloric sphincter. The pyloric function is precisely regulated by intrinsic and extrinsic nerves. Impaired neural regulation could result in pyloric sphincter dysfunction and gastric emptying malfunction. The aim of the study was to determine the effect of gastric antral ulcerations on the density and distribution of intramural gastric descending neurons supplying the pyloric sphincter in pigs.Conclusions/SignificanceObtained results revealed for the first time significant impact of antral ulcerations on intramural descending nerve pathways supplying the pyloric sphincter in pigs, animals of increasing value in biomedical research and great economic importance.     

Comparative study on mucus glycoproteins in rat stomach and duodenum

The density of mucus glycoprotein compared to that of the corpus, antrum and duodenum was; 1.52, 1.49 and 1.57 g/ml respectively. Carbohydrate composition of gastrointestinal mucus glycoprotein consisted of N-acetylgalactosamine, N-acetylglucosamine, galactose, fucose and sialic acid. Ratios of carbohydrate composition among corpus, antral and duodenal mucus glycoproteins differed. The average length of an oligosaccharide was found to be about 12-13, 14 and 10 sugars in the corpus, antrum and duodenum, respectively. In the corpus, the amino acid content was found to have the following quantitative order: Thr greater than Ser greater than Glx = Pro; in the antrum: Thr greater than Ser greater than Glx; and in the duodenum: Thr greater than Ser greater than Pro. Corpus, antral and duodenal mucus glycoproteins have the blood-group A antigen; antral mucus glycoprotein in particular exhibited strong blood-group A activity.     

Obestatin inhibits motor activity in the antrum and duodenum in the fed state of conscious rats

Obestatin is a novel peptide encoded by the ghrelin precursor gene; however, its effects on gastrointestinal motility remain controversial. Here we have examined the effects of obestatin on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats. We examined the effects of intravenous (IV) injection of obestatin on the percentage motor index (%MI) and phase III-like contractions in the antrum and duodenum. The brain mechanism mediating the action of obestatin on gastroduodenal motility and the involvement of vagal afferent pathway were also examined. Between 30 and 90 min after IV injection, obestatin decreased the %MI in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats given 3 g of chow after 18 h of fasting. Immunohistochemical analysis demonstrated that corticotropin-releasing factor- and urocortin-2-containing neurons in the paraventricular nucleus in the hypothalamus were activated by IV injection of obestatin. Intracerebroventricular injection of CRF type 1 and type 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Capsaicin treatment blocked the effects of obestatin on duodenal motility but not on antral motility. Obestatin failed to antagonize ghrelin-induced stimulation of gastroduodenal motility. These results suggest that, in the fed state, obestatin inhibits motor activity in the antrum and duodenum and that CRF type 1 and type 2 receptors in the brain might be involved in these effects of obestatin on gastroduodenal motility.     

Determinants of transpyloric fluid transport: a study using combined real-time ultrasound,manometry, and impedance recording

Intraluminal impedance recording has made it possible to record fluid transport across the pylorus during the interdigestive state without filling the stomach. During antral phase II, fluid transport occurs with and without manometrically detectable antral contraction. Our aim was to investigate the relationships between ultrasonographic patterns of antral contraction, manometric pressure waves, and transpyloric fluid transport during antral phase II. Antral wall movements were recorded by real-time ultrasound (US) in eight healthy volunteers (mean age 24 +/- 7 yr) during 17 +/- 5 min of antral phase II. Concomitantly, a catheter positioned across the pylorus, monitored by transmucosal potential difference measurement, recorded five impedance signals (1 antral, 1 pyloric, and 3 duodenal) and six manometric signals (2 antral, 1 pyloric, and 3 duodenal). Antral contractions detected by US at the level of the two antral impedance electrodes were classified according to their association with a pyloric opening or a duodenal contraction. Transpyloric liquid transport events (impedance drop of >40% of the baseline with an antegrade or retrograde propagation) and manometric pressure waves (amplitude and duration) were identified during the whole study and especially during each period of US antral contraction. A total of 110 antral contractions was detected by US. Of these, 79 were also recorded by manometry. Fluid transport across the pylorus was observed in 70.9% of the US-detected antral contractions. Pyloric opening was observed in 98.6% of the contractions associated with fluid transport compared with 50% in the absence of fluid transport (P < 0.05). Antral contractions associated with fluid transport were significantly (P < 0.05) more often propagated to the duodenum (92%) than those without fluid transport (53%). Pressure waves associated with fluid transport were of higher amplitude (208 mmHg, range 22-493) and longer duration (7 s, range 2.5-13.5 s) than those not associated with fluid transport (102 mmHg, range 18-329 mmHg, and 4.1 s, range 2-8.5 s; P < 0.05). The propagation of the antral contractions in the duodenum in US was always associated with a pyloric opening, whereas only 8 of the 25 contractions without duodenal propagation were associated with a pyloric opening (P < 0.05). The presence of duodenal contractile activity before the onset of an antral contraction in US was always accompanied by pyloric opening and with fluid transport in 93.3%, compared with 56.8% in its absence (P < 0.05). In antral phase II, US is the most sensitive technique to detect antral contractions. Transpyloric fluid transport observed in relation to antral contractions occurs mainly in association with contractions of high amplitude and long duration and is associated with pyloric opening and/or duodenal propagation.     

Central origin on the excito-motric action of morphine on intestine]

In ewew fitted with a cerebro-ventricular cannula and equipped with extra-cellular bipolar electrodes on the antrum and proximal small intestine, an intraventricular injection of morphine at a dose (40 micrograms/kg) ineffective peripherally was followed within 1 min by an increased spike activity of the duodenum without disruption of the occurrence of migrating myoelectric complexes. This effect was paralleled by a reduction of antral motility and abolished by small intraventricular doses of nalorphine. After an intravenous injection of large doses of the drug drug (0.8 mg/kg), spike activity was increased at both jejunal and duodenal level without changes in the antrum and followed by a long-lasting disorganization of the motor profile. The results suggested a centrally mediated gastro-duodenal effect of morphine.     

The pacemaker activity of interstitial cells of Cajal and gastric electrical activity

Interstitial cells of Cajal (ICC) are the pacemaker cells in the gut. They have special properties that make them unique in their ability to generate and propagate slow waves in gastrointestinal muscles. The electrical slow wave activity determines the characteristic frequency of phasic contractions of the stomach, intestine and colon. Slow waves also determine the direction and velocity of propagation of peristaltic activity, in concert with the enteric nervous system. Characterization of receptors and ion channels in the ICC membrane is under way, and manipulation of slow wave activity markedly alters the movement of contents through the gut. Gastric myoelectrical slow wave activity produced by pacemaker cells (ICC) can be reflected by electrogastrography (EGG). Electrogastrography is a perspective non-invasive method that can detect gastric dysrhythmias associated with symptoms of nausea or delayed gastric emptying.     

Mechanical factors regulating gastric emptying examined by the effects of exogenous cholecystokinin and secretin on canine gastroduodenal motility

The aim of this study was to elucidate the variables of gastroduodenal motility determining gastric emptying. For this purpose the effects of exogenous cholecystokinin, secretin, and gastric inhibitory polypeptide on motility and gastric emptying were studied during a meal. Motility was measured with extraluminal strain gage force transducers and induction coils in unanaesthetized dogs. The pyloric diameter and the duodenal lumen were evaluated from radiographs. Gastric emptying of an acaloric cellulose meal was determined radiographically. When compared with control infusion of saline, cholecystokinin (1.7 Ivy units X kg-1 X h-1) and secretin (1.7 clinical units X kg-1 X h-1) delayed gastric emptying and diminished the force of the antral contractions, the force and frequency of the duodenal contractions, and opening of the pylorus. The contractile patterns of the duodenum were changed from propulsive to segmenting activity. Cholecystokinin additionally diminished the duodenal lumen. In contrast, gastric inhibitory polypeptide (1.5 microgram X kg-1 X h-1) did not influence gastroduodenal motility and gastric emptying. It is concluded that the motility parameters that were significantly altered by cholecystokinin and secretin are involved in the control of gastric emptying, while other parameters that remained unchanged play a minor role in the regulating process.     

Observations on the anatomy of the stomach and duodenum of the bowhead whale, Balaena mysticetus

Gastric and cranial duodenal structure of the bowhead whale (Balaena mysticetus) was examined grossly and microscopically. The stomach was arranged in a series of four compartments. The first chamber, or forestomach, was a large nonglandular sac lined by a keratinized stratified squamous epithelium. It was followed by the fundic chamber, a large, somewhat globular and entirely glandular compartment. At the entrance of the fundic chamber, a narrow cardiac gland region could be defined. The remaining mucosa of the chamber contained the proper gastric glands. A narrow, tubular connecting channel, the third distinct gastric division, was lined by mucous glands and joined the fundic chamber with the final stomach compartment, or pyloric chamber. This fourth chamber was also tubular and lined by mucous glands but was of a diameter considerably larger than the connecting channel. The stomach terminated at the pyloric sphincter which consisted of a well-developed band of circular smooth-muscle bundles effecting a division between the pyloric chamber and small intestine. The small intestine began with the duodenal ampulla, a dilated sac considerably smaller than the fundic chamber of the stomach. The mucosa of this sac contained mucous glands throughout. The ampulla led without a separating sphincter into the duodenum proper which continued the intestine in a much more narrow tubular fashion. The mucosal lining of the duodenum was composed of villi and intestinal crypts. Although their occurrence varied among whales, enteroendocrine cells were identified within the mucous glands of the cardiac region, connecting channel, pyloric chamber, and cranial duodenum. The hepatopancreatic duct entered the wall of the duodenum shortly after the termination of the duodenal ampulla and continued intramurally along the intestine before finally joining the duodenal lumen.     

Similarities and differences in the propagation of slow waves and peristaltic waves

The relationship between slow waves and peristaltic reflexes has not been well analyzed. In this study, we have recorded the electrical activity of slow waves together with that generated by spontaneous peristaltic contractions at 240 extracellular sites simultaneously. Recordings were made from five isolated tubular and six sheet segments of feline duodenum superfused in vitro. In all preparations, slow waves propagated as broad wave fronts along the longitudinal axis of the preparation in either the aborad or the orad direction. Electrical potentials recorded during peristalsis (peristaltic waves) also propagated as broad wave fronts in either directions. Peristaltic waves often spontaneously stopped conducting (46%), in contrast to slow waves that never did. Peristaltic waves propagated at a lower velocity than the slow waves (0.98 +/- 0.25 and 1.29 +/- 0.28 cm/s, respectively; P < 0.001; n = 24) and in a direction independent of the preceding slow wave direction (64% in the same direction, 46% in the opposite direction). In conclusion, slow waves and peristaltic waves in the isolated feline duodenum seem to constitute two separate electrical events that may drive two different mechanisms of contraction in the small intestine.