Regulatory Peptides #

For a brief historical review of the regulatory peptides, one is indebted to Royston et al (l978) and others. It was pointed out that Solcia and his colleagues (l967) described endocrine-like cells in the gastric "antrum" which were argyrophilic, but non-argentaffin in quality. The next year McGuigan (l968), by means of an immunofluorescent technique, identified gastrin in cells of the antral mucosa, which he named G cells. Bussolati and Pearse (l970), using immunofluorescent and silver techniques, showed that these two types of cell were the same.

G cells belong to the APUD cell line; the technique of immunocytochemistry shows the precise localization of the cells in the walls of the gastrointestinal tract. Individual cells contain secretory granules in the basal part of the cytoplasm, whereas the Golgi complex is supranuclear. In the pyloric mucosal zone most of the cells extend to the lumen in a pyramidal way, with tufts of microvilli at the apex; these probably act as receptor sites. Secreted peptides are demonstrated by radioimmunoassay of tissue extracts.

The following regulatory peptides appear to be among the more important in the present context.

Gastrin #

Edkins (1906) showed that an extract of pyloric mucosa administered intravenously stimulated secretion of gastric acid and pepsinogen; he suggested that the active principle was of hormonal origin and named it gastrin. It was soon apparent that this action was similar to that of histamine, and many authorities considered gastrin and histamine to be the same substance. As pointed out by Dockray (l978), nearly 60 years of uncertainty about the existence, nature and specificity of the antral hormone gastrin, and its relationship to histamine, followed. This was resolved when Gregory and Tracy (l96l, l964) isolated two related heptadecapeptides from hog antral mucosa, which proved to be gastrin. It was shown to occur in highest concentration in the pyloric mucosal zone, where its concentration was 500 times higher than in the corpus of the stomach (McGuigan l968).

Gastrin producing G cells originate from neuroectoderm together with other cells of the APUD series. They have a clear appearance, are piriform in shape and located in the mid and deep zones of the pyloric mucosal glands; electronmicroscopy shows that they possess microvilli extending into the lumen and that secretory granules are present in the basal parts of the cells. This organisation allows for secretion of hormone into the bloodsteam in response to luminal stimuli (Dockray l978). Normally there are approximately half a million G cells per cmª in the stomach in man, amounting to a total of approximately 10 million G cells (Mortensen l980).

Synthesis of gastrin I and II occurs predominantly in the G cells of the pyloric mucosal zone; less important sources are G cells in the duodenum, D cells in the islands of Langerhans in the pancreas, and isolated G cells in the proximal acid producing region of the fornix and body of the stomach. Some authorities hold that normally G cells do not occur in the oxyntic zone of the stomach; they may however, be present in pathological conditions (Stave and Brandtzaeg l976).

While G cells are interspersed among the more frequent mucus producing cells, the question arises whether their spatial distribution is equal to that of the pyloric mucosal zone; are G cells found throughout the pyloric mucosa, or are they confined to certain areas of this zone? Stave and Brandtzaeg (l976) pointed out that there were few quantitative data on the actual G cell mass of the stomach at that time; however, variations in the numbers of antral G cells had been reported in relation to pathological states. By means of immunohistochemical methods these authors attempted a systematic mapping of the numerical distribution of G cells in the human stomach and duodenum in specimens resected for peptic ulcer. In a small series (8 gastric ulcer cases and 8 cases of duodenal ulcer with uraemia), no G cells were found in the oxyntic zone of the stomach. A low number occurred in the transitional zone at the proximal border of the antrum (Comment: The term "antrum" was not defined, but appeared to be equated with the pyloric mucosal zone). In the gastric ulcer group no significant difference was found between the numbers of G cells at various levels of the "antrum"; in the cases of duodenal ulcer with uraemia there was a statistically significant increase in the number of G cells from the proximal to the distal part of the "antrum". The first part of the duodenum contained considerably fewer G cells than the "antrum", and the numbers in the duodenum were virtually equal in the two groups.

In a second and larger series of cases, Stave and Brandtzaeg (l978) determined the antral density, mucosal distribution and total mass of G cells in gastric resection specimens. The series of 42 cases consisted of 12 cases of gastric ulcer, 14 cases of duodenal ulcer with uremia, 11 cases of duodenal ulcer without uremia, and 5 cases of gastric carcinoma. Immuno-reactive G cells were not seen in the oxyntic zone of the stomach in any of the cases, and low numbers occurred in the transitional zone along the proximal border of the pyloric antrum. The first part of the duodenum contained only a fifth to an eighth of the number in the "distal antrum". (The distal antrum was now said to be the area extending proximally from the pylorus for a distance of 3.0cm). In the duodenal ulcer group, as well as in the group of duodenal ulcer with uraemia, and the gastric carcinoma group, the density of G cells increased from the proximal to the distal part of the antrum; in the group of gastric ulceration the overall density in various parts of the antrum remained the same. G cell density was found to be significantly lower along the lesser curvature and on the anterior and posterior walls than along the greater curvature. This held true in all patient groups excepting that of duodenal ulcer with uraemia. It was concluded that the densest concentration of G cells occurred in the terminal antrum, i.e. the distal 3.0cm of the stomach; that the G cell density was significantly higher along the greater than along the lesser curvature; that individual variations existed in the antral G cell density, the total G cell mass and the spatial distribution of G cells in the antrum; that a transitional zone, of varying width, occurred in all patients; and that the G cell density in the distal antrum was lower in patients with gastric ulceration than in the other patient categories.

A study by Royston et al. (l978) showed results similar to those of Stave and Brandtzaeg (l976, l978). The highest density of G cells was found in "antral" mucosal glands near the pylorus, the number gradually decreasing in an orad direction until the junctional zone between antrum and corpus was reached, where a marked decrease in numbers occurred. These authors found significant direct correlations between antral area and G cell density, between peak acid output and G cell population, and between basal plasma gastrin and G cell density.

G cells act in an endocrine rather than a paracrine or neurocrine way; being secreted into the bloodstream, circulating gastrin (consisting of different molecular types) produces its effects on distant target cells. It should therefore be looked upon as a hormone. There is evidence that some gastrin is also secreted into the lumen, but the physiological significance of this is not clear (Uvnäs-Wallensten l978). Gastrin or its synthetic analogues has a number of effects on the upper gastrointestinal tract, some of the most important being stimulation of hydrochloric acid, pepsinogen and intrinsic factor secretion by the stomach; stimulation of bicarbonate and enzyme secretion by the pancreas; increase in tone of the lower esophageal sphincter; increase in amplitude of smooth muscle contractions in the stomach and jejunum (Theron and Meyer l976); and trophic action on the fundic mucosa, pentagastrin inducing hypertrophy of the mucosa and increases in DNA, RNA and protein synthesis (Johnson and Guthrie l976; Dockray l978). Removal of the "antrum" leads to atrophy of the oxyntic glandular zone (Dockray l978).

Gastrin release is induced by vagal activity, mechanical distension of the stomach, certain food constituents, and is controlled by intra-antral pH (Uvnäs-Wallensten l978). Acidification of antral mucosa inhibits release of gastrin and is probably an important physiological mechanism for the control of gastrin secretion (Walsh and Grossman l975). The kidneys and small intestine catabolise gastrin (Dockray l978).

Hypergastrinaemia is produced by the following conditions: (1) gastrinomas, which generally arise in the pancreas, occasionally in the duodenum and only rarely in the "antrum" (Yalow and Berson l970; Gregory and Tracy l975; Dockray l978); (2) removal or disease of organs participating in the catabolism of gastrin, e.g. after loss of kidney function or after extensive small bowel resection (Dockray l978); (3) pernicious anaemia, in which the atrophic gastritis may spare the antrum and in which there is a tendency toward hyperplasia of G cells, resulting in serum gastrin concentrations which may be in the gastrinoma range (Yalow and Berson l970; Dockray l978). Achlorhydric and hypochlorhydric patients also tend to have high circulating gastrin concentrations due to diminished acid inhibition (Dockray l978); (4) increased secretion from antral G cells (Walsh and Grossman l975).

Somatostatin #

Krulich et al. (l968, l969) and Brazeau et al (l973) isolated a tetradecapeptide from ovine, and Schally et al (l976) from porcine hypothalamic tissue, which was shown to inhibit release of growth hormone (GH) from the pituitary gland. Later named somatostatin, it has subsequently been found to be widely distributed in the central nervous system (Brownstein et al. l975; Arimura et al. l978; Forssmann et al. l979), the gastrointestinal tract (Arimura et al. l975, l978) and other organs in experimental animals and man. Using radioimmunoassay the distribution in rat organs other than the central nervous system was determined (Arimura et al. l975, l978); it was shown that the pancreas had the highest concentration, namely 34ng/mg protein, followed by the stomach with a concentration of 12ng/mg. In the stomach the hormone was found in the pyloric and oxyntic mucosal zones but not in the cardiac zone. The total amount in either the pancreas or stomach was greater than in the hypothalamus; the duodenum, jejunum and ileum contained lesser amounts, ranging from 1.2 to 1.8ng/mg protein. Other organs such as the liver, spleen, kidneys and adrenals did not contain significant amounts.

Combined immunocytochemical and histological methods for demonstrating endocrine granules showed that somatostatin was present in D cells in the islet system of the pancreas (Polak et al. l975) and in morphologically similar D cells in the gastrointestinal tract (Polak et al. l976), localized predominantly in the midzone of the mucosal glands. According to Bloom and Polak (l978) the highest concentration of D cells occurs in the pancreas and pyloric mucosal zone, where the incidence is more than 31 cells per mm². In the remainder of the stomach and duodenum there are 11 to 30 cells per mm², and in the jejunum 1 to 10 cells per mm²; in the ileum and colon the number is zero.

Somatostatin not only suppresses the secretion of growth hormone, but possesses a wide variety of inhibitory actions on other pituitary and extra-pituitary secretions. It suppresses the release of thyroid-stimulating hormone by the pituitary, the release of glucagon, insulin and exocrine secretions by the pancreas, the secretion of cholecystokinin, motilin and secretin by the intestine, and the secretion of gastrin, gastric acid and pepsin by the stomach (Pearse et al. l977; Konturek et al. l978).

Experimental lowering of "antral" pH induces a release of somatostatin by D cells in the pyloric mucosal zone. It appears that somatostatin suppresses gastric acid secretion by direct action on the parietal cells of the cardiac and oxyntic mucosal zones (Arimura et al. l978). Lowering the pH also inhibits the secretion of gastrin; consequently low pH suppresses both gastric acid and gastrin secretion (Arimura et al. l978). Somatostatin is considered to be a potent vasoconstrictor of the intestinal circulation, and some of the inhibitory effects in the gastrointestinal tract may be the result of diminished mesenteric blood flow (Konturek et al. l978). It also suppresses motility of the intestine and contractions of the gall bladder and it possesses neurotrophic effects. The findings suggest that somatostatin not only serves as a hypophysiotrophic hormone, but also as a neurotransmitter (Vale et al. l977).

Somatostatinomas of the pancreas have been documented; patients had hypoglucagonaemia, hypoinsulinaemia and mild diabetes, with remission of hyperglycaemia after removal of the tumor (Ganda et al. l977; Larsson et al. l977).

Holle et al. (l985) determined the number of somatostatin-secreting D cells in the "antrum", pre- and post-operatively, in 20 patients with duodenal and 8 with gastric ulceration. In patients with a normal population of gastrin-immunoreactive G cells, the D cells were within the normal range. High G cell values were accompanied by high D cell values and low G cell values by low D cell values. The G cell to D cell ratio was 8:1 in duodenal, and 6.6:1 in gastric ulceration. Morphologic coupling of the gastrin- somatostatin system in the "antrum" was assumed; this was constant in ulcer disease both before and after vagotomy.

According to Holle et al. (l985) the almost exclusively inhibitory function of somatostatin, combined with the proximity to glucagon A and insulin B cells in the pancreas, as well as to parietal and gastrin G cells in the stomach, raises the question of a paracrine-like mechanism. However, in addition to the direct interaction of somatostatin D cells with neighbouring cells, adrenergic and cholinergic pathways also appear to exist.

Vasoactive Intestinal Peptide (VIP) #

Said and Mutt (l970) isolated a polypeptide with strong vascular effects from porcine small intestine. Termed vasoactive intestinal peptide (VIP), it was subsequently purified by Said and Mutt (l972). For some time VIP was considered to be a solely gastrointestinal hormone; later studies, however, demonstrated VIP in central and peripheral neurons, suggesting a neurotransmitter function (Larsson et al. l976). It is now known that VIP nerves have an ubiquitous occurrence in the body, being particularly numerous in the gastrointestinal, genito-urinary and respiratory tracts (Alumets et al. l978). In the peripheral autonomic system these nerves were shown to occur in various regions, including the superior and inferior mesenteric ganglia, and the submucous (Meissner's) and myenteric (Auerbach's) plexuses of the intestinal wall (Said l978).

Structures believed to exert a sphincteric function receive a particularly rich supply of VIP nerves, more so than the smooth muscle of adjacent regions. Among these are the oesophago-gastric junction, the pyloric "sphincter", sphincter of Oddi, internal anal sphincter, and the openings of the ureters and urethra into the trigonum of the bladder. The very rich supply of VIP nerves is a consistent finding in the smooth muscle of all recognized sphincters; it is thought that an evaluation of the density of VIP innervation may assist in anatomically defining a sphincter (Alumets et al. l978) (Chap. 2).

Using immuno-fluorescent techniques, Polak et al (l974) determined the cellular distribution of VIP in the mammalian (dog, pig and baboon) gastrointestinal tract, mucosal samples being taken from the gastric fornix, pyloric "antrum", duodenum, jejunum, ileum and colon. The distribution of cells was found to be wide; they were present in all regions examined, the highest number occurring in the colon in all three species. According to Bloom and Polak (l978) the highest concentration of VIP cells, more than 31 per mm², occurred in the colon. There were 11 to 30 cells per mm² in the duodenum, and in the stomach, including the pyloric mucosal zone, the concentration was 1 to 10 cells per mm². The relative numerical frequency of these cells in the different gastric mucosal zones was not determined in detail. Small numbers of cells occurred in the pancreas.

Walsh (l983) pointed out that while VIP was originally thought to be located in gastrointestinal endocrine-type cells, later data were consistent with a purely neural localization in the gut; VIP was also distributed throughout the brain and in peripheral nerves outside the gastrointestinal tract. In the stomach Ferri et al. (l984) found a dense VIP-containing nerve supply around oxyntic and pyloric mucosal glands. In the duodenum VIP (and substance P) were present in striking nerve networks in the villi and muscularis mucosae and around blood vessels. VIP was also immunostained in nerve bundles and neuronal perikarya between the lobules of Brunner's glands, while very few fibres reached the proximity of the acinar cells of these glands (Chap. 4).

The biological actions of VIP are numerous and include vasodilatation, lowered blood pressure, increased cardiac output, glycogenolysis and relaxation of smooth muscle (Piper et al. l970). VIP release from the gut was demonstrated upon electric stimulation of the vagus in pigs; significant inhibition of gastric secretion was associated with enhanced VIP release (Said l978). The physiological role of VIP, however, was uncertain (Said l978), but it appeared to be implicated in the following actions: it might serve as a neurotransmitter in the central nervous as well as the peripheral autonomic systems; its wide distribution in many tissues and the relatively constant plasma values suggested that it probably acted as a neurotransmitter in a paracrine, rather than in an endocrine, way (Modlin et al. l978). The VIP neurons have been shown to be under dual (both vagal and splanchnic) control of the autonomic system; release of VIP into venous effluent has been correlated with specific physiological mechanisms known to be mediated via non-cholinergic and non-adrenergic nerve fibres, and elicited by electrical stimulation of the vagus nerves (Fahrenkrug et al. l977). Vagal stimulation caused a frequency-dependent increase in the release of VIP; splanchnic stimulation caused a decrease in the release of VIP, an action which was annulled by alpha-adrenergic blockade. The inhibitory effect of splanchnic stimulation significantly diminished vagally induced VIP release. It was suggested that VIP functioned as the mediator of actions in the gastrointestinal tract known to be elicited via non-cholinergic, non- adrenergic vagal fibres (Fahrenkrug et al. l977).

VIP may participate in the regulation of gastrointestinal tone, motility and secretion (Said l978). It has been proposed as a possible neurotransmitter of inhibitory nerves of the gut (Fahrenkrug et al. l977, l978) and it appears likely that it is involved in sphincter relaxation (Alumets et al. l978). It is a strong candidate as a neurotransmitter responsible for relaxation of the lower oesophageal sphincter (Goyal et al. l980) and the internal anal sphincter in some vertebrates (Biancani et al. l985). It inhibits the amplitude of smooth muscle contractions of the gastric "antrum" in canines (Morgan et al. l978); its usual effect on gastrointestinal smooth muscle is relaxation (Walsh l983).

VIP appears to be an important mediator of paraneoplastic syndromes associated with islet-cell tumors of the pancreas, especially the watery diarrhoea hypokalaemia achlorhydria (WDHA or Verner-Morrison) syndrome. Although disputed by some authors, the findings of Welbourn et al (l978) left little doubt that a WDHA syndrome could occur in association with a pancreatic or certain neural tumors. Other tumors which may secrete large amounts of VIP or VIP-like peptides are neuroblastoma, ganglioneuroma, pheochromocytoma, medullary thyroid carcinoma and bronchogenic carcinoma (Said l978).

Substance P #

While studying the biological effects of extracts of intestinal wall on isolated jejunum preparations, Von Euler and Gaddum (l930) described contractions occurring as a result of a "novel" or unknown substance. Its effects were two fold: it lowered arterial pressure (presumably as a result of vasodilatation), and it caused contraction of smooth muscle in various organs. Fourty years later Chang and Leeman (l970) isolated and identified the unknown factor as an 11-amino-acid peptide called substance P. It was shown to be present in various tissues, including the central nervous system; particularly high concentrations occurred in the posterior horns of the spinal cord.

In the gastrointestinal tract, substance P containing nerve fibres and cell bodies are encountered along its entire length; they are least prominent in the oesophagus and upper part of the stomach (Polak and Bloom l98l). According to Walsh (l983) the highest concentrations occur in the duodenum. Substance P neuronal cell bodies are mainly located in the myenteric plexuses; their nerve fibres richly innervate the circular musculature, whereas the longitudinal muscle contains only a sparse network of fibres. Substance P nerve fibres are also in close contact with the blood vessels (Polak and Bloom l98l).

In the human gastric mucosa Ferri et al. (l984) demonstrated substance P immunoreactivity in the oxyntic zone in a few, thin fibres only. Fibres containing this peptide were more numerous and interconnecting in the "antrum" 3.0cm above the pyloric aperture. In the duodenum substance P (and VIP) were present in striking nerve networks in the villi as well as in the muscularis mucosae and around blood vessels. The peptide was also immunostained in nerve fibres in the submucosa, in neuronal perikarya between the lobules of Brunner's glands and in Meissner's plexus.

Substance P has been found to cause contraction of the muscularis mucosae; it is also a well-known vasodilator (Ferri et al. l984).

Enkephalin #

Hughes et al (l975) isolated two endogenous opiate-like compounds from pig brain. The two pentapeptides, endorphin and enkephalin, were subsequently demonstrated in other mammalian species (Polak et al. l977).

The distribution of endorphins and enkephalins in man was studied by a combination of immunocytochemistry and radioimmunoassay (Polak et al l977, l978). Endorphin immuno-reactivity was found to be confined to the intermediate and anterior lobes of the pituitary. Enkephalins on the other hand, were found to have a much wider distribution, being present in many areas of the central nervous sytem, spinal cord and peripheral nerves and being widely distributed in the gastrointestinal tract (Polak et al. l977; Skov Olsen et al. l98l). It was of interest that enkephalins were absent from the pituitary.

In the gastrointestinal tract enkephalin was found in most areas, the highest concentration being in the "antrum" (i.e. the pyloric mucosal zone) with lesser amounts in the duodenum and jejunum and even less in the colon; it was not present in the gastric fornix. The "antrum" contained 31 to 103 ng/gm wet weight, the duodenum l7 to 93 ng/gm, and the colon 6 to 15 ng/gm; the gall bladder and pancreas contained smaller amounts (Polak et al. l977, l978). Distribution of enkephalin cells closely paralleled the localization as determined by radioimmunoassay. According to Polak et al (l977) enkephalin was found in endocrine cells of the "antrum" and duodenum similar to G cells; it was presumed that the peptide could be stored either within gastrin containing granules or in different granules, as several granule types might occur in the same cell. However, the exact intracellular localization of these peptides was not clear; according to Skov Olsen (l98l) enkephalins were localized to specific endocrine-paracrine cells (other than G cells) of the APUD series, as well as to nerve fibres of the myenteric plexuses.

In the human gastric mucosa Ferri et al (l984) found metenkephalin immunoreactivity in a few scattered nerve bundles in the basal parts of the mucosa and in the muscularis mucosae. Enkephalins were rapidly degraded by blood and were unlikely to have a hormonal function; a paracrine function was more probable (Skov Olsen l98l).

The localization of enkephalins in neural tissue parallels that of opiate receptor sites (Polak et al. l978). Both are found in high concentrations in areas associated with sensory input of pain signals; the small molecular size and short half-life of this peptide suggest a neurotransmittive function. The pharmacology of morphia probably provides the best clue as to the role of enkephalins. Morphia acts by increasing muscle tone, delaying gastric emptying and slowing intestinal transit. In the gastrointestinal tract enkephalins may act in a similar manner; gastrointestinal enkephalins may aid in the control of intestinal motility, whereas brain enkephalins are thought to be involved in pain tolerance.

Konturek et al. (l978, l980) determined the effects of enkephalin on the gastrointestinal tract in canines. The results showed that enkephalin mimicked most of the motor effects of opiates; following administration there was a decrease in the rate, but increase in the amplitude of gastric contractions, with a delay in gastric emptying. In the small bowel enkephalin caused a marked reduction in postprandial spike potential activity, and conversion of the fed pattern of activity to a fasting pattern. Intra-arterial enkephalin and morphia increased intraluminal pressure values dose dependently, and decreased mesenteric vascular resistance.

Galanin #

Bishop et al (l986) showed that galanin immunoreactivity was localized exclusively to neuronal elements in the walls of the gastrointestinal tract in the rat, pig and man, and that it occurred at all levels of the tract. Galanin immunoreactive neuronal cells were noted in the submucous plexuses and immunoreactive nerves were present in all layers of the wall, with the possible exception of the mucosa; most fibres were located in the muscle layers. In the human stomach galanin immunoreactive nerves were equally numerous in the "antrum" and fornix. Preliminary pharmacological experiments showed that galanin caused smooth muscle contractions in the rat intestine and induced mild hyperglycaemia (Bishop et al. l986); it appeared to act as a regulatory factor in the control of gastrointestinal motility.

A close relationship existed between galanin and VIP immunoreactivity, both peptides occurring in the same ganglion cells of the submucous plexuses. The distribution of galanin and VIP immunoreactive nerves in the walls of the gastrointestinal tract was also similar, with the following exceptions: galanin fibres were infrequent in the mucosal layer as compared with VIP fibres, which formed dense mucosal plexuses; and galanin nerves did not appear to be associated with the vascular system of the gastrointestinal tract. (Bishop et al. 1986).

Neurotensin #

According to Buchan et al. (l977) the neurotensin secreting N cell is a typical endocrine cell with a connection to the lumen via microvilli and electron dense secretory granules grouped at the basement membrane. Radioimmunoassay and immunocytochemistry of fresh surgical and endoscopic samples showed that the highest concentration of neurotensin occurs in ileal mucosa, with significant amounts in the jejunum and only traces in the pyloric mucosal zone and duodenum. The concentration of neurotensin in plasma rises after a meal, but its function is still unclear. In the belief that it is a modulator of secretory and motor functions of the stomach, Blackburn et al (l980) infused it intravenously into healthy volunteers at a dose of 2.4 pmol/kg/min, designed to mimic postprandial levels. It was found that neurotensin caused significant inhibition of pentagastrin stimulated gastric acid and pepsin secretion. It also caused significant delay in gastric emptying, making it one more candidate for the hormone postulated to be released from the small intestine and to cause a feedback delay in gastric emptying.

Discussion #

Although individual variations in the distribution of APUD cells in the gastrointestinal tract exist, it is generally agreed that the highest density of gastrin producing G cells occurs in the distal 3.0cm of the stomach, i.e. in that part of the pyloric mucosal zone which lines the sphincteric cylinder. The number gradually decreases in an orad direction until the junctional zone between pyloric and oxyntic mucosa is reached, where a marked decrease in numbers occurs. The first part of the duodenum contains a fifth to an eighth of the number of G cells in the distal stomach. The physiological effects of gastrins, and the sequelae of overproduction in gastrinomas, are well known and need no recapitulation. In a small series of cases of gastric carcinoma Stave and Brandtzaeg (l978) found that the density of G cells increased from the proximal to the distal part of the "antrum", as in normal subjects. In acid corrosive injury to the gastric mucosa damage of G cells may produce histamine-fast achlorhydria, occurring as part of a delayed gastric syndrome (Chap. 39).

In the stomach somatostatin occurs mainly in the pyloric and oxyntic, and not in the cardiac mucosal zones.

Vasoactive intestinal peptide has a predominantly neural localization in the gastrointestinal tract. A dense VIP containing nerve supply occurs around glands in the pyloric and oxyntic mucosal zones; in the duodenum VIP is encountered in neuronal elements between the lobules of Brunner's glands. A particularly rich supply of VIP nerves occurs in structures believed to exert a sphincteric function, a factor which may assist in anatomically defining a sphincter. To the best of our knowledge this finding has not yet been utilized to determine the exact roles of the pyloric ring and pyloric sphincteric cylinder in the mechanism at the pylorus.

Substance P-containing nerve fibres in the gastrointestinal tract occur in highest density in the duodenal villi, muscularis mucosae, blood vessels, Meissner's plexuses and between the lobules of Brunner's glands. In the stomach these fibres have been found to be numerous and interconnecting in the "antrum" 3.0 cm proximal to the pyloric aperture. This is the region of the left pyloric loop in man; whether the occurrence is of any significance in relation to the sphincteric cylinder is not known. Substance P fibres are much less prominent in the upper part of the stomach.

In the gastrointestinal tract enkephalin occurs in highest concentration in the pyloric mucosal zone. Like morphia it causes a decrease in rate, but increase in amplitude of gastric contractions, with delay in emptying. Its effect on cyclical contractions of the sphincteric cylinder has not been determined; it is surmized that it will be of a similar nature.

Galanin immunoreactive fibres are equally numerous in the "antrum" and fornix; the peptide causes smooth muscle contractions and appears to act as a regulatory factor in motility.

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