Adrenergic effects on secretion of epidermal growth factor from Brunner's glands.

The influence of the sympathetic nervous system and adrenergic agonists on flow rate and secretion of epidermal growth factor (EGF) from Brunner's glands has been investigated in the rat. Chemical sympathectomy by administration of 6-hydroxydopamine increased volume secretion and output of EGF from Brunner's glands but depleted the glands of EGF. Infusion of noradrenaline, an alpha-adrenergic agonist, inhibited basal and vasoactive intestinal polypeptide (VIP) stimulated flow rate and output of EGF from Brunner's glands and increased the amount of EGF in the tissue. Vasoactive intestinal polypeptide also increased the amount of EGF in Brunner's gland tissue and this was unchanged after simultaneous infusion of VIP and noradrenaline as well as VIP and isoproterenol, a beta-adrenergic agonist. Isoproterenol had no effect on basal and VIP stimulated secretion of EGF from Brunner's glands. The presence of PAS-positive mucus in Brunner's glands was unchanged during infusion of noradrenaline whereas VIP induced a depletion of Brunner's gland mucus which in turn was prevented by simultaneous infusion of noradrenaline. This study indicates that the sympathetic nervous system influence the volume secretion, output of EGF and mucus content in Brunner's glands probably by activation of alpha-adrenergic pathways.     

Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner''s glands

The effect of VIP and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands was investigated in the rat. Vasoactive intestinal polypeptide infused in doses of 10 and 100 ng/kg/h significantly increased epidermal growth factor and bicarbonate output, but the concentrations did not change. Somatostatin infused at doses of 1, 10, 100 and 1000 ng/kg/h against a background of VIP 100 ng/kg/h inhibited in dose-dependent fashion the stimulated epidermal growth factor and bicarbonate outputs from rat Brunner's gland pouches. Also basal secretion was inhibited by somatostatin. Infusion of antisomatostatin serum stimulated Brunner's gland secretion. By immunohistochemical studies of rat duodena, it was found that epidermal growth factor, is almost exclusively present in the secretory cells of Brunner's glands. It is concluded that VIP stimulates secretion of epidermal growth factor and bicarbonate from Brunner's glands, an effect which is inhibited by somatostatin. A possible role for somatostatin in the control of Brunner's gland secretion is suggested.     

Immunocytochemical study of peptidergic structures in Brunner's glands

Nervous and endocrine peptidergic structures in human Brunner's glands were studied by immunofluorescence. Endocrine cells storing immunoreactive components respectively similar to somatostatin 14, the amino-terminal portion (1-14) of somatostatin 28, gastrin-cholecystokinin, and peptide YY were distributed throughout the acini. Peptidergic nerve structures contained materials immunologically related to vasoactive intestinal peptide, peptide histidine methionine, substance P, neuropeptide Y, and gastrin-releasing peptide. The latter peptide was detected in discrete fibers running into the acini but within no cell body in the submucosa. All other neuropeptides were stored in fibers, isolated or grouped in bundles, and in perikarya of submucosal ganglia close to the acini. No immunoreactive structures were detected using antisera directed against pancreatic polypeptide, secretin, motilin, neurotensin, or calcitonin gene-related peptide. The results suggest that several regulatory peptides may be involved in the control of Brunner's glands in humans.     

Vasoactive intestinal polypeptide gene expression in the developing human gastrointestinal tract.

Expression of vasoactive intestinal polypeptide has been shown, by immunocytochemistry and biochemical assay, to follow the craniocaudal neural colonization of the mammalian gut. The aim of this study was to use in situ hybridization to see if it could provide more information on vasoactive intestinal polypeptide gene expression in the developing human gut. Immunocytochemistry of vasoactive intestinal polypeptide and, to visualize the total innervation, protein gene product 9.5 was also applied. By 8 weeks of gestation, protein gene product 9.5-immunoreactive neurons had colonized the gut lengthwise (17% of intestinal muscle area) but not transversely. Vasoactive intestinal polypeptide immunoreactivity was first detected at 9 weeks of gestation in a few nerve fibers of the upper gut, the origin of which could not be determined. Vasoactive intestinal polypeptide-immunoreactive ganglion cells were not seen until 18 weeks of gestation, whereas in situ hybridization showed messenger RNA in ganglion cells of the upper gut at 9 weeks. An adultlike pattern of peptide gene products (e.g., 2.5% and 3.1% of intestinal mucosal or muscle area, respectively) was detected by 20 weeks' gestation. The finding that the vasoactive intestinal polypeptide gene is expressed first in the upper human gut is consistent with craniocaudal neuronal colonization and maturation.     

Ultrastructural localization of four different neuropeptides within separate populations of p-type nerves in the guinea pig colon

The ultrastructural localization of four neuropeptides, substance P, vasoactive intestinal polypeptide, Met-enkephalin, and somatostatin, in the guinea pig colon was investigated using electron immunocytochemistry. Each peptide was localized to the large granular vesicles in separate subpopulations of p-type nerves. These nerves could often be distinguished by the size and appearance of their immunostained granular vesicle cores. Thus, vasoactive intestinal polypeptide- and somatostatin-immunoreactive vesicles contained cores that were significantly larger (p less than 0.005) than those of substance P- or Met-enkephalin-positive vesicles. In addition, vasoactive intestinal polypeptide-immunoreactive vesicle cores were less well defined and more variable in shape than those of somatostatin-positive vesicles. Substance P- and Met-enkephalin-immunoreactive vesicle cores, however, were very similar in size (p greater than 0.05) and appearance and could only be differentiated using immunocytochemistry. This study demonstrates that the four neuropeptides under investigation are present within separate, often ultrastructurally distinct, neuronal systems in the gut. The distribution of these nerves within the colon is also described.     

Peptide-containing neurons in different regions of the submucous plexus of human sigmoid colon.

Specimens of the sigmoid colon were obtained from male and female patients (n = 11) with carcinoma of the colon or rectum and studied immunohistochemically for vasoactive intestinal polypeptide-, somatostatin-, substance P-, neuropeptide Y-, calcitonin gene-related peptide-, met- and leu-enkephalin-, 5-hydroxytryptamine-, and dopamine beta-hydroxylase-containing nerves. In the subdivisions of the submucous plexus (namely, Schabadasch's, Meissner's, and the intermediate plexuses), substance P- and vasoactive intestinal polypeptide-immunoreactive nerve fibers were the most numerous, and equal densities of these nerves were found in all three layers. In contrast, few neuropeptide Y-, met-enkephalin-, leu-enkephalin-, calcitonin gene-related peptide-, somatostatin-, 5-hydroxytryptamine-, and dopamine beta-hydroxylase-immunoreactive nerves were found in these regions. The nerve cell bodies of the submucous plexus contained vasoactive intestinal polypeptide, substance P, leu-enkephalin, somatostatin, and 5-hydroxytryptamine but not neuropeptide Y, met-enkephalin, calcitonin gene-related peptide, and dopamine beta-hydroxylase. Vasoactive intestinal polypeptide-containing nerve cell bodies were found in all three subdivisions. Substance P-, leu-enkephalin-, and somatostatin-immunoreactive nerve cell bodies were found in Schabadasch's plexus and the intermediate region of the submucous plexus, but they were absent from Meissner's plexus; 5-hydroxytryptamine-containing nerve cell bodies were only observed in Schabadasch's plexus. The possible function of the neuropeptide-, dopamine beta-hydroxylase-, and 5-hydroxytryptamine-containing neurons in the different layers of the submucous plexus is discussed.     

Lack of release of vasoactive intestinal polypeptide and calcitonin gene-related peptide during electrical stimulation of enteric nerves in streptozotocin-diabetic rats

The simultaneous release of endogenous acetylcholine, serotonin, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide was measured during electrical field stimulation of isolated preparations of rat ileum from control and 8-wk streptozotocin-treated diabetic rats. Electrical field stimulation of the control rat ileum caused a significant increase in the release of all the above substances from the enteric nerves. The electrically evoked, but not the basal, release of these substances was inhibited by tetrodotoxin. In the diabetic rat ileum, however, there was no increase in the release of vasoactive intestinal polypeptide and calcitonin gene-related peptide during electrical stimulation, whereas endogenous release of acetylcholine, serotonin, and substance P was unaffected by the diabetic state. This was surprising in view of the increased fluorescence intensity and tissue content of vasoactive intestinal polypeptide-like immunoreactivity in the same tissue reported previously. The lack of increase in evoked release of vasoactive intestinal polypeptide in the diabetic preparations might be due to an impaired mechanism of release at the terminal site or to defective axonal transport of the peptide, whereas in the case of calcitonin gene-related peptide, it might be the result of the low level of the peptide present in the enteric nerve fibers of the diabetic rat ileum. The differential effect of diabetes on enteric nerves is discussed.     

Watery diarrhea syndrome due to an adrenal pheochromocytoma secreting vasoactive intestinal polypeptide

Summary A 55-year-old woman presented with several protracted episodes of diarrhea; it was found to be secretory in origin. In the course of evaluating the diarrhea, an ultrasound of the abdomen was performed which disclosed a large right adrenal mass. Endocrinologic studies revealed elevated serum levels of gastrin, vasoactive intestinal polypeptide (VIP), catecholamines, and its metabolites. Surgery was performed successfully without any intraoperative complications, and postoperatively the patient was asymptomatic without further episodes of diarrhea. Histologically the tumor was a pheochromocytoma with neuroendocrine granules of vasoactive intestinal polypeptide and norepinephrine. To our knowledge, there have been six previously reported cases of pheochromocytoma secreting vasoactive intestinal polypeptide. In a patient with secretory diarrhea of unknown etiology, the adrenal glands as well as the pancreas should be examined by ultrasound and/or computerized tomography for the presence of a mass. Should an adrenal mass be disovered, it is necessary to evaluate the tumor for catecholamine production, despite the absence of clinical symptoms of a pheochromocytoma.     

Galanin inhibition of vasoactive intestinal polypeptide release and circular muscle motility in the isolated perfused canine ileum.

The role of porcine galanin, infused arterially into isolated perfused canine ileal segments, in modulating the tonically elevated neural release of vasoactive intestinal polypeptide and possible concomitant motor actions dependent on vasoactive intestinal polypeptide modulation was studied. Galanin infusions (9-minute) inhibited vasoactive intestinal polypeptide release in a concentration-dependent manner (maximum during minutes 8-10) irrespective of the absence (quiescence) or presence of phasic circular muscle contractions induced by local electrical field stimulation of nerves. During quiescence, galanin induced phasic contractions in four of five segments beginning in the 8th minute of the infusion. During stimulated contractions, galanin inhibited phasic motor activity within 2 minutes of initiation of the infusion; this inhibition may result from direct smooth previously reported muscle inhibition. Thus galanin may inhibit both neural release of vasoactive intestinal polypeptide and circular muscle motility directly. The delayed period of phasic activity initiated by galanin during quiescence may be related to inhibition of vasoactive intestinal polypeptide release, freeing the muscle from tonic inhibition by vasoactive intestinal polypeptide. Because galanin and vasoactive intestinal polypeptide are colocalized in some enteric nerves, galanin may regulate vasoactive intestinal polypeptide release by negative feedback.     

Altered inhibitory innervation of circular smooth muscle in Crohn's colitis. Association with decreased vasoactive intestinal polypeptide levels

To determine whether decreased tissue vasoactive intestinal polypeptide levels might affect inhibitory neural input, fresh colonic specimens were obtained from patients with Crohn's colitis (n = 7) and normal subjects (n = 13). Immunoreactive vasoactive intestinal polypeptide levels were measured in the muscularis externa by radioimmunoassay and localized in tissue sections by immunostaining. Circular muscle strips were maintained in an organ bath; inhibitory junction potentials evoked by short- and long-duration field stimulation and resting membrane potentials were recorded using intracellular impalements. In Crohn's colitis, vasoactive intestinal polypeptide levels displayed a bimodal distribution in which 3 specimens had vasoactive intestinal polypeptide levels greater than or equal to 4 SE lower than the mean in normal specimens. In 3 specimens from Crohn's colitis with decreased vasoactive intestinal polypeptide levels, immunoreactive material was absent from the circular muscle layer and the myenteric plexus. Mean resting membrane potentials, mean amplitude of inhibitory junction potentials evoked by short-duration stimulation, and mean amplitude of initial inhibitory junction potentials evoked by long-duration stimulation were not different between the two groups. However, the mean amplitude of the 60th inhibitory junction potential during prolonged stimulation was decreased (p less than 0.01) in Crohn's colitis (6 mV) compared with normal specimens (11 mV). These results show that diminished neural input to circular muscle in Crohn's colitis was associated with decreased extractable vasoactive intestinal polypeptide levels and decreased staining of nerve fibers containing vasoactive intestinal polypeptide.     

Vasoactive intestinal polypeptide in brain: localization in and release from isolated nerve terminals.

The vasoactive intestinal polypeptide was present in synaptosomal (nerve ending) preparations from cerebral cortex, hypothalamus, and striatum of rat brain in higher concentrations than in these tissues as a whole. The total content and relative specific activity of the peptide increased with progressive purification of the synaptosomal fractions and generally followed the distribution of known synaptosomal constituents--dopamine, norepinephrine, and lactate dehydrogenase (L-lactate:NAD+ oxidoreductase, EC 1.1.1.27). The peptide was also released from synaptosomal pellets with increased K+ concentration, and this release was Ca2+-dependent. The findings suggest a role for vasoactive intestinal polypeptide as a transmitter or modulator of synaptic function.     

Effect of secretin and glucagon on Brunner''s gland secretion in the rat

Brunner's gland secretion in response to infusion of secretin and glucagon was studied in the rat. Secretin was infused in doses of 15, 150 and 1500 ng/kg/h. All dose significantly increased bicarbonate and protein output and depleted Brunner's glands of PAS-positive mucin. Bicarbonate secretion was related to plasma secretin concentration, and a marked stimulatory effect of secretin was found in very low, probably physiological, plasma concentrations. Maximal bicarbonate output was obtained at a plasma concentration of secretin about 20 pmol/l. Glucagon was infused at a rate of 1.0 micrograms/kg/h and did not influence secretion rate or cell morphology. Also large doses of 5.0 and 50.0 micrograms/kg/h had no effect on Brunner's gland secretion. It is concluded that secretin in very low plasma concentrations stimulates secretion of bicarbonate, protein and mucus from Brunner's glands in the rat, while glucagon has no effect, and it is suggested that secretin may be involved in the physiological regulation of Brunner's gland secretion.     

Nodular hyperplasia of Brunner''s glands

A clinical, endoscopic, and histological study of 206 cases of nodular hyperplasia of Brunner's glands was carried out. Firm nodules with a reddened surface due to hyperplastic Brunner's glands were limited mainly to the first part of the duodenum and affected almost exclusively male patients. Gastric acid secretion after pentagastrin stimulation was significantly increased compared to normal. In most cases, biopsies of the nodule center revealed spreading of Brunner's glands from within the lamina propria to the surface epithelium, whereas in biopsies performed between nodules, Brunner's glands were limited to the deeper part of the mucosa. Thirty-six nodules completely removed by diathermy were composed almost entirely of Brunner's glands. The frequent association with duodenal ulcer, chronic gastric erosions, and cobblestone pattern of the gastric body mucosa, as well as the significant hypersecretory state, suggest that hyperacidity plays a role in the pathogenesis of nodular hyperplasia of Brunner's glands.     

Neuropeptides in the thyroid gland: distribution of substance P and gastrin/cholecystokinin and their effects on the secretion of iodothyronine and calcitonin

Previously, vasoactive intestinal polypeptide was localized to intrathyroidal nerve fibers. It stimulates iodothyronine secretion in mice. In the present study two populations of nerve fibers containing substance P and gastrin/cholecystokinin (CCK)-like immunoreactivity, respectively, were demonstrated in the thyroid gland of several mammals. The substance P fibers occurred around blood vessels and follicles, whereas the gastrin/CCK fibers occurred mainly around follicles. In the chicken thyroid and ultimobranchial glands only substance P-containing fibers could be demonstrated. Such fibers were particularly numerous in the ultimobranchial gland. CCK-4, CCK-8, and substance P did not increase thyronine secretion measured as release of radioiodine into the circulation of mice pretreated with Na125I and T4. The TSH-induced release of radioiodine was also unaffected. Calcitonin secretion in rats was stimulated by CCK-4, CCK-8, substance P, and vasoactive intestinal polypeptide.     

Effects of vasoactive intestinal polypeptide, TRH, and dopamine on prolactin secretion in estrogen-primed postmenopausal women

Prolactin secretion is influenced by at least three important hypothalamic neurotransmitters: TRH, vasoactive intestinal polypeptide and dopamine. The purpose of this study was to determine whether, in estradiol-primed postmenopausal women, the PRL response to TRH, vasoactive intestinal polypeptide, and dopamine differed. Ten postmenopausal women were studied during treatment with estradiol benzoate at a dose of 0.625 mg per day during 15 days. TRH (200 micrograms iv), saline infusion, vasoactive intestinal polypeptide (75 micrograms infused iv during 15 min), coadministration of vasoactive intestinal polypeptide and TRH, and dopamine (4 micrograms.kg-1.min-1 iv for 3 h) were administered for 5 consecutive days before and during the last 5 days of estradiol benzoate treatment. Before estradiol benzoate administration, the PRL, response to TRH was significantly greater than that of vasoactive intestinal polypeptide. Estradiol benzoate treatment increased significantly the PRL release induced by TRH (p less than 0.01), but did not modify the response to vasoactive intestinal polypeptide. At the end of estradiol benzoate treatment, the maximal increase in PRL after the combined (vasoactive intestinal polypeptide + TRH) test was greater than that obtained with TRH alone and occurred earlier (p less than 0.04). Dopamine suppressed PRL secretion to a similar extent after estradiol benzoate treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolactin responses to vasoactive intestinal polypeptide and thyrotropin releasing hormone in chronic renal failure.

Prolactin response to iv bolus injection of 1 micrograms/kg vasoactive intestinal polypeptide was determined in 8 patients with chronic renal failure undergoing chronic hemodialysis and in 8 normal controls, age- and sex-matched. Plasma prolactin in the patients showed a blunted response following vasoactive intestinal polypeptide injection, whereas the controls showed significantly higher mean peak prolactin value over the baseline value (p less than 0.002). The net rise (peak levels minus basal levels) in plasma prolactin and area under the curve after vasoactive active intestinal polypeptide injection in the controls were significantly greater than those in the patients (p less than 0.001). On a separate day, each individual underwent a TRH (500 micrograms) challenge with the prolactin response determined. The patients had significantly higher peak prolactin values over baseline levels (p less than 0.02) which, however, were not significantly different from those in the control group. In the patients, the peak net prolactin increments and area under the curve were significantly higher following TRH than following vasoactive intestinal polypeptide (p less than 0.05). The net prolactin increments to TRH challenge were significantly higher in the control group than in the patients (p less than 0.001). The results demonstrate the blunted prolactin response to the stimulatory effect of vasoactive intestinal polypeptide and TRH in chronic renal failure. In chronic renal failure prolactin release after vasoactive intestinal polypeptide is more blunted than after TRH. These data suggest that the responsiveness of plasma prolactin to vasoactive intestinal polypeptide is defective in these patients, though the mechanism(s) are yet to be defined.     

Effects of substance P and vasoactive intestinal polypeptide on contractile activity and epithelial transport in the ferret jejunum.

Previous studies in the ferret demonstrated that vagal nerve stimulation induced an atropine-resistant water secretion. Substance P and vasoactive intestinal polypeptide are possible mediators of this secretory response. The objectives of this study were to investigate the in vivo effects of substance P and vasoactive intestinal polypeptide on the jejunal musculature and epithelium. Substance P caused an increase in jejunal motility, water secretion, and transmural potential difference. Cholinergic blockade did not affect the substance P-induced contractions, but did reduce the increase in transmural potential difference, suggesting an inhibition of water secretion. Vasoactive intestinal polypeptide abolished motor activity; however, it induced an increase in transmural potential difference that was atropine and tetrodotoxin resistant. By immunohistochemical methods, immunoreactive vasoactive intestinal polypeptide and immunoreactive substance P were localized to both nerve cell bodies and nerve fibers in the ferret intestine. Determination of intestinal concentrations of vasoactive intestinal polypeptide and substance P in the ferret showed concentrations of these two neuropeptides that were similar to those in human intestine and demonstrated much higher concentrations of these substances in the muscular layer than in the epithelial layer. Our data demonstrate that in the ferret substance P excites and vasoactive intestinal polypeptide inhibits jejunal motor activity. However, both peptides increase water secretion. Our results suggest that in response to vagal stimulation, neuronally released substance P or vasoactive intestinal polypeptide may participate in the atropine-resistant water secretion.     

Vasoactive intestinal polypeptide stimulates parathyroid hormone release by interaction with cyclic adenosine monophosphate production of bovine parathyroid cells.

Influence of vasoactive intestinal polypeptide, neuropeptide Y, calcitonin gene-related peptide, and substance P was investigated on dispersed parathyroid cells of adult cattle. At a physiological concentration of extracellular calcium, vasoactive intestinal polypeptide stimulated the parathyroid hormone release in a dose-dependent manner, whereas no effects were noted for the other peptides. The dependency of PTH secretion upon extracellular calcium was shifted to the right by vasoactive intestinal polypeptide at 10(-6) mol/l, with a tendency for greater effects at low (0.5 mmol/l) than high concentrations (2.0-3.0 mmol/l) of the cation. Vasoactive intestinal polypeptide significantly enhanced cAMP release of the parathyroid cells, whereas no influence was noted on cytoplasmic calcium or pH within the cells. The results suggest that vasoactive intestinal polypeptide stimulates the PTH release by interaction with cAMP production of the parathyroid cells. This effect may contribute to the development of hypercalcemia in patients with neuroendocrine tumours secreting vasoactive intestinal polypeptide.     

Thickness of Brunner's glands and its clinical significance in peptic ulcer diseases

The thickness of Brunner's glands was measured using an ocular micrometer in 297 cases of surgically resected peptic ulcer and in 120 autopsy cases (control group). The mean maximum thickness of Brunner's glands in the control group was 1.55 +/- 0.37mm (mean +/- SD) and no difference in thickness was noted for each decade of age. The mean maximum thickness of Brunner's glands in patients with gastric ulcer, duodenal ulcer and gastroduodenal ulcer was 2.34 +/- 1.06, 3.18 +/- 1.07 and 3.24 +/- 1.05mm, respectively. When an ulcer is within the duodenum, Brunner's glands near the ulcer were thicker than those contralateral to it. In patients with gastric ulcer, Brunner's glands were the thickest in the pyloric ulcer group and negative correlation was noted between the thickness of Brunner's glands and the distance to the ulcer from the pyloric ring. Since gastric acidity is supposed to be lower when an ulcer is located more proximally, these results suggest that Brunner's glands become hyperplastic not only with the presence of an ulcer in the duodenum but also by acid hypersecretion of the stomach.     

Gastrointestinal bleeding after endoscopic treatment of polypoid hamartoma (adenoma of Brunner's glands)

The incidence of polypoidal tumors in the duodenum is scarce and Brunner's gland tumors represent 11% of these proliferations. Brunner's gland polypoid hamartoma or adenoma is a highly infrequent benign polypoid proliferation of Brunner's glands that is usually asymptomatic, although gastrointestinal bleeding or intestinal obstruction may sometimes occur. We present the case of a woman with an incidental diagnosis of duodenal polypoid hamartoma. The lesion was resected with polypectomy loop and at 48 h, the patient presented gastrointestinal bleeding as a complication. We describe the endoscopic treatment of the lesion and this complication.