CGRP immunoreactivity in the mammalian pancreas.
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Animals↗
Biomedical subjects
V L Go
Publications and source records attributed to V L Go.
Species differences in the immunoreactive patterns of calcitonin gene-related peptide in the pancreas.
In the pancreas, calcitonin gene-related peptide (CGRP) immunoreactivity has been described in nerve fibers and in distinct types of islet cells. This unique, apparently species-specific cell-type expression prompted the present investigation to clarify further the pattern of CGRP immunoreactivity in different mammalian species (i.e., different strains of rats, mice, guinea pigs, rabbits, cats, dogs, pigs, and humans) commonly used for functional and anatomical studies of the pancreas by means of immunohistochemistry using three different CGRP antibodies. In each species, CGRP-immunoreactive neurites innervate the exocrine and endocrine compartments, the vasculature, and the intrapancreatic ganglia, where they form dense networks encircling unstained cell bodies. The only exception is the pig pancreas, where the islets appear to be devoid of immunoreactive fibers. The overall density of immunoreactive pancreatic axons in different species is as follows: rat, mouse, and rabbit greater than guinea pig greater than or equal to pig and cat much greater than dog and human. CGRP-immunoreactive endocrine cells appear to be restricted to the rat pancreas, where they form a subpopulation of somatostatin-containing D cells. In contrast, in mouse, guinea pig, cat, dog, and human pancreas, a homogeneous staining of the core of the islets, where insulin-producing B cells are located, was visualized in sections incubated with the rabbit CGRP antiserum at 4 degrees C, but not at 37 degrees C (an incubation temperature that does not affect the islet cell staining in the rat nor the fiber labeling in any species). Furthermore, the staining of islet B cells was not reproducible with all the CGRP antibodies used, all of which comparably stain nerve fibers in each species, and islet D cells in the rat. Immunoreactive islet cells were not visualized in pig and rabbit pancreas. These results are consistent with the hypothesis that the expression of CGRP in nerve fibers is a common feature of mammalian pancreas, whereas its expression in endocrine cells appears to be restricted to the D cells of the rat pancreas.
Animals↗
Adrenergic modulation of interdigestive pancreatic secretion in humans.
Whether the adrenergic pathways participate in the control of interdigestive pancreatic function in humans is uncertain. To determine if changes in alpha- or beta-adrenergic tone modulate interdigestive pancreatic enzyme output, 16 healthy subjects were intubated with an orojejunal tube to collect and quantify pancreatic trypsin secretion and record motility. After observation of a complete interdigestive cycle (control period), eight groups of two subjects each received 2-hour intravenous infusions of the alpha- and beta-agonist epinephrine (50 ng.kg-1.min-1), the alpha-antagonist phentolamine (5 mg/2 min followed by 500 micrograms/min), the beta-antagonist propranolol (5 mg/2 min followed by 80 micrograms/min), or saline as control, alone or in combination. Drugs were assigned in a random mode according to a 2(3) factorial design. Analysis of variance showed that epinephrine decreased trypsin output by 43% (P less than 0.05). By contrast, trypsin output was increased fourfold in the presence of phentolamine (P less than 0.01), whereas propranolol had no effect. These data suggest that an inhibitory alpha-adrenergic tone modulates human interdigestive pancreatic enzyme secretion whereas beta inputs are less important.
Adrenergic Fibers↗
Patterns of innervation of vasoactive intestinal polypeptide, neuropeptide Y, and gastrin-releasing peptide immunoreactive nerves in the feline pancreas.
In this study, we performed a detailed analysis of the immunoreactive (IR) patterns and tissue distribution of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and gastrin-releasing peptide (GRP) in the feline pancreas by means of immunohistochemical and radioimmunological techniques. Immunoreactivity for each peptide is localized to varicose nerve fibers distributed throughout the exocrine and endocrine pancreas, with some differences in the density and pattern of fiber distribution. In the acinar and stromal compartments, VIP-IR processes have a higher density than NPY- and GRP-containing fibers, the latter being the least abundant. The vasculature receives a particularly prominent NPY innervation, while GRP- and VIP-IR fibers are found occasionally in association with blood vessels. Around ducts, NPY- and VIP-IR nerves are more numerous than those positive for GRP-IR, which are quite sparse. One of the most interesting findings of the present work is the visualization of all peptide-IRs both in neuronal cell bodies and fibers within the intrapancreatic ganglia. VIP-IR is observed in virtually all ganglion cells, while GRP- and NPY-IRs are seen in a few neuronal cells. VIP and NPY tissue levels are much higher than GRP concentrations in all regions of the pancreas. VIP content in the head and body is greater than in the tail. The morphological relationship of VIP-, NPY-, and GRP-IR fibers with different pancreatic structures is consistent with specific peptidergic neural inputs in the regulation of pancreatic functions.
Animals↗
Responses of gastrointestinal peptides and motor activity to milk and water feedings in preterm and term infants.
Because duodenal motor activity differs between preterm and term infants during fasting, this study evaluated the responses of motor activity and peptide release in response to feeding. In the first study, fasting concentrations of gastrin, gastric inhibitory peptide, neurotensin, and peptide YY (PYY) were determined in 53 preterm and 20 term infants. Plasma concentrations of gastrin and neurotensin were significantly lower in preterm infants than in healthy adults reported previously by our lab (p less than 0.01). Plasma concentration of gastric inhibitory peptide and PYY were higher than in healthy adults (p less than 0.01). Gastrin concentrations in preterm and term infants varied directly with gestational age (p less than 0.005); PYY varied inversely with gestational age (p less than 0.005). In a secondary study, intestinal manometry was recorded and serial peptide concentrations were determined in 43 preterm babies who were given their first enteral feeding intraduodenally with formula or sterile water. Although none of the four peptide plasma concentrations changed in response to feeding with water, plasma concentrations of gastric inhibitory peptide, neurotensin, and PYY significantly increased with formula feedings (p less than 0.05 or less). In addition, plasma gastrin increased significantly in seven infants fed milk compared with eight fed water by orogastric tube (p less than 0.01). In contrast to the peptide response to feeding, motor activity changed in response to feeding with either water or milk; motility indices increased and periods of motor quiescence decreased significantly during feeding as compared with fasting (p less than 0.02). Responses of both motor activity and peptides to feeding were time related.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Segmental distribution of colonic neuropeptides in Hirschsprung's disease.
Despite continued research, the pathophysiologic mechanism responsible for functional obstruction in the aganglionic segment of bowel in Hirschsprung's disease remains controversial. Narrowing of the affected segment is thought by many investigators to be the result of loss of intrinsic inhibitory innervation. For this hypothesis to be consistent, inhibitory neuropeptides should be present in the dilating, transitional segment of bowel. In order to quantitate reported changes in peptidergic nerve staining in Hirschsprung's disease, we measured concentrations of five neuropeptides (vasoactive intestinal peptide, peptide histidine-methionine, met5-enkephalin, substance P and bombesin-like immunoreactivity) by radioimmunoassay in the affected segments of bowel from six patients with Hirschsprung's disease. Tissue extracts were prepared using gut obtained at surgery from the: (1) constricted, aganglionic segment, (2) dilating, aganglionic transitional segment and (3) dilated, proximal ganglionic segment. Concentrations of vasoactive intestinal peptide, peptide histidine-methionine, substance P and met5-enkephalin were significantly reduced in both the muscularis externa and the mucosal-submucosal layers from the constricted aganglionic segment. By contrast, concentrations of the candidate inhibitory neuropeptides, vasoactive intestinal peptide and peptide histidine-methionine, were minimally reduced in the dilating, aganglionic transitional segment. These results are consistent with the hypothesis that constriction of the aganglionic segment is due to loss of intrinsic inhibitory innervation. Concentrations of bombesin-like immunoreactivity were similar in the three segments of human gut, suggesting the presence of this immunoreactive neuropeptide in extrinsic nerve fibers.
Bombesin↗
Influence of gastric inhibitory polypeptide (GIP) and glucose on the regulation of glucagon secretion by pancreatic alpha cells.
The effects of glucose and GIP on glucagon secretion were studied in perifused microdissected murine pancreatic islets. Glucagon levels were determined in effluent samples collected at 1-min intervals by radioimmunoassay using the glucagon-specific antibody, 30 K. There was no significant difference in the total amount (7740 +/- 212 pg vs 8630 +/- 36 pg, n = 10) of glucagon secreted over a 20 min period when the glucose concentration was alternately shifted between 5.5 mM and 11.1 mM, respectively. However, 22.2 mM glucose profoundly suppressed glucagon secretion. The suppressive effect of high glucose on glucagon release was partially, yet significantly, reversed by the presence of GIP, as glucagon secretion increased from a non-detectable level at 22.2 mM glucose alone to 10,175 +/- 145 pg, n = 10 (P less than 0.01). The glucagonotropic effect of GIP was dose-dependent in the range of 2 x 10(-9) - 2 x 10(-7) M, at 11.1 mM glucose. Our data show that GIP is able to substantially reverse the suppressive effect of a high glucose load on glucagon secretion.
Animals↗
Influence of in situ neural isolation of jejunoileum on postprandial pancreatobiliary secretion and gastric emptying.
Our aims were to examine the influence of neural isolation of the jejunoileum on postprandial pancreatobiliary secretion. In four dogs, duodenal perfusion and aspiration catheters were implanted, and serosal electrodes were placed along the proximal small bowel. Control studies of gastric emptying, output of bile acids and amylase, and plasma concentrations of peptide YY and neurotensin were performed on three occasions following ingestion of a 340-kcal mixed-nutrient liquid meal. The dogs then underwent our model of in situ jejunoileal neural isolation, and the meal studies were repeated. Neural isolation, when compared to control, did not affect either postprandial conversion of intestinal myoelectric activity to the "fed" pattern, gastric emptying (T1/2, X +/- SE of the liquid meal (74 +/- 6 vs 79 +/- 7 min; P greater than 0.05), or cumulative amylase output (373 +/- 59 vs 305 +/- 66 kU; P greater than 0.05). Neural isolation decreased cumulative postprandial bile acid output from 6.6 +/- 0.9 mM to 3.4 +/- 1.1 mM (P less than 0.05) and increased postprandial plasma concentrations of peptide YY and neurotensin. Our findings suggest that the jejunoileal denervation that accompanies the in situ neural isolation of the jejunoileum is not associated with changes in postprandial motility patterns, gastric emptying, or pancreatic amylase secretion. Loss of this innervation, however, may decrease postprandial output of bile acids and lead to a compensatory increase in the postprandial release of neurotensin and peptide YY.
Amylases↗
Inhibitory neuropeptides and intrinsic inhibitory innervation of descending human colon.
The effects of aging on inhibitory neuropeptide concentrations and intrinsic inhibitory innervation of circular muscle were investigated using normal descending colon obtained at surgery. Immunoreactive vasoactive intestinal peptide, peptide histidine-methionine, met5-enkephalin, neuropeptide Y, and somatostatin were extracted from specimens of muscularis externa (patient ages: 19-84 years) and measured by radioimmunoassay. Intracellular electrical activity was recorded from strips of circular muscle (patients ages: 49-84 years) using glass microelectrodes; inhibitory junction potentials were evoked by electrical field stimulation. There were no significant differences (t tests: P greater than 0.05) between neuropeptide concentrations in patients less than 70 years old (N = 28) compared to patients greater than or equal to 70 years old (N = 12). However, the amplitude of inhibitory junction potentials declined with increasing patient age (r = -0.58, P = 0.02, N = 16), with no change in resting membrane potentials (r = 0.22; P greater than 0.05). The decline in amplitude in women (r = -0.68, P = 0.03, N = 9) preceded the decline in men (r = -0.62, P = 0.10, N = 7). Age-related decline in inhibitory junction potentials could be related to decreased: density of inhibitory nerves, release of inhibitory neurotransmitter, density of binding sites for inhibitory neurotransmitter on smooth muscle, or a combination thereof. Alternatively, this decline might represent a change in interaction of inhibitory neurotransmitter with the smooth muscle membrane, such as a change in coupling of binding site with the potassium channel, decreased number of potassium channels, or altered permeability of the potassium channel.
Adult↗
Plasma vasoactive intestinal polypeptide concentration determination in patients with diarrhea.
Determination of plasma levels of vasoactive intestinal polypeptide (VIP) has been used for screening patients with chronic diarrhea to identify potential neuroendocrine tumors. This 6-year blinded study from 1981 to 1986 examines the causes of elevated VIP levels in patients. In healthy volunteers ( n = 144), VIP concentrations ranged from 14 to 76 pg/mL (mean +/- SE, 28 +/- 12), whereas in chronic renal failure, 4 of 34 patients or 12% [serum creatinine 4.5 - 9.0 mg/dL (397-795 mumols/L)] had an elevation to greater than 100 pg/mL. No patient with idiopathic hepatic cirrhosis (n = 12) had elevation of serum concentration of this peptide. Among 588 consecutive unselected patients undergoing evaluation for chronic diarrhea (n = 362; 62%) or possible neuroendocrine tumor (n = 214; 36%), 23 patients (3.9%) had concentrations greater than 76 pg/mL. In this group, 5 patients had functioning (VIP, 160-5975 pg/mL) and 5 had nonfunctioning (VIP, 80-120 pg/mL) pancreatic islet cell carcinomas: all 10 patients had hepatic metastases. Other known cases of elevated levels of VIP, ranging from 80 to 340 pg/mL, included other neurogenic tumors (n = 3), small- bowel resection (n = 2), inflammatory bowel disease (n = 2), chronic renal failure (n = 1), and prolonged fasting (n = 1). Patients with diarrhea in which VIP-secreting tumors were identified had plasma vasoactive intestinal peptide concentrations greater than 140 pg/mL. In patients with chronic diarrhea, determination of plasma vasoactive intestinal peptide levels did identify tumors secreting this peptide, but the results from this referral institution did not show identification of these tumors early in their clinical course.
Adolescent↗
Effect of nerve blockade on pulsatile insulin and glucagon secretion in vitro.
We recently reported that the secretion of insulin and glucagon by isolated murine islets is pulsatile and suggested that the pacemaker controlling these hormone oscillations is present in the islet. In the present study, we tested the hypothesis of an intrinsic islet neural controlling mechanism for the observed hormone pulsatility. Nerve blockade was attempted by infusion of tetrodotoxin (TTX) on a background of combined adrenergic and cholinergic blockade with atropine, propranolol, and phentolamine, (ATX). Because TTX acts by blocking Na+ channels, we also studied the effects of other cationic channel manipulations on the amplitude and frequency of the oscillations. The normal frequency and amplitude of glucagon and insulin oscillations were not affected by ATX. In contrast, TTX infusion increased the amplitude of insulin (198.6 +/- 20.9 vs. 507.2 +/- 62.8 pg/min, p less than 0.05, n = 4) and shortened the period from 5.03 +/- 0.26 to 3.33 +/- 0.0 min without affecting glucagon cycles. Whereas the Ca2+ ionophore A23187 had no effect on either hormone oscillation, the ATP-sensitive K+ channel blocker glyburide only increased the amplitude of insulin and decreased the amplitude of glucagon, without altering the frequencies. These data suggest that an intrinsic autonomously functioning islet nervous system is the pacemaker for the insulin oscillations and that the control of glucagon cycles differs from that of insulin.
Animals↗
In vivo neural isolation of the canine jejunoileum: temporal adaptation of enteric neuropeptides.
This study was designed to assess temporal changes in concentrations of neuromodulatory peptides in plasma and gastrointestinal tissues after in vivo neural isolation of the entire canine jejunoileum. Fasting plasma and transmural biopsy specimens of stomach, duodenum, jejunum, ileum, and colon were obtained from the same dogs before and two, six, and 12 weeks after in situ neural isolation of the entire jejunoileum. Concentrations of vasoactive intestinal peptide, substance P, and neuropeptide Y were determined by quantitative radioimmunoassay. Tissue concentrations of vasoactive intestinal peptide and substance P in the neurally isolated regions increased progressively with time (198% and 217% average maximal increases, respectively), while fasting plasma concentrations changed little. Neuropeptide Y concentrations in plasma and in the jejunoileum were decreased (by 30% to 70%) at two weeks and remained decreased thereafter. Temporal changes in tissue neuropeptide concentrations occur in the neurally isolated jejunum and ileum. These adaptive changes in the neuropeptidergic innervation of the gut may play a role in the alterations in enteric function that occur after extrinsic denervation and after intestinal transplantation.
Adaptation, Physiological↗
Distribution of neuropeptide Y in the spinal cords of cat, dog, rat, man and pig.
Regional distribution of neuropeptide Y (NPY) in spinal cord, dorsal root ganglia (DRG) and peripheral nerves was quantitated in rat, cat, dog, pig, and man. Spinal cords were harvested post mortem and dissected into regions or individual segments. A further dissection into dorsal and ventral horns was carried out, and DRG were harvested in all species except rat. Tissues were extracted into boiling 0.1 M HCl, and NPY was measured by radioimmunoassay using a specific antibody and I125-labeled NPY. Highest concentrations of NPY were consistently found in the dorsal horn of the lumbo-sacral cord (200-800 ng/g). DRG concentrations, in contrast, were routinely low or undetectable. Sciatic nerve concentrations in rat and pig were considerable. High performance liquid chromatography (HPLC) confirmed that the NPY immunoreactivity measured in dorsal horns of each species coeluted with authentic NPY (1-36) as a single peak.
Adolescent↗
Are diets associated with different rates of human interdigestive and postprandial pancreatic enzyme secretion?
To determine if diets are associated with different rates of interdigestive and postprandial enzyme secretion and how quickly enzyme secretion is modulated by nutrients, 27 healthy humans were randomly selected to follow one of five diets. The calorie proportions of carbohydrate, fat, and protein in each diet was assigned by a mixture design. After the subjects followed a diet for 2 weeks, they were intubated with an oroduodenal tube, and enzyme outputs were measured during the interdigestive period and after eating a meal identical to meals eaten during the previous 2 weeks. For the next 24 hours subjects either followed the same diet or a diet that contained the same amount of fat, but the percent of carbohydrate and protein was changed by 30%. Then interdigestive and postprandial pancreatic enzyme outputs were remeasured. After 2 weeks, diets containing the most carbohydrate (50%-80%) were associated with the lowest interdigestive and postprandial amylase and lipase (P less than 0.05) and trypsin outputs (P less than or equal to 0.05). In contrast, diets containing the most fat (40%) were associated with the highest interdigestive and postprandial outputs of amylase (P less than 0.05) and trypsin (P less than 0.05). Maintaining or altering diets for 24 hours did not change interdigestive pancreatic enzyme outputs, but postprandial amylase output was significantly increased (P less than 0.05) by increasing protein and decreasing carbohydrate content of the diets by 30% for 24 hours. We conclude that diets containing a high proportion of calories as carbohydrate for 2 weeks are associated with lower interdigestive and postprandial pancreatic secretion than diets that have a high fat content. In response to diets, changes in postprandial pancreatic enzyme secretion occur within 24 hours whereas changes in interdigestive secretion (no nutrients in the lumen) occur after 24 hours.
Adult↗
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.
Adolescent↗
The 'ileal brake' after ileal pouch-anal anastomosis.
The aim of this study was to assess if infusion of oleic acid into the ileal pouch would slow gastric emptying and small-bowel transit, delay defecation, and increase plasma levels of enteroglucagon, neurotensin, or peptide YY in patients with colectomy and ileal pouch-anal anastomosis. Eight subjects with chronic ulcerative colitis who had undergone the operation were studied on 2 consecutive days. On 1 day, saline (154 mM NaCl) was infused into the ileal pouch, and on the other day emulsified oleic acid (152 mM) was infused. The subjects ate a 300-kcal mixed meal containing liquid labelled with 99mTc-DTPA. To assess small-bowel transit concurrently with gastric emptying, a second marker, 111In-DTPA, was instilled through a tube into the duodenum at the end of the meal. Transit of both markers was monitored scintigraphically. Infusion of oleic acid into the ileal pouch slowed gastric emptying and small-bowel transit, and delayed the time to defecation compared with saline infusion. Neither the ileal pouch infusion alone or the meal alone altered plasma levels of enteroglucagon, neurotensin, or peptide YY, but the combination of the oleic acid infusion and the meal increased the levels of all 3 hormones. It was concluded that an "ileal brake" on gastrointestinal transit is functional following ileal pouch-anal anastomosis. Oleic acid placed into the ileal pouch slowed gastrointestinal transit and delayed defecation, effects which may have clinical application. The mechanism mediating the ileal brake may in part be hormonal.
Adult↗
Sites in the brain at which cholecystokinin octapeptide (CCK-8) acts to suppress feeding in rats: a mapping study.
In this study, an examination was made of the sites in the brain of the rat at which the injection of cholecystokinin octapeptide (CCK-8) would alter food intake. Rats fasted for 24 hr received intracerebral injections of CCK-8 (1 nmol) or an equal volume of saline (0.5 microliters), into various sites in the brain through permanently implanted stainless steel cannulae. After prior acclimatisation to individual plexiglass compartments, latency to feed, as well as consumption of food and water during 0-20, 20-40 and 40-60 min after the injection, were recorded. The available food was the standard rat pellets, to which the animal otherwise had constant daily access. With this paradigm, active sites at which CCK-8 suppressed feeding were defined as sites at which consumption of food for 0-20 min was reduced by 25% or more, or the latency to feed was increased by 3 min or more after the injection of CCK-8, as compared to the effect of the injection of saline, made at the same site. Such active sites were most densely distributed in the rostral diencephalon, e.g. hypothalamus, the medial pontine area and lateral medulla, in the vicinity of the nucleus tractus solitarii (NTS). By grouping data for injections according to histologically identified sites, statistical analysis of groups of injections confirmed that these three major areas of the brain were active with regard to the suppression of feeding by CCK-8. These data suggest that CCK may not only initiate satiety messages, as a circulating hormone at peripheral sites, but also participate in the conduction of such information to the target in the brain by serving as a neurotransmitter in the lateral medulla (e.g. NTS), medial pontine area (e.g. relay station between the NTS and hypothalamus) and the lateral hypothalamus, where local release of CCK-8 after stomach loading has been observed.
Animals↗
Postpartum changes in pattern of gastrointestinal regulatory peptides in human milk.
Concentrations of gastrointestinal neuropeptides in serial human milk samples from 28 women were determined over the first 6 postpartum mo. All gut neuropeptides were present during the first postpartum week. Gastric inhibitory peptide (GIP) concentration remained constant but the others decreased by 6 wk. Bombesin concentration in breast milk was threefold greater than concurrent plasma concentration (p less than 0.001); all other neuropeptides were at the same or lower concentrations in milk than in plasma. At 36 wk gestation plasma concentrations of GIP were lower and concentrations of vasoactive intestinal peptide were higher than concentrations in age-matched control subjects. Concentrations of gastrin and cholecystokinin, bombesin, peptide histidine methionine, peptide YY, and neurotensin in plasma were similar in pregnant and nonpregnant women. These gut neuropeptides in milk may be important for growth and maturation of the gastrointestinal system in neonates. Bombesin may contribute to neonatal hypergastrinemia.
Adult↗