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PubMed1999

Veratridine-stimulated amylase secretion from rabbit pancreatic lobules: role of cholinergic and noncholinergic receptors.

Stimulation of pancreatic nerves results in marked increases in exocrine secretion. However, the neurotransmitters and pre- and postsynaptic receptors, which determine synaptic transmission between nerves and acinar cells, are poorly defined. We used rabbit pancreatic lobules, which contain nerve terminals and secrete independently of the influences of vascular perfusion or gastrointestinal hormones, to study the role of cholinergic and noncholinergic nerves in regulating amylase secretion. Pancreatic nerves were stimulated by veratridine (Ver; 50-200 microM), an activator of voltage-dependent sodium channels, in a concentration-dependent and tetrodotoxin-sensitive manner, resulting in an increase of 138+/-15% in amylase secretion above basal at 100 microM. This stimulation was unaffected by either hexamethonium (100 microM) or the combination of phentolamine and propranolol (10 microM). Atropine (5 microM) inhibited Ver-stimulated secretion by approximately 65-70%. Bethanechol (Bch; 0.01-100 microM) increased amylase secretion in a concentration-dependent manner (EC50, 6.2 microM), with a maximal stimulation of 177+/-15% above basal. Antagonism of Bch-stimulated secretion with 4-diphenylacetoxy-N-methyl-piperidine, pirenzepine (Pzp), or methoctramine (Met) resulted in IC50 values of 7.9 nM, 282 nM, and 79.8 microM, respectively. Ver-stimulated secretion was unaffected by Pzp (0.1 and 1 nM) or Met (1 and 100 nM) at concentrations that had no significant effect on Bch-stimulated secretion. Thus cholinergic nerves, activating postsynaptic M3 receptors, provided the predominant stimulatory innervation of rabbit pancreatic acini. Nonadrenergic, noncholinergic nerves also made a significant contribution to secretion. Adrenergic nerves did not appear to innervate acini or the excitatory cholinergic nerves directly.

Adrenergic Antagonists↗
PubMed2002

Peptide YY improves local and systemic parameters and prevents death in lethal necrotizing pancreatitis.

INTRODUCTION: Peptide YY (PYY) is a gastrointestinal hormone with multiple inhibitory effects on the proximal digestive tract, including suppression of secretion by the exocrine pancreas. AIM: To determine whether peptide YY would reduce mortality in a lethal model of necrotizing pancreatitis by improving local and systemic parameters of this disease. METHODOLOGY: Necrotizing pancreatitis was induced in three groups of 30 mice by feeding a choline-deficient ethionine-supplemented diet. Osmotic pumps placed in 10 control mice delivered normal saline. In the two study groups, PYY was delivered at 200 pmol/kg/hr. The prophylactic group received PYY pumps at the onset; the therapeutic group received pumps 24 hours later. Ten mice from each group were followed to assess survival. Remaining mice were killed at 24, 48, 72, and 96 hours. Pancreata were graded on a nine-point histologic scale. Amylasemia was quantified by kinetic determination. Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) values were determined by ELISA. RESULTS: Both prophylactic and therapeutic PYY significantly reduced mortality compared with that seen in controls ( p = 0.05 and p = 0.007). Five-day survival was 33% in controls, 80% in those receiving prophylactic PYY, and 100% in the therapeutic group. Amylasemia was reduced in the therapeutic group by day 3 ( p < 0.02) and in the prophylactic group by day 4 ( p < 0.01). Histologic changes mirrored those in serum amylase. Prophylactic and therapeutic administration of PYY suppressed early circulating levels of IL-6. CONCLUSION: PYY reduces mortality and improves local and systemic parameters in this murine model and may be of clinical benefit in the management of human necrotizing pancreatitis, particularly as this study demonstrates a clear survival benefit when PYY is given after the onset of disease.

Amylases↗
PubMedDate not supplied

Gastrin, cholecystokinin, and somatostatin in a laboratory experiment of patients with functional dyspepsia.

OBJECTIVE: To explore the pattern of gastrointestinal hormonal variations in plasma and to relate this to possible pathophysiological mechanisms in functional dyspepsia. METHOD: There were 25 patients, 12 men and 13 women, aged 24 to 50 years, with recurrent functional dyspepsia, compared with community control subjects pair-wise, matched for age and sex. The subjects participated in a laboratory stress experiment with timed provocations. At fixed intervals, 22 samples of blood were drawn from each subject and frozen for later peptide analyses. Levels of gastrin, cholecystokinin (CCK), and somatostatin were measured by radioimmunoassay. Peptide levels were studied during a friendly greeting, a stress interview, and a food stimulation. RESULTS: Mean hormone values did not differ between the groups. Smokers had lower mean CCK than nonsmokers. Patients with a high degree of dyspeptic symptoms during the week preceding the experiment had a higher mean somatostatin level than patients with a low degree of dyspeptic symptoms. Heartburn correlated positively with the mean somatostatin level. Mean gastrin correlated with body mass index. During the 15-minute stress interview, significant changes in peptide variations were noted: Gastrin increased in both patient and control group subjects. CCK levels increased in patients from 7.2 pmol/l (6.0-8.5) to 9.8 pmol/l (8.2-11.4), but not in control subjects (p < 0.04, two-way interaction). Somatostatin increased significantly earlier in patients than in the control subjects during the stress interview. CONCLUSIONS: A positive relationship was found between the mean level of somatostatin and the degree of dyspeptic symptoms. Gastrin, CCK, and somatostatin were all sensitive to an anxiety-provoking interview. CCK and somatostatin may possibly link psychological reactions to the pathophysiology of functional dyspepsia.

Adult↗
PubMed2003

PYY-Tag transgenic mice displaying abnormal (H+-K+)ATPase activity and gastric mucosal barrier impairment.

The mechanism by which the gastrointestinal hormones peptide YY and glucagon inhibit gastric acid secretion is largely unknown. PYY-Tag transgenic mice develop endocrine tumors in the colon that are composed mainly of peptide YY/enteroglucagon-producing L type cells. Therefore we studied the functional activity of such tumors and the gastric functions of PYY-Tag mice. Fasting and fed PYY-Tag transgenic mice and CD1 controls were assayed for circulating levels of peptide YY, glucagon, insulin, and gastrin. The gastric pH was determined and gastric samples were examined for (a) histologic appearance; (b) K(+)-stimulated p-nitrophenylphosphatase activity and [(14)C]aminopyrine accumulation of apical and tubulovesicle membranes; (c) adherent mucus determination by Alcian blue recovery; and (d) DNA/RNA/protein epithelial content and in vivo incorporation of [(3)H]thymidine into DNA. Transgenic mice showed high serum levels of peptide YY and glucagon, increased gastric pH, and a high incidence of gastric ulcers after fasting. p-Nitrophenylphosphatase activity, [(14)C] aminopyrine accumulation, and proton pump redistribution from cytoplasmic tubulovesicles to apical membranes were significantly lower in the gastric mucosa of transgenic mice compared with the controls. In addition, the adherent mucus was thinner, and [(3)H]thymidine incorporation into the DNA was decreased. The abnormal and unregulated levels of circulating peptide YY and glucagon led to gastric acid inhibition and an impairment of gastric barrier function as a result of a striking reduction in epithelial proliferation.

Animals↗
PubMed1983

Increased plasma pancreatic polypeptide in chronic alcohol abuse.

Post-prandial plasma gastrointestinal hormone profiles were measured in nine chronic alcoholics, one and fourteen days after complete alcohol withdrawal. Basal plasma pancreatic polypeptide concentration (PP--mean +/- SE mean) was significantly greater in alcoholics (control, 28 +/- 5 pmol/l; alcoholics, post-withdrawal day 1, 62 +/- 14 pmol/l, P less than 0.05; and post-withdrawal day 14, 89 +/- 17 pmol/1, P less than 0.005). The total integrated (TIR) PP response following a test breakfast was similarly elevated (control, 442 +/- 63 units; alcoholics, day 1, 1310 +/- 231 units, P less than 0.005; day 14,1066 +/- 66, P less than 0.005). Basal and TIR values for gastrin, gastric inhibitory peptide, insulin and glucagon were similar in alcoholics and controls. As PP has been shown to inhibit pancreatic exocrine enzyme secretion, these findings may help explain the abnormal pancreatic function seen frequently in alcoholics.

Adult↗
PubMed2005

Ghrelin in human medullary thyroid carcinomas.

OBJECTIVE: Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. It has been identified previously in several normal and tumoral neuroendocrine tissues, including human medullary thyroid carcinomas (MTCs). The aim of the study was to evaluate ghrelin levels in patients with MTC and nontoxic goitre (NTG) with elevated calcitonin (CT) levels, as an additional marker of the disease. PATIENTS AND DESIGN: The study included 22 patients with MTC (four before and 18 after thyroidectomy), 12 patients with NTG with basal CT levels exceeding 10 ng/l and 15 healthy subjects matched for age, sex and body mass index (BMI). After thyroidectomy, MTC patients were considered cured when basal and pentagastrin-stimulated CT levels were < 0.2 and < 10 ng/l, respectively. A pentagastrin-induced CT peak over 50 ng/l was considered as an abnormal response while 100 ng/l was the cut-off accepted for the diagnosis of C-cell hyperplasia or tumour. Circulating ghrelin and CT levels were evaluated at baseline in patients and controls and at -10, 0, 1, 2, 5 and 15 min after pentagastrin injection (0.5 microg/kg body weight) in 12 patients with MTC and nine with NTG. Four surgically removed MTCs were tested for ghrelin expression. MEASUREMENTS: Total plasma ghrelin and CT levels were measured with a commercially available radioimmunoassay (RIA) and two-site chemiluminescence immunometric assays, respectively. In paraffin-embedded MTC samples ghrelin immunostaining was performed with a polyclonal antibody (1:1000) and the reaction visualized by an indirect immunoperoxidase system. RESULTS: Plasma ghrelin levels found in cured or not cured MTC and in NTG patients were similar to those of BMI-matched healthy controls. No correlation between ghrelin and CT levels, thyroid disease or previous thyroidectomy was observed. The administration of pentagastrin caused a 17% increase in ghrelin levels (basal ghrelin vs. peak: 162 +/- 62 pmol/l vs. 189 +/- 58 pmol/l, P < 0.05) that was particularly evident (33% increase) in patients with an abnormal CT response to the test (CT > 50 ng/l). Immunohistochemistry showed positivity for ghrelin in a small proportion of CT positive cells from the four MTCs removed. CONCLUSIONS: Patients with MTC, NTG and controls showed similar ghrelin levels, ruling out this parameter as a marker of MTC. The increase in ghrelin levels in patients with a positive CT response to pentagastrin, together with the immunopositivity for ghrelin in some MTC cells, suggests C cells as minor source of ghrelin production.

Adult↗
PubMed1994

Structure/activity characterization of glucagon-like peptide-1.

Glucagon-like peptide-1 is a gastrointestinal hormone that strongly stimulates insulin release via specific receptors on the pancreatic beta-cell. To characterize the side-chain groups required for interaction of glucagon-like peptide-1 with its receptor, we performed binding studies with alanine-substituted glucagon-like peptide-1 analogues on RINm5F insulinoma cells. The binding affinity and biological activity of glucagon-like peptide-1 have been found to be sensitive to alanine exchanges in the N-terminal positions 1, 4, 6 and the C-terminal positions 22 and 23. Alanine substitutions at positions 5, 8, 10-12, 14, 16-21 and 25-30 do not change receptor affinity. These findings could be exploited to design glucagon-like peptide-1 agonists and probably antagonists for further physiological studies.

Amino Acid Sequence↗
PubMed1989

Influence of theophylline on the electrical potential difference and ion fluxes (Na, Cl, K) across the isolated rumen epithelium of sheep.

Although it is well established that Na and Cl are actively absorbed by the rumen epithelium, nothing is known about the regulation of electrolyte transport across the rumen mucosa. Therefore, we have investigated the influence of theophylline, a known inhibitor of the enzyme phosphodiesterase, on the electrical parameters of the rumen epithelium as well as on electrolyte (Na, Cl, K) transport across this tissue. The experiments were performed using isolated rumen mucosa from sheep mounted in a Ussing type chamber. Serosal addition of theophylline resulted in a significant drop of the transepithelial potential difference as well as the short circuit current. The effect of theophylline is probably mediated by cAMP, since the addition of cAMP yielded qualitatively similar results. With respect to the ion fluxes only transport of Na in the muco-serosal direction and as a result the net flux of Na were significantly reduced in the presence of theophylline. The effects of theophylline on rumen epithelium are best explained by an inhibition of electrogenic as well as electroneutral Na transport. Since cAMP serves as a second messenger for the effect of various regulatory substances including gastrointestinal hormones and transmitters regulation of electrolyte transport across the rumen epithelium possibly occurs under physiological conditions.

Animals↗
PubMed1995

Age-related decrease in plasma levels of gastrin, cholecystokinin and somatostatin.

Newborn babies have higher concentrations of gastrointestinal hormones than adults. The aim of the present study was to investigate the relationship between age and plasma levels of the three peptides gastrin, cholecystokinin and somatostatin in healthy children aged 1-15 years. Gastrin, cholecystokinin and somatostatin concentrations were twice as high at 1-2 years of age compared with children older than 10 years. Significant negative correlations between age and hormone concentrations were established. It is suggested that these age-dependent differences are related to the growth rate and relative energy consumption during the early years of life.

Adolescent↗
PubMed1979

Effects of vasoactive intestinal polypeptide on blood flow, motility and fluid transport in the gastrointestinal tract of the cat.

The effect of close intraarterial infusions of vasoactive intestinal polypeptide (VIP) on gastric motility, intestinal fluid transport and colonic motility were studied in the cat. Regional blood flow was also followed in all experiments. In the stomach VIP produced a gastric relaxation and a blood flow increase. The motility response was similar to that observed when eliciting the vago-vagal reflex relaxation by distending the esophagus. In the small intestine a hyperemia and a decrease of net water uptake was observed. When infusing small amounts of VIP a decrease of net water uptake was seen without any change of intestinal blood flow. Large amounts of VIP produced a transient secretory state in the small intestine. In the colon a hyperemia was seen immediately upon starting the infusion of the drug. After 2-3 min of infusion a contraction of the colon was apparent. The administration of atropine to the animal did not significantly affect any of the responses produced by VIP. The results are discussed in relation to VIP as a possible neurotransmitter in the gastrointestinal tract.

Animals↗
PubMed1984

Influence of suckling and feeding on insulin, gastrin, somatostatin and VIP levels in peripheral venous blood of lactating sows.

Blood samples were collected in peripheral venous blood of seven lactating sows, when their piglets were suckling. In four of the experiments samples were also taken when the sows were fed a meal. Gastrin, insulin, somatostatin and VIP levels were measured by radioimmunoassay. Insulin levels increased by approximately 100% for about 10 min in response to suckling, in some experiments even before the suckling occurred, i.e. when the sows saw, heard and smelled their piglets. In four of the sows suckling caused a biphasic twofold increase in gastrin levels - one immediate peak which lasted for a few min and a second peak of longer duration (about 30-60 min), whereas gastrin levels remained unchanged in three animals. Somatostatin levels usually reflected gastrin levels in a reciprocal way. Thus, a biphasic decrease of somatostatin levels occurred in the high gastrin responders. In contrast, somatostatin levels increased in the experiments, in which gastrin levels did not change. Immediate and short-lasting (a few minutes long) increases of VIP levels were also induced by suckling. Large litters and long suckling periods appeared to be related to greater changes of the levels of all the peptides measured. Feeding influenced insulin, gastrin and somatostatin levels in the same way as did suckling from both a qualitative and a quantitative point of view. In contrast, VIP levels were not increased by feeding. The possible functional effects of the suckling-induced release of gastrointestinal hormones and possible mechanisms of their release are discussed.

Animals↗
PubMed1990

Effect of transplantation on tissue levels of substance P, vasoactive intestinal polypeptide, and serotonin in rat small intestine.

Denervation of the gut, resulting in altered bowel function, has been viewed as an impediment to the clinical success of small intestinal transplantation. This study examined the effect of complete extrinsic denervation of the jejunum and ileum on tissue levels of VIP, SP, and 5-HT in a rat model of small intestinal transplantation. Orthotopic total small bowel isograft transplants were performed in 18 Lewis inbred rats. Sham operations consisted of occluding the superior mesenteric artery of 18 Lewis rats for 10 minutes to provide comparable degrees of ischemia. Six rats from each group were sacrificed 1, 2, and 4 weeks following transplantation or sham operation. The jejunum and ileum were removed and extracted in acid for measurement of VIP, SP, and 5-HT by radioimmunoassay. There were no statistically significant differences in the jejunal or ileal content of VIP or 5-HT or the jejunal content of SP between the transplant and sham groups. An initial decrease in ileal SP content at 1 week following transplantation was no longer evident by the fourth week. We conclude that the extrinsic denervation of small intestinal transplantation has minimal effects on the intestinal content of VIP, SP, and 5-HT and should not significantly affect physiologic function controlled by these gastrointestinal hormones.

Animals↗
PubMed1986

The role of ingestion in the development of the small intestine in fetal sheep.

We have examined the influence of preventing the passage of swallowed fluid on the development of the small intestine during late gestation in fetal sheep. In four fetuses at 90 d of gestation, the oesophagus was ligated and fistulated, causing swallowed fluid to enter the amniotic sac. Tissue was removed from proximal and distal parts of the small intestine for histological analysis at 136 d (term is 147 d). The body weights of the four experimental fetuses were not significantly different from those of fourteen age- and breed-matched fetuses which were used as controls. However, the width of the mucosal layers at both sites in the small intestine was reduced by approximately 25% in the fistulated fetuses. This was largely attributable to a reduction in villus height of approximately 30%. The densities of villi and crypts increased significantly at the proximal and distal sites respectively. These findings indicate that the ingestion of fluid during late gestation plays a role in promoting growth of the mucosal elements of the small intestine. The way in which this occurs is not clear although it may be mediated either by trophic factors present in either amniotic or pulmonary fluid, or by the release of gastrointestinal hormones, such as gastrin, as a result of gut distension.

Animals↗
PubMed1987

Trophic stimulation of cultured neurons from neonatal rat brain by epidermal growth factor.

Epidermal growth factor (EGF) is a potent polypeptide mitogen originally isolated from the adult male mouse submaxillary gland. It also acts as a gastrointestinal hormone. EGF-immunoreactive material has recently been identified within neuronal fibers and terminals in rodent brain. In the present study, EGF was found to enhance survival and process outgrowth of primary cultures of subneocortical telencephalic neurons of neonatal rat brain in a dose-dependent manner. This effect was observed with EGF concentrations as low as 100 picograms per milliliter (0.016 nanomolar) and was dependent on the continuous presence of EGF in the medium. Similar effects were observed with basic fibroblast growth factor, but several other growth-promoting substances, including other mitogens for glial elements, were without effect. Thus EGF, in addition to its mitogenic and hormonal activities, may act as a neurite elongation and maintenance factor for select neurons of the rodent central nervous system.

Animals↗
PubMed1987

Modulation of memory processing by cholecystokinin: dependence on the vagus nerve.

Allowing mice access to food immediately after an aversive training session enhances memory retention. Cholecystokinin-octapeptide (CCK-8), which is a gastrointestinal hormone released during feeding, also enhances memory retention when administered intraperitoneally. This memory-enhancing effect of CCK-8 is blocked when the vagus nerve is cut, indicating that CCK-8 may produce its effect on memory retention by activating ascending fibers in the vagus nerve. Thus, CCK-8, a peripherally acting peptide, may mediate the memory-enhancing effects of feeding.

Animals↗