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Dumping syndrome: pathophysiology and treatment.

Anatomic and physiologic changes introduced by gastric surgery result in clinically significant dumping syndrome in approximately 10% of patients. Dumping is the effect of alteration in the motor functions of the stomach, including disturbances in the gastric reservoir and transporting function. Gastrointestinal hormones play an important role in dumping by mediating responses to surgical resection. Treatment options of dumping syndrome include diet, medications, and surgical revision. Poor nutrition status can be anticipated in patients who fail conservative therapy. Management of refractory dumping syndrome can be a challenge. This review highlights current knowledge about the mechanisms of dumping syndrome and available therapy.

Combined Modality Therapy↗

Hypersensitive prostaglandin and thromboxane response to hormones in rabbit colitis.

Inflammation of the colon is associated with increased production of prostaglandins (PG) and thromboxanes (Tx), and these eicosanoids may contribute to the inflammatory, secretory, and motility dysfunctions in colitis. To evaluate the potential role of peptide hormones in the enhanced eicosanoid release, colitis was established in rabbits by a delayed-type hypersensitivity reaction to dinitrochlorobenzene and by an immune-complex-mediated reaction. PG and Tx were identified in the venous effluent of isolated perfused colons by radiochromatography after [14C]arachidonic acid prelabeling, as well as by bioassay, and then quantitated by immunoassay. The two colitis models were morphologically similar. Basal release of PGE2, PGI2, and TxA2 was two- to threefold greater from colitis tissue than from control tissue. Bradykinin (BK) and angiotensin II (ANG II) increased release of 14C-labeled eicosanoids, whereas several gastrointestinal hormones had no effect. In control colons, BK and ANG II increased PGE2 and PGI2 release (by about 2-fold) but did not alter TxA2. In contrast, BK and ANG II markedly exaggerated the release of eicosanoids in colitis. BK increased TxA2 release with 10-ng bolus injections in colitis, but there was no response with up to 10-micrograms bolus injections in control colons. The BK-induced Tx release in colitis was associated with an increase in vascular resistance (measured as perfusion pressure). Infusion of the selective Tx inhibitors dazoxiben and OKY-046 reduced TxB2 release by 96% and blunted the transient rise in perfusion pressure (from 17 +/- 5 to 5 +/- 2 mmHg). Since BK and possibly ANG II are increased at sites of inflammation, the hypersensitive eicosanoid response to these peptides may augment the eicosanoid-mediated manifestations of colitis.

Animals↗

Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.

Adult↗

Factors affecting the voluntary intake of food by sheep. 3. The effect of intravenous infusions of gastrin, cholecystokinin and secretin on motility of the reticulo-rumen and intake.

1. Sheep given ground and pelleted lucerne hay (Medicago sativa) ad lib. were infused intravenously with pentagastrin, secretin, cholecystokinin (CCK) and its analogues to assess their effects on motility of the reticulo-rumen and on food intake. In the latter experiments the animals were deprived of their diet for periods of up to 6 h to induce hunger and the infusions were made before and during 3-10 min periods of feeding. 2. Pentagastrin, and analogue of gastrin, depressed intake by 35-50% (P less than 0.05) when it was infused at 9 microgram/kg per h during 30 min of feeding. The threshold may however be below 1 microgram/kg per h as this dose decreased intake of 12-17%. The frequency of reticular contractions decreased by 13, 35, 39 and 44% when 1, 3, 9, and 27 microgram pentagastrin/kg per h respectively was infused (P less than 0.025). 3. Secretin depressed food intake 38% after 30 min (P less than 0.025) when 8 Clinical Units (CU)/kg per h was infused but the threshold could be less than this dose since 0.5 CU/kg per h depressed intake by 12%. Contraction amplitude but not frequency decreased at 8 CU/kg per h. 4. CCK produced a 39% decrease in intake during the first 10 min of feeding (P less than 0.05) and the threshold was between 5 and 15 Ivy Dog Units (IDU) or 425 and 1276 pmol/kg per h. The frequency of reticular contractions was not affected by 1.7 IDU/kg per h but it was depressed 21 and 63% by 5 and 15 IDU/kg per h. Octapeptide at 1.5 and 3 microgram (1312 and 2624 pmol) kg per h depressed intake by 11 and 43% respectively after 10 min (not significant) and 1.5 microgram/kg per h depressed motility by 39% (P less than 0.01). Ceruletide at 810 ng (599 pmol)/kg per h depressed intake by 31% (not significant) after 10 min and decreased motility by 52% (P less than 0.05). The threshold dose for ceruletide on intake appeared to be about 90 ng or 66 pmol/kg per h which is considerably less than that for CCK or octapeptide. 5. The biological significance of gastrointestinal hormones as signals of satiety in normal sheep is not known since doses of pentagastrin and CCK that suppressed intake also interfered quite markedly with motility. However there is good reason to suspect that elevated concentrations of gastrin and CCK in blood of parasitized sheep may account at least in part for their symptoms of rumen atony and reduced food intakes.

Animals↗

VIP and secretin augment cardiac L-type calcium channel currents in isolated adult rat ventricular myocytes.

Vasoactive intestinal peptide (VIP) is colocalized in parasympathetic nerve terminals in the heart and coreleased from these nerve terminals with the "classical" neurotransmitter acetylcholine (Ach). VIP also exerts a positive inotropic effect on the intact heart and enhances adenylyl cyclase activity in isolated heart membranes. Using the whole-cell patch-clamp technique, we show here that VIP enhances Ca2+ and Ba2+ currents (IBa) through voltage-dependent L-type Ca2+ channels in adult rat ventricular myocytes. Neither the kinetics nor the voltage-dependent properties of the currents are affected. The effect of VIP on IBa is dose dependent with a half-maximal concentration of approximately 0.4 microM. The onset of the effect of VIP and the recovery phase are slow, suggesting the involvement of an intracellular second messenger. The effect of VIP on IBa is antagonized by a peptide analog of the growth hormone releasing factor ([Ac-Tyr1, D-Phe2]-GRF) which belongs to the same peptide family as VIP. Although VIP and the beta-adrenergic receptor agonist isoproterenol (ISO) enhance IBa peak amplitudes to approximately the same extent, the effect of VIP is not seen on all cells. Only approximately 50% of the isolated myocytes respond to 5 microM VIP, whereas 95% of the cells respond to ISO. Similar results were obtained using the amphotericin B perforated-patch whole-cell-recording technique, suggesting that the variable response to VIP does not reflect the loss of a pivotal intracellular regulator. The gastrointestinal hormone secretin, a peptide structurally related to VIP, also potentiates IBa in adult rat ventricular myocytes, although secretin is substantially more potent than VIP (half-maximal concentration for secretin is about 0.7 nM). Taken together, these results suggest that the VIP- (and secretin-) induced potentiation of IBa in adult rat ventricular myocytes is mediated through a non-VIP-preferring class of VIP receptors.

Animals↗

[The Longmire gastrectomy in the animal model: postoperative changes in fat resorption and the hormones cholecystokinin and secretin].

In this animal study we investigated the absorption of free fatty acids and triglycerides after gastrectomy. The levels of the hormones cholecystokinin and secretin were measured in response to a controlled enteral fat load (Lipofundin 20% MCT emulsion). We studied fat absorption in three groups of animals: the gastrectomy group in which lipid emulsion was administered in the duodenum, and two groups of controls that received the same infusion in the duodenum or stomach, respectively. Infusing the fat load directly into the duodenum, rather than the stomach, resulted in delayed absorption of fatty acids. In the gastrectomized animals there was, in addition, increased absorption of triglycerides. Medium- and long-chain fatty acids were found to be an adequate stimulus for secretion of the gastrointestinal hormones cholecystokinin (CCK) and secretin. In the gastrectomized group, higher baseline levels of both CCK and secretin were observed. CCK showed no response to the lipid stimulus, whereas a secretin response was observed over and above the raised baseline level. The gastrectomized animals showed a markedly restricted growth rate, as measured by body weight; however, they continued to gain weight in a linear fashion up to the end of the study period. No alterations in morphology of CCK-secreting cells were found.

Animals↗

Effects of surgical manipulation of the intestine on peptide YY and its physiology.

PYY is a gastrointestinal hormone, mainly released from the distal intestine in response to intraluminal nutrients or via a neurohormonal pathway originating in the proximal intestine. Although there are several molecular forms of circulating PYY with different bioactivity, and further more than six subtypes of Y-receptors, the function is essentially inhibitory to digestive organs located upstream of the digestive tract. These inhibitory mechanisms are named jejunal, ileal and colonic brakes, and play an important supplementary role in adaptation following intestinal resection. When massive resection of the small intestine is performed, the release of PYY from the distal intestine increases, suppressing gastric acid secretion and motility of the gastrointestinal tract, and stimulating pancreatic secretion. After total colectomy, PYY release is reduced first due to reduction of PYY-containing cells, then gradually increases with time, contributing to adaptation of the digestive organs to the new condition.

Colectomy↗

Effect of suckling on the release of oxytocin, prolactin, cortisol, gastrin, cholecystokinin, somatostatin and insulin in dairy cows and their calves.

The aim of the present study was to examine how different types of early interaction between dairy cows and their calves influence milking/suckling-related hormone release in the cows and sucking/bucket-drinking related hormone release in calves. Eighteen cows of the Swedish Red and White breed were studied during the first week after parturition. The cows were machine milked twice daily, and allotted to one of three treatments: [1] cow and calf were kept together and the cow was allowed to suckle the calf for 30 min about 1 h before each milking; [2] cow and calf were kept together and the calf was bucket fed twice daily; and [3] cow and calf were separated immediately after parturition, and the calf was kept in a single box and was bucket fed twice daily. Blood samples were collected around day 7 from both cows and calves. The plasma levels of oxytocin, prolactin, cortisol, gastrin, cholecystokinin (CCK), somatostatin and insulin were analysed. In the cows the levels of oxytocin, prolactin and cortisol were influenced by all three treatments, except for the level of cortisol which did not respond to suckling. The main finding was that the release of oxytocin was as significantly greater during suckling compared with machine milking. In the calves, the hormone levels were also influenced by the different milk feeding routines. The plasma concentrations of oxytocin, gastrin, CCK and insulin increased in response to milk ingestion in all treatments. However, during sucking, the increase of oxytocin was significantly greater than during bucket drinking. In addition, a strong correlation between oxytocin and insulin was found in response to sucking. Further, significant increases in prolactin and somatostatin, and a decrease in cortisol were found during sucking. The level of somatostatin also increased in response to bucket feeding when calves were kept separately. During bucket feeding, no significant correlation was found with oxytocin, but strong correlations between the gastrointestinal hormones gastrin, CCK, somatostatin and insulin were seen. Together these data suggest that different hormonal patterns were triggered in the cows by suckling and milking and in the calves by sucking and bucket drinking. This is further supported by different correlation patterns observed in the calves in response to sucking and bucket feeding. The present findings imply that management routines for cows and calves during the first week after parturition have consequences for the physiology of the animals.

Animal Husbandry↗

Effect of pentagastrin, secretin and cholecystokinin on intestinal water and sodium absorption in the rat.

To test the effect of pentagastrin, secretin and cholecystokinin on intestinal absorption of water and sodium, duodenal , jejunal and ileal loops were prepared in situ in fasted rats, filled with NaCl solution containing 14C PEG and 22Na as markers. Hormones were given by intracardiac injection, the content of the loops was collected 1 h later. In control rats, water and sodium absorption were 5, 30 and 50% of the injected quantities in duodenum, jejunum and ileum, respectively. Pentagastrin (ICI; 1.25, 5 and 20 microgram/100 g) increased the duodenal absorption of water and sodium and decreased the ileal absorption. Secretin (GIH; 0.17, 0.85 AND 3.5 CU/100 g) induced a duodenal secretion and decreased the ileal absorption. Cholecystokinin (GIH; 1, 4, 8 AND 12 IDU) induced a duodenal secretion and decreased the ileal absorption at the lowest dose while the effect disappeared with higher doses. As previously known, the gastrointestinal hormones modulate intestinal absorption of water and sodium. This study indicates that the effect depends on dose and segment under study.

Animals↗

Bombesin in human neuroendocrine (NE) neoplasms.

Bombesin is a 14 amino acid peptide isolated from amphibian skin which was found to have stimulatory effects upon gastric and pancreatic secretions, release of gastrointestinal hormones, gallbladder contraction and bronchoconstriction. It is present in amphibian gastric endocrine cells, avian proventriculus endocrine cells and avian brain. In mammals it is present mainly in nerve cells and fibers. The only mammalian endocrine cell shown to date to have bombesin is the P-cell in fetal lung. Bombesin is also found in mammalian brain, with its highest concentration in the hypothalamus. We examined several groups of human neuroendocrine neoplasms for the presence of bombesin by immunohistochemistry. Our findings indicate that bombesin is present 68% of bronchial carcinoids, 65% of pulmonary neuroendocrine carcinomas, 62% of neuroendocrine carcinomas of the skin, 5-10% of pheochromocytomas and extraadrenal paragangliomas and 35% of gastrointestinal carcinoids and neuroendocrine carcinomas. Parallel studies in a wide variety of non neuroendocrine neoplasms failed to reveal the presence of bombesin. We conclude that bombesin is a highly specific marker of neuroendocrine differentiation and thus a valuable tumor marker. Furthermore, its specificity compares favorably with another neuroendocrine marker, neuron specific enolase, an enzyme thought to be present only in neural tissues and neuroendocrine cells but recently found in non neural human tissues and non neuroendocrine neoplasms.

Bombesin↗

Effect of infusion of salmon calcitonin on the secretion of somatostatin and gastrin in man.

In vitro and animal studies have pointed out complex interrelations between gastrointestinal hormones and calcitonin. To analyse the acute effects of calcitonin in more detail, patients undergoing surgery were infused intravenously with synthetic salmon calcitonin, a potent analog of the human hormone. Samples were taken after 0, 30 and 60 minutes from the hepatic, portal and a peripheral vein. Somatostatin and gastrin were determined by radioimmunoassay. The mean basal levels of somatostatin in peripheral and hepatic venous plasma (14.2 and 15.6 pg/ml) were significantly lower than in portal plasma (45.6 pg/ml), indicating effective removal by the liver. After infusion of calcitonin there was a general rise in somatostatin levels and an increase in the gradient between hepatic and portal blood. Basal gastrin levels were highest in the portal vein when compared intraindividually. The differences disappeared after calcitonin infusion with a concomitant systemic reduction of gastrin levels. Thus, calcitonin is able to stimulate the secretion of somatostatin from the gastrointestinal tract and does reduce gastrin secretion, possibly via the stimulation of somatostatin secretion.

Adult↗

Early satiety in cancer patients: a common and important but underrecognized symptom.

INTRODUCTION: The severity of anorexia correlates with the presence of early satiety. The sense of fullness limits nutritional intake. The symptom is poorly understood because most assessment questionnaires do not include early satiety. METHODS: Patients rarely volunteer early satiety. Central and peripheral mechanisms may be involved in the genesis of early satiety. These would include central sensory specific satiety, food aversions, diurnal changes in intake, gastric motility and accommodation and as gastrointestinal hormones. CONCLUSIONS: Prokinetic medications, such as metoclopramide are used to treat early satiety. However, other medications which influence gastric accommodation such as clonidine, sumatriptan, or sildenafil, or diminish enteric afferent output such as kappa opioid receptor agonists, may favorably influence early satiety and should be subject to future research. Translational research is needed to understand the relationship of early satiety to gastric motility and accommodation.

Anorexia↗

[Pancreatic blood flow and its regulation].

Regulatory mechanisms of the pancreatic circulation include general hemodynamics, autonomic nervous system, circulating vasoactive peptides, hormones and certain autoregulatory properties of the pancreatic vasculature. The pancreatic response to sympathetic stimulation is a decrease in pancreatic blood flow (PBF) due to co-release of norepinephrine and NPY. In contrast parasympathetic stimulation increase PBF and this could be attributed to the co-release of acetylcholine, VIP, PHI, GRP and other neuropeptides. Neurotransmitters of the NANC system such as: SP, NK, SK, CCK, VIP, cGRP are also potent neurogenic vasodilatators of the pancreatic vasculature. Control of the pancreatic circulation is related, in part to the exocrine function of the gland. Several factors have been implicated as mediators of functional hyperemia in the pancreas. Among these factors are such low PO2, ions, kinins, PGs, nucleotides and gastrointestinal hormones. Recently endothelium-derived NO has been shown to play an important role in the mediation of the pancreatic vasodilation in response to various endogenous factors.

Animals↗

Tissue-specific expression of the rat secretin precursor gene.

Secretin is a 27-amino acid gastrointestinal hormone that stimulates the secretion of bicarbonate-rich pancreatic fluid. We previously demonstrated that the secretin precursor gene is expressed in the brain as well as in the small intestine. In this study, we demonstrated that the abundance of secretin precursor mRNA in the heart, lung, and kidney was comparable to that of the small intestine. The nucleotide sequences of the coding regions of the secretin precursor mRNAs in these tissues were identical to those of the small intestine, indicating that secretin precursor proteins produced in these tissues are identical to those in the small intestine. This is the first report that the secretin precursor gene is also expressed in the heart, lung, kidney, and testis as well as in the gastrointestinal tract and brain.

Animals↗

PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line.

The rat pancreatic carcinoma cell line AR4-2J was screened for growth-associated genes linked to the mitogenic effect of the novel gut brain hormone, pituitary adenylate cyclase activating polypeptide (PACAP). Using the mRNA differential display technique, we identified and sequenced an unknown rat gene, PACAP-responsive gene 1 (PRG1), which is highly homologous to gly96, a novel murine gene of unknown function. The PRG1 cDNA sequence of 1.1 kb encodes a 160-amino acid protein. Using targeted PCR, the gene structure of PRG1, constituting 0.6 kb of the promotor region, and the DNA coding region, including a single 107-bp intron, were established from rat genomic DNA. In AR4-2J cells, PACAP(1-38) increased PRG1 mRNA levels up to 10-fold in a rapid (30 min), transient (3-6 h), and dose-dependent (ED50, <1 nM) fashion. The growth-stimulating gastrointestinal hormones cholecystokinin and gastrin showed a similar degree of PRG1 induction, and the PACAP-related peptides vasoactive intestinal peptide and secretin were without effect. The transcriptional inhibitor actinomycin D, various protein kinase C inhibitors, and the calmodulin inhibitor W-7 strongly reduced PRG1 induction by PACAP, whereas the translational inhibitor cycloheximide potently increased PRG1 mRNA levels in unstimulated and PACAP-stimulated cells. Feedback-mediated hyperplasia of the rat exocrine pancreas induced by oral treatment of rats with the protease inhibitor camostate (FOY-305) was preceded by a 15-fold transient elevation of PRG1 mRNA levels. These data suggest that PRG1 is an early-response gene linked to PACAP-induced growth of AR4-2J cells as well as to hyperplasia of the rat exocrine pancreas in vivo.

Amino Acid Sequence↗

[Effect of antacids on intestinal motility].

Disturbances of gut motility occur frequently under a highdose antacid regimen. Typical symptoms are diarrhea and constipation. They are due to the cations of the antacids. Aluminum causes constipation, magnesium induces diarrhea, and calcium has no definite motor effect. The following mechanisms of action have to be taken into consideration: effects of the cations on the smooth muscle of the gut, on the enteric nervous system and on the release of gastrointestinal hormones as well as alterations of the physiochemical properties of the intraluminal contents. Aluminum inhibits the motor activity of the stomach and intestine, magnesium stimulates muscle contractions; however, the simultaneous activation of the intrinsic nerves, which are predominantly inhibitory, by magnesium may conceal the muscular effects of this cation. The diarrhea under a highdose regimen of antacid combinations appears to be due predominantly to the osmotic-secretory effects of the antacids.

Animals↗

Immunohistochemical and in situ hybridization studies of gonadotropin releasing hormone (GnRH) and its receptor in rat digestive tract.

GnRH(LH-RH) is first discovered in the hypothalamus and found to have a role in regulation of reproduction. With the study on it deepening, GnRH was demonnstrated that it also exists in a number of organs beyond the hypothalamus and acts on extrapituitary organs. To study whether digestive tract synthesizes GnRH and its receptor and, if it does, by what cells. In the experiment, the locallizations of GnRH and its receptors in rat digestive tract were studied using immunohistochemistry and in situ hybridization. The parietal cells of gastric gland, the villous and glandular epithelium in small and large intestine and parasympathetic ganglion cells of myenteric plexus showed GnRH immunoreactivity; GnRH mRNA hybridization signal was detected. The epithelium of gastric pit and the cells above in digestive tract showed GnRH receptor immunoreactivity; GnRH receptor mRNA hybridization signal was detected. The immunoreactive and signal materials distributed in cytoplasm of all positive cells, with nuclei being immunonegative and with no hybridization signal. These results suggested that the digestive tract can produce GnRH and express GnRH receptor; GnRH may also be a gastrointestinal hormone.

Animals↗

Effects of peptide hormone structure on H+ secretion by Necturus gastric mucosa.

The actions of human synthetic gastrin I(G), the C-terminal tetrapeptide of gastrin (T), and the C-terminal octapeptide of cholecystokinin (OP) on acid secretion and transepithelial potential difference (PD) of the isolated Necturus gastric mucosa were determined. All three peptides induced H+ secretion, but the maximum H+ output was less with OP than with G or T. G and OP produced their maximum H+ output at lower molar concentrations than T. G- and OP-stimulated secretion was long sustained, but T-stimulated secretion rapidly returned to basal levels. T- and G-stimulated secretion was partially inhibited by the addition of OP. Evidence is presented that T rapidly disappears from solutions exposed to gastric mucosa, whereas G does not. Washing sensitized the mucosa to subsequent addition of T. The results suggest that the action of the common C-terminal tetrapeptide of G, T, and OP is modified by the preceding amino acid sequences, and that T, the smallest of the three peptides, is rapidly degraded by gastric tissue in vitro. The implications of the work for the study of gastrointestinal hormone structure-function relationships in isolated tissue preparations are discussed.

Animals↗