The controls of gastrointestinal movements: some old and new views.
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Action Potentials↗
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Letter: Pancreatic cholera and vip.
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Diarrhea↗
Impaired cholecystokinin secretion in bulimia nervosa.
Bulimia nervosa is a prevalent disorder of unknown cause, characterized by recurrent episodes of uncontrollable eating. In the light of recent evidence that the gastrointestinal hormone cholecystokinin induces satiety and reduces food intake in laboratory animals and humans, we investigated the hypothesis that abnormalities in cholecystokinin secretion and satiety may occur in patients with bulimia and contribute to their disturbed eating patterns. Blood levels of cholecystokinin and subjective satiety were measured in 14 women with bulimia and 10 normal women before and after a mixed-liquid meal. The total integrated plasma cholecystokinin response to eating was significantly impaired in patients with bulimia (P less than 0.05) as was postprandial satiety. Fasting cholecystokinin levels were similar in both populations (approximately 0.8 pmol per liter). After eating, however, mean (+/- SEM) peak plasma cholecystokinin levels increased to 4.1 +/- 0.9 pmol per liter in normal controls but to only 2.1 +/- 0.2 pmol per liter in patients with bulimia nervosa (P less than 0.05). After an open trial of tricyclic antidepressants in a subgroup of five patients with bulimia, the postprandial cholecystokinin response to eating increased significantly, to 6.6 +/- 1.2 pmol per liter (P less than 0.05), and there was an increase in the satiety response. We conclude that patients with bulimia do not have normal satiety and have impaired secretion of cholecystokinin in response to a meal. Preliminary evidence suggests that both these abnormalities may be improved by treatment with tricyclic antidepressants.
Adolescent↗
Localization of vasoactive intestinal polypeptide (VIP) to central and peripheral neurons.
The localization of the vasoactive intestinal polypeptide (VIP) has been studied with immunohistochemistry and radioimmunoanalysis. VIP immunoreactivity is present in gastrointestinal nerves, which constitute a quantitatively important nerve population that may be intrinsic to the gut wall. VIP-immunoreactive neurons are also found within the ventromedial hypothalamus and give off processes that travel latteral to the third ventricle. Results of radioimmunoanalysis strongly indicate that the immunoreactive material represents true VIP. Thus VIP, at present a gastrointestinal hormone candidate, appears to represent a new neuronal peptide occurring in both the central and peripheral nervous system.
Animals↗
Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood flow and motility.
In immunohistochemical studies using antisera to peptide YY (PYY), a 36 amino acid polypeptide isolated from porcine duodenum, it was found that PYY-like immunoreactivity occurred mainly in endocrine cells of the gastrointestinal mucosa. PYY-immunoreactive cells were particularly abundant in the distal intestine and have been observed in five species, including man. By radioimmunoassay it was found that, in the rat, the amount of PYY immunoreactivity was about 100-fold higher in the colon than in the duodenum. The chromatographic profiles of PYY immunoreactivity from the rat colon and porcine PYY on a SP-Sephadex ion exchanger were similar. Furthermore, serial dilutions of extracts from the rat colon and porcine PYY had parallel displacement curves in radioimmunoassay. Close intraarterial administration of PYY in cats caused an intestinal vasoconstriction and an inhibition of jejunal and colonic motility. Simultaneously there was a rise in systemic arterial blood pressure. These effects of PYY were also observed after pretreatment with adrenergic blocking agents. It is concluded that PYY is a gastrointestinal peptide that is present mainly in endocrine cells of distal intestine and that has effect on both intestinal motility and the cardiovascular system.
Animals↗
Primary structure of the gene encoding rat preprosomatostatin.
The somatostatins are peptides of 14 and 28 amino acids that are produced in a variety of endocrine and nonendocrine tissues. These peptides inhibit the secretion of many different pituitary, pancreatic, and gastrointestinal hormones. Previously, we have reported the isolation and nucleotide sequence of a cDNA derived from a rat medullary thyroid carcinoma that encoded preprosomatostatin , a 116-amino-acid precursor of somatostatin. We now report the structural characterization of the rat somatostatin gene isolated from recombinant bacteriophage libraries prepared from rat liver DNA. The gene spans 1.2 kilobases and is interrupted within the coding sequence of prosomatostatin by a single intron of 630 bases. A sequence characteristic of a Goldberg- Hogness promoter ("TATA" box), T-T-T-A-A-A-A, is located 31 bases upstream from the transcriptional initiation site. A repetitive DNA sequence, highly reiterated in the rat genome, is located in the 5' flanking region of the gene within 900 bases of the initiation site.
Amino Acid Sequence↗
A bombesin immunoreactive peptide in milk.
Immunoreactivity to the amphibian peptide bombesin was found in instant nonfat dry milk (ca. 0.7 ng/ml) and in the whey of whole or skim bovine milk (ca. 1.2 ng/ml) even after ultracentrifugation. The soluble immunoreactivity was associated with a peptide exhibiting the following characteristics: (i) parallel displacement in an immunoassay using an antiserum recognizing bombesin amino acid residues 5-8; (ii) separation from both gastrin-releasing peptide and amphibian bombesin by gel filtration--the approximate Mr was 3,200; (iii) denaturation in urea, reduction by dithiothreitol, and acetylation by iodoacetamide had no effect on its elution profile by gel-filtration chromatography and the aggregation of added bombesin to milk proteins or peptides was not observed; (iv) reversed-phase HPLC separated milk immunoreactivity from gastrin-releasing peptide and bombesin; (v) digestion by trypsin yielded a smaller immunoreactive peptide fragment, whereas nearly all immunoreactivity was lost by treatment with alpha-chymotrypsin; and (vi) the level of immunoreactivity was unaffected by boiling. These data show that milk is an exogenous source of bombesin-like immunoreactivity, which may account for the increase of gastric acid and gastrointestinal hormone levels after the consumption of milk.
Animals↗
Modulation of cytosolic free calcium levels by extracellular phosphate and lanthanum.
The effects of extracellular phosphate and lanthanum on cytosolic free Ca2+ [( Ca2+]i) levels were studied in isolated rat pancreatic acini. In the presence of 1.28 mM Ca2+ and 1.0 mM phosphate, the mean resting [Ca2+]i level was 120 nM. Omission of phosphate from incubation medium significantly lowered this value to 94 nM. The gastrointestinal hormone cholecystokinin octapeptide (CCK-8) rapidly enhanced both [Ca2+]i levels and 45Ca2+ efflux, irrespective of the presence or absence of phosphate. Lanthanum (0.1 mM), a compound known to block transmembrane Ca2+ fluxes, attenuated both actions of CCK-8, but only in the absence of extracellular phosphate. There was a concomitant decrease in amylase secretion induced by 0.1 nM CCK-8 but not by 10 nM CCK-8, without a significant change in cellular ATP levels. The inhibitory actions of lanthanum on CCK-8-stimulated [Ca2+]i levels were very rapid and were mimicked only by prolonged incubation of acini in Ca2+-free medium supplemented with EGTA. Omission of phosphate from incubation medium also lowered basal [Ca2+]i levels in IM-9 lymphocytes. These findings suggest that extracellular phosphate may modulate resting [Ca2+]i levels in pancreatic acini and other cell types and that mobilization of intracellular Ca2+ may partly depend on the availability of a lanthanum-sensitive pool of cell-surface Ca2+ that is not readily removed by EGTA.
Aminoquinolines↗
Processing of prosecretin: isolation of a secretin precursor from porcine intestine.
A precursor to the gastrointestinal hormone secretin has been isolated. The starting material for the purification of the precursor was a peptide fraction purified from pig intestinal extracts, containing peptides with a molecular weight higher than that of secretin. The purification could be followed by measurement of secretin bioactivity (alkali secreted in the pancreatic juice of anesthetized cat). Sequence analysis of the isolated secretin precursor revealed a 71-amino acid residue polypeptide that contained the sequence of secretin N terminally, followed by a Gly-Lys-Arg sequence and a C-terminal extension of 41-amino acid residues. With the exception of an arginine residue, which occurs directly after the Gly-Lys-Arg sequence, the remainder of the C-terminal residues in this precursor are identical to the 40 C-terminal residues predicted by the recently described cDNA sequence for porcine preprosecretin. Compared to the deduced preprosecretin sequence, a stretch of 32 amino acid residues directly following the Gly-Lys-Arg sequence is missing in the now purified secretin precursor. This implies that differential splicing may occur when the secretin gene transcript is processed to mRNA.
Amino Acid Sequence↗
Secretin: structure of the precursor and tissue distribution of the mRNA.
Secretin is a 27-amino acid gastrointestinal hormone that stimulates the secretion of bicarbonate-rich pancreatic fluid. The unusually high number of serine, leucine, and arginine residues in secretin has precluded the use of oligonucleotides to screen cDNA libraries to isolate a secretin cDNA. In the present study, a short cDNA encoding porcine secretin was amplified from duodenal mucosal first-strand cDNA template by using 16,384- and 4096-fold degenerate primers in the DNA polymerase chain reaction. From the sequence of the amplified cDNA, an unambiguous oligonucleotide probe was designed to screen a cDNA library. Here we report the sequences of cDNAs encoding the porcine and rat secretin precursors. The predicted amino acid sequences reveal that each precursor consists of a signal peptide, an N-terminal peptide, secretin, and a 72-amino acid C-terminal peptide. Secretin has been highly conserved through evolution. Rat secretin differs from its porcine counterpart by a single glutamine-for-arginine substitution at position 14. In contrast, the amino acid sequences of the C-terminal peptides are only 39% conserved between the two species, suggesting that the C-terminal peptide does not have an essential physiologic function. RNA blot hybridizations reveal that the rat secretin gene is expressed throughout the small intestine. Although secretin immunoreactivity has been localized in the central nervous system by some laboratories, we are unable to detect secretin mRNA in tissues of the central nervous system by Northern blot hybridization.
Amino Acid Sequence↗
A role for the p38 mitogen-activated protein kinase/Hsp 27 pathway in cholecystokinin-induced changes in the actin cytoskeleton in rat pancreatic acini.
Cholecystokinin (CCK) and other pancreatic secretagogues have recently been shown to activate signaling kinase cascades in pancreatic acinar cells, leading to the activation of extracellular signal-regulated kinases and Jun N-terminal kinases. We now show the presence of a third kinase cascade activating p38 mitogen-activated protein (MAP) kinase in isolated rat pancreatic acini. CCK and osmotic stress induced by sorbitol activated p38 MAP kinase within minutes; their effects were dose-dependent, with maximal activation of 2.8- and 4.4-fold, respectively. The effects of carbachol and bombesin on p38 MAP kinase activity were similar to those of CCK, whereas phorbol ester, epidermal growth factor, and vasoactive intestinal polypeptide stimulated p38 MAP kinase by 2-fold or less. Both CCK and sorbitol also increased the tyrosyl phosphorylation of p38 MAP kinase. Using the specific inhibitor of p38 MAP kinase, SB 203580, we found that p38 MAP kinase activity was required for MAP kinase-activated protein kinase-2 activation in pancreatic acini. SB 203580 reduced the level of basal phosphorylation and blocked the increased phosphorylation of Hsp 27 after stimulation with either CCK or sorbitol. CCK treatment induced an initial rapid decrease in total F-actin content of acini, followed by an increase after 40 min. Preincubation with SB 203580 significantly inhibited these changes in F-actin content. Staining of the actin cytoskeleton with rhodamine-conjugated phalloidin and analysis by confocal fluorescence microscopy showed disruption of the actin cytoskeleton after 10 and 40 min of CCK stimulation. Pretreatment with SB 203580 reduced these changes. These findings demonstrate that the activation of p38 MAP kinase is involved not only in response to stress, but also in physiological signaling by gastrointestinal hormones such as CCK, where activation of Gq-coupled receptors stimulates a cascade in which p38 MAP kinase activates MAP kinase-activated protein kinase-2, resulting in Hsp 27 phosphorylation. Activation of p38 MAP kinase, most likely through phosphorylation of Hsp 27, plays a role in the organization of the actin cytoskeleton in pancreatic acini.
Actins↗
Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway.
The gastrointestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is one of the most important regulators of insulin secretion following ingestion of a meal. GIP stimulates insulin secretion from the pancreatic beta-cell via its G protein-coupled receptor activation of adenylyl cyclase and other signal transduction pathways, but there is little known regarding subsequent protein kinase pathways that are activated. A screening technique was used to determine the relative abundance of 75 protein kinases in CHO-K1 cells expressing the GIP receptor and in two pancreatic beta-cell lines (betaTC-3 and INS-1 (832/13) cells). This information was used to identify kinases that are potentially regulated following GIP stimulation, with a focus on GIP regulation of the ERK1/2 MAPK pathway. In CHO-K1 cells, GIP induced phosphorylation of Raf-1 (Ser-259), Mek1/2 (Ser-217/Ser-221), ERK1/2 (Thr-202 and Tyr-204), and p90 RSK (Ser-380) in a concentration-dependent manner. Activation of ERK1/2 was maximal at 4 min and was cAMP-dependent protein kinase-dependent and protein kinase C-independent. Studies using a beta-cell line (INS-1 clone 832/13) corroborated these findings, and it was also demonstrated that the ERK1/2 module could be activated by GIP in the absence of glucose. Finally, we have shown that GIP regulation of the ERK1/2 module is via Rap1 but does not involve Gbetagamma subunits nor Src tyrosine kinase, and we propose that cAMP-based regulation occurs via B-Raf in both CHO-K1 and beta-cells. These results establish the importance of GIP in the cellular regulation of the ERK1/2 module and identify a role for cAMP in coupling its G protein-coupled receptors to ERK1/2 activity in pancreatic beta-cells.
Animals↗
A novel effect of bismuth ions: selective inhibition of the biological activity of glycine-extended gastrin.
Although bismuth salts have been used for over two centuries for the treatment of various gastrointestinal disorders, the mechanism of their therapeutic action remains controversial. Because gastrins bind two trivalent ferric ions with high affinity, and because ferric ions are essential for the biological activity of glycine-extended gastrin 17, we have investigated the hypothesis that trivalent bismuth ions influence the biological activity of gastrins. Binding of bismuth ions to gastrins was measured by fluorescence quenching and NMR spectroscopy. The effects of bismuth ions on gastrin-stimulated biological activities were measured in inositol phosphate, cell proliferation, and cell migration assays. Fluorescence quenching experiments indicated that both glycine-extended and amidated gastrin 17 bound two bismuth ions. The NMR spectral changes observed on addition of bismuth ions revealed that Glu-7 acted as a ligand at the first bismuth ion binding site. In the presence of bismuth ions the ability of glycine-extended gastrin 17 to stimulate inositol phosphate production, cell proliferation, and cell migration was markedly reduced. In contrast, bismuth ions had little effect on the affinity of the CCK-2 receptor for amidated gastrin 17, or on the stimulation of inositol phosphate production by amidated gastrin 17. We conclude that bismuth ions may act, at least in part, by blocking the effects of glycine-extended gastrin 17 on cell proliferation and cell migration in the gastrointestinal tract. This is the first report of a specific inhibitory effect of bismuth ions on the action of a gastrointestinal hormone.
Bismuth↗
Effect of age on the exocrine pancreatic secretion of the preruminant milk-fed goat.
The effect of age on the exocrine pancreatic function was studied in fifteen Granadina goat kids during the second, third and fourth postnatal week. The animals, chronically catheterized, were bottle-fed on goat milk twice a day. Pure pancreatic juice was collected from 1 hour before and throughout 8 hours after milk ingestion. Pancreatic flow rate, bicarbonate and chloride concentrations, total protein content and enzyme activities were determined. In resting conditions, pancreatic flow rate augmented with age, probably reflecting an increase in body and pancreas weight. Resting amylase and lipase activities recorded significant increases during the fourth week of life. That may be associated, respectively, to the immediate change to a high-starch diet and to a simultaneous decrease in the salivary lipase levels. Our results also showed age-related differences after ingestion of milk, mainly concerning the volume response and the lipase output. The latter can be explained in the same way as regarding resting conditions. With respect to the volume response, several factors could be implicated, such as the circulating levels of gastrointestinal hormones, the sensitivity of the pancreas to such stimuli, the maturation degree in the secretory mechanisms of the gland or the development of the digestive tract.
Aging↗
Different effects of whole milk and a fermented milk with the same fat and lactose content on gastric emptying and postprandial lipaemia, but not on glycaemic response and appetite.
Longitudinal studies indicate that milk and fermented milk products lower basal plasma cholesterol concentrations, despite their high content of saturated fat, and therefore have favourable health effects. However, there have been few studies on the postprandial effects of milk products. The present study compared the effect of whole milk with a fermented milk, A-38, on postprandial carbohydrate and lipid metabolism, gastric emptying and appetite. Eight healthy young men participated. On the two test days, they arrived fasting for collection of baseline values before consuming the meals, which for a 75 kg subject consisted of 1.4 litre milk or fermented milk, plus 165 mg [13C]acetate (for later determination of gastric emptying by a [13C]acetate breath test). Lactose (15 g) was added to the A-38 meal to equalize the lactose content. Postprandially the A-38 meal resulted in a slower gastric emptying rate than milk (P<0.001). Furthermore, the A-38 meal resulted in a greater increase and a quicker decrease of the triacylglycerol content in all lipoprotein fractions (LDL-fraction, P<0.05; other fractions, P<0.001) and of the gastrointestinal hormones (cholecystokinin and peptide YY, P<0.05; gastric inhibitory polypeptide and glucagon-like polypeptide-1, P<0.001). There were no significant differences in appetite sensations (measured by visual analogue scale) or in the glucose and insulin response (P>0.10). The slower emptying rate of the liquid phase after the A-38 meal is probably due to the higher viscosity of A-38. The lower and more prolonged triacylglycerol response after the milk meal might be caused by coagulation of milk in the stomach.
Adult↗
The influence of the migrating motor complex on the postprandial endocrine response.
BACKGROUND: The phase of the migrating motor complex (MMC) in the proximal small intestine at meal intake modulates gastric emptying, which is accelerated after intake during phase II. In the present study the relationship between phase of the MMC at meal intake and the postprandial endocrine response was studied. METHODS: Eight healthy subjects ingested a caloric liquid meal of 2020 kJ during phase I and late phase II of the intestinal MMC, respectively, in a randomized order. Blood samples were drawn at regular intervals after meal intake and analysed for insulin, gastrin, neurotensin, cholecystokinin, motilin, and somatostatin by radioimmunoassays. RESULTS: The area under the curve (AUC) until 15 min for serum insulin (P<0.05) and plasma neurotensin (P<0.02) and AUC until 120 min for serum gastrin (P<0.05) were higher after intake during late phase II than after phase I. Plasma cholecystokinin increased earlier (P<0.05) after intake during late phase II than after phase I. Plasma motilin and somatostatin were not influenced by preceding phase of the MMC. CONCLUSIONS: This study shows that the phase of intestinal MMC at meal intake modulates the postprandial endocrine response, which may be explained by the prior entry of nutrients to the small intestine after intake during phase II.
Adult↗
Temporal aspects of the pathophysiology of human ulcer disease.
In this paper, a peptic ulcer is considered from the perspective that it is representative of a heterogeneous group of multifactorial determined or influenced disorders having a common pathomorphologic expression. This heterogeneity involves pathophysiological attributes, including both functional (including secretory and motility events and their respective driving mechanisms) and morphologic alterations that relate to mucosal resistance. Patients with duodenal ulcer (DU) have been observed to exhibit alterations, in comparison to normal subjects, in the circadian rhythm characteristics of several gastrointestinal functions. Prominent among these are altered amplitudes of several circadian-organized gastric variables, such as intragastric pH, gastrin, pepsinogen and gastric mitotic index. With respect to any given variable, a reduced group amplitude (a measure of one-half the peak-trough difference of a 24-hr rhythm) could signify an increased dispersion of acrophases (the location of the peak of a circadian rhythm along the 24-hr time scale) reflecting interindividual variation in synchronization schedules, sleep-wake patterns, or chronobiologic alterations. A reduced interindividual amplitude further supports the concept of the heterogeneity of peptic disease. A decrease in the intraindividual amplitude of certain gastric rhythms implies an altered temporal pattern over the 24 hr. This is consistent with the hypothesis of a decrease in the amount of time available for recovery of a given function or set of integrated functions, and hence, increased susceptibility to mucosal injury. Normal high-amplitude variation in gastrointestinal functioning over the 24 hr appears to be required for natural restoration of the gut.
Circadian Rhythm↗
Multiple doses of secretin in the treatment of autism: a controlled study.
UNLABELLED: Dramatic effects on autistic behaviour after repeated injections of the gastrointestinal hormone secretin have been referred in a number of case reports. In the absence of curative and effective treatments for this disabling condition, this information has created new hope among parents. Although controlled studies on the effect of mainly one single dose have not documented any effect, many children still continue to receive secretin. Six children enrolled in a double-blind, placebo-controlled crossover study in which each child was its own control. Human synthetic secretin, mean dose 3.4 clinical units, and placebo were administered intravenously in randomized order every 4th wk, on three occasions each. The measurement instruments were the visual analogue scale (VAS) and the aberrant behaviour checklist (ABC). Statistically significant differences were found for placebo in 3 out of 6 children and for secretin in one child, using parental ratings only (VAS scores). Differences were small and lacked clinical significance, which was in accordance with the overall impression of the parents and teachers and visual inspection of graphs. CONCLUSION: In this placebo-controlled study, multiple doses of secretin did not produce any symptomatic improvement.
Appetite↗