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Effect of drugs, hormones and electrical field stimulation on isolated muscle strips from human choledochoduodenal junction.

The behaviour of in vitro strips from the human choledochoduodenal junction would appear to be related to the anatomical location of origin of the strip. Strips from the papillary region showed low tone and obvious spontaneous rhythmic contractions (0 X 5-6/min). Strips from the region of the inferior choledochal sphincter showed, in ten out of fifteen specimens, spontaneous myogenic tone and gave a relaxation or a biphasic response (relaxation followed by contraction) to electrical field stimulation (0 X 3 ms pulses at 10 Hz for 5 s). All strips from human choledochoduodenal junction are remarkably insensitive to a variety of gastrointestinal hormones and to opioid agents.

Acetylcholine↗

The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide (GIP) in man.

The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide were investigated in six healthy volunteers. At the maximum infusion dose (0 . 5 pmol kg-1 min-1) a plateau concentration of 115 +/- 5 . 0 pmol/l plasma was obtained. On discontinuation of the infusion, the half-time of disappearance was calculated to be 20 . 3 +/- 1 . 2 min. The metabolic clearance rate was 2 . 6 +/- 0 . 1 ml kg-1 min-1 and the apparent space of distribution was 75 . 8 +/- 5 . 7 ml kg-1. Blood glucose, pancreatic and gastrointestinal hormones remained at basal concentrations throughout. No side effects were noted by any of the subjects studied.

Adult↗

[Synthesis of gastrointestinal agents].

The importance of syntheses of biologically active polypeptides especially of gastrointestinal hormones for medical research, is analyzed; six points, as the main goals of a synthetic approach, are discussed with respect to their special significance and are confirmed by six examples.

Chemistry, Organic↗

The recognition system of dietary fatty acids by the rat small intestinal cells.

Small intestinal epithelial cells interact with a rather high concentration of fatty acids derived from the diet. These fatty acids directly or indirectly regulate the functions of the small intestine. We report here that linoleic acid and oleic acid markedly increased the influx of 45Ca2+ into the small intestinal epithelial cell line (IEC 6). By contrast, octanoic acid, methyl linoleate, and linolyl alcohol had no effect on the influx. Acidic amino acids, methyl linoleate, and linolyl alcohol, inhibited the linoleic acid-induced influx of 45Ca2+, indicating that activation of the influx by linoleic acid depended on the chain length and was affected by the presence of a carboxyl group. Of the gastrointestinal hormones, somatostatin specifically inhibited the linoleic acid-induced influx of 45Ca2+.

Amino Acids↗

Sepsis increases production of total secreted proteins, vasoactive intestinal peptide, and peptide YY in isolated rat enterocytes.

The effect of sepsis on the synthesis of endogenous and secretory proteins, including vasoactive intestinal peptide (VIP) and peptide YY (PYY), was determined in enterocytes from jejunum of rats. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. Total endogenous and secreted protein synthesis was assessed in incubated jejunal enterocytes by measuring incorporation of 3H-phenylalanine into protein. Release of VIP and PYY into the medium of incubated enterocytes and cellular levels of the gut peptides were measured by radioimmunoassay. Sixteen hours after CLP, synthesis rates of both endogenous and secreted proteins were increased, and this effect of sepsis was most pronounced in cells from the lower parts of the villi and crypts. Enterocytes from septic rats released more VIP and PYY into the incubation medium, and approximately half of the peptides they released were newly synthesized VIP and PYY. Intracellular levels of VIP and PYY were increased as early as 4 hours after induction of sepsis. Our results suggest that sepsis stimulates the synthesis of endogenous and secretory proteins, including certain gut peptides, in small intestine mucosa. This is consistent with previous observations of increased circulating levels of VIP, PYY and other gastrointestinal hormones during sepsis. The biological significance of increased synthesis of gut peptides and other intestinal proteins during sepsis remains to be determined.

Analysis of Variance↗

Stimulation by gastro-intestinal hormones of cyclic adenosine 3': 5'-monophosphate accumulation and insulin release in isolated pancreatic islets of the rat.

In collagenase isolated rat pancreatic islets, CCK-PZ, SHG, secretin and glucagon stimulated the accumulation of cAMP, in physiological ranges. The resulting increment of cAMP showed a good correlation with insulin release stimulated by either glucagon or secretin, but not by SHG or CCK-PZ. In the same system, 14CO2 production from glucose-U-14C was significantly increased by either SHG or CCK-PZ. The results presented in this report are compatible with the hypothesis that insulin release by gastrointestinal hormones may be mediated by cAMP in the B-cell in the case of either glucagon or secretin; whereas, in the case of either SHG or CCK-PZ, it may presumably be mediated by an unknown mechanism in glucose metabolism, other than c-AMP.

Animals↗

The effect of GIH and Boots secretin and cholecystokinin on duodenal ulcers in the rat.

The effects of two commercially available preparations of secretin and cholecystokinin have been studied on experimental duodenal ulcers in the rat. Pentagastrin and carbachol infused subcutaneously over 24 hours produced a 100% incidence of duodenal ulcers. A dose-related inhibition of these ulcers was found using secretin obtained from the Gastrointestinal Hormone Laboratory, Stockholm (GIH). Boots secretin had no such inhibitory action and may even have aggravated the duodenal ulcerogenesis. Similar results were obtained with both GIH cholecystokinin and Boots pancreozymin.

Animals↗

Isolation, characterization, and developmental expression of the rat peptide-YY gene.

In the present study we describe the isolation, structural characterization, and developmental expression of the gene encoding the intestinal hormone peptide-YY. Examination of the nucleotide sequence of the peptide-YY gene reveals that each of the four exons encodes a functional domain of its mRNA that is analogous to the corresponding exons of the genes encoding two closely related peptides neuropeptide-Y and pancreatic polypeptide. The highly conserved structural organization of the genes encoding this family of three peptides suggests that each gene arose from the duplication of a common ancestral gene. Developmental studies reveal that the peptide-YY gene exhibits a complex pattern of tissue-specific expression in the gastrointestinal tract. Unlike many gastrointestinal hormones, peptide-YY mRNA levels are highest before birth. The pancreas appears to be the major site of peptide-YY gene expression in the fetus, exceeding colonic expression by 7-fold. The abundance of peptide-YY mRNA in the pancreas declines rapidly after birth, in contrast to the colon, where mRNA levels are maintained throughout development into adulthood. Expression of the peptide-YY gene before birth antedates the presence of known enteral secretagogues for this hormone, suggesting alternate mechanisms that control its biosynthesis during development.

Amino Acid Sequence↗

Peptide YY: metabolism and effect on pancreatic secretion in dogs.

Peptide YY is an ileocolonic peptide that inhibits meal-stimulated pancreatic secretion when infused in a dose of 400 pmol/kg X h. In this study pancreatic secretion was monitored in response to increasing doses of secretin or cholecystokinin-octapeptide (62.5, 125, 250, and 500 ng/kg X h) during the simultaneous infusion of either saline or peptide YY (400 pmol/kg X h). Peptide YY significantly (p less than 0.05) inhibited the secretory response to the three lowest doses of each pancreatic secretogogue, reducing the bicarbonate response to the 62.5-ng/kg X h dose of secretin by 86% +/- 6% and the protein response to the same dose of cholecystokinin by 57% +/- 16%. In the second limb of the study, the half-life of peptide YY (11.7 +/- 21 min) and the metabolic clearance rate (13.8 +/- 1.6 ml/kg X min) were found to be similar to those of other gastrointestinal hormones. We conclude that inhibition of meal-stimulated pancreatic secretion by peptide YY can be explained by its ability to decrease the responsiveness of the pancreas to endogenous secretogogues.

Animals↗

Feedback regulation of pancreatic exocrine secretion in animal and man.

This chapter focuses on studies dealing with the feedback mechanism of pancreatic exocrine secretion in animal and man. Clear evidence is presented that this feedback mechanism is working in the rat and the pig and that this feedback is mediated in the rat by the gastrointestinal hormones pancreozymin (enzyme secretion) and secretin (volume and bicarbonate secretion). Two novel peptides have been described--the 'CCK-releasing peptide' originating from the small intestinal mucosa, and the 'monitor peptide' cosecreted together with the enzymes in the pancreatic juice--to account for the stimulation of pancreatic enzyme secretion by the release of CCK. A similar feedback regulation of pancreatic secretion is working in man. It remains as yet controversial whether the feedback in humans is regulated via hormonal or neural pathways. It is also a matter of debate whether this feedback regulation of pancreatic enzyme secretion could be utilized for therapeutic aims in the treatment of pain in patients with chronic pancreatitis.

Animals↗

Evidence for vasoactive intestinal polypeptide (VIP) altering the firing rate of preoptic, septal and midbrain central gray neurons.

The effect of the iontophoretic application of vasoactive intestinal polypeptide (VIP) on the extracellular electrical activity (neuronal firing rate) of 91 neurons localized in the preoptic (PO), septal (S) region and midbrain central gray (MCG) was studied in urethane-anesthetized female rats. When applied in minute quantities, VIP induced both excitatory (N = 14) and inhibitory (N = 8) changes in the membrane excitability of PO and S neurons (total N = 58), while only inhibitory (N = 9) changes were observed in the MCG neurons (total N = 33; thus 24 MCG neurons were found to be unresponsive to VIP). The latency and duration of the VIP-induced response was, for the most part, characterized by a rapid onset and persisted for the duration of the ejecting pulse. However, five out of the 58 PO and S neurons and one out of the 33 MCG neurons did show responses that were longer and more variable in latency and duration. Of 26 PO neurons recorded and tested with VIP, only five neurons were determined to be antidromically identified (AI) as having their axons in the median eminence. The application of VIP increased the neuronal firing rate in two AI PO neurons, decreased the activity in one, and was ineffective in altering the activity in two other AI PO neurons. The VIP-induced changes in the neuronal firing rate appear to be specific and reproducible, and not related to the ejecting current nor pH of the solution. The results suggest that VIP, a gastrointestinal hormone that is also localized in the brain, can alter the neuronal firing rate of hypothalamic and midbrain neurons, thus providing additional evidence of its possible influence on brain and neuroendocrine function.

Animals↗

[The pancreas and alcohol].

The action of acute and chronic administration of ethanol on pancreatic exocrine secretion in humans and several animal species is reviewed. If the data concerning the secretory action of ethanol on the pancreas are to the property assessed, several experimental variables have to be considered. Acute intravenous administration of ethanol inhibits basal and hormonally stimulated pancreatic secretion of bicarbonate and protein in nonalcoholic humans and most species of animals tested. Oral or intraduodenal ethanol causes moderate stimulation of pancreatic bicarbonate and enzyme secretion. Since anticholinergic agents and truncal vagotomy diminish the ethanol-induced inhibition of pancreatic secretion in the intact animal, it is possible that the action of ethanol on the pancreas is at least partly mediated by inhibitory cholinergic mechanisms. The action of ethanol on the pancreas may also be mediated by release of gastrointestinal hormones. Intravenous and oral administration of ethanol releases gastrin in dogs but not in humans. Pancreatic polypeptide is unlikely to be the hormonal mediator of the ethanol-induced inhibition of exocrine pancreatic secretion in humans and dogs, since ethanol does not release pancreatic polypeptide. The main secretory changes induced by chronic alcoholism in humans and dogs are increased basal secretion of pancreatic enzymes and decreased basal bicarbonate output, and these secretory changes may favour the occurrence of protein precipitates which are believed to be the first lesion of chronic pancreatitis in man. A decrease in the concentration of "pancreatic stone protein" in pancreatic juice may favour the development of protein precipitates in chronic alcoholic patients.

Acute Disease↗

[Etiology of benign papillary stenoses].

In domestic pigs repeated applications of gastrointestinal hormones (pancreozymin, secretin) as well as cholecystectomy lead to histologic transformation of the epithelium in the area of the papilla of Vater and to inconstant pressure changes in the common duct.

Ampulla of Vater↗

Chemical messengers: a view from the gut.

The peptides usually called gastrointestinal hormones belong to a broader group of regulatory substances distributed in many parts of the body and delivered to their targets not only by the blood but also by neural and paracrine paths. The neural, endocrine, and paracrine cells as a group might be called "regulator cells" and the chemical messengers they produce might be called "regulins." Twenty peptides have been isolated from the alimentary tract and pancreas: 12 have been sequenced, 4 have been partially sequenced, and 4 more have been identified only by immunoreactivity. Gastrin, gastric inhibitory peptide, glucagon, insulin, and secretin can be regarded as established hormones that are released into the blood by identified stimuli and produce identified physiological responses. The evidence for the hormonal status of cholecystokinin, pancreatic polypeptide, and motilin is incomplete but suggestive. The possible physiological roles of the other 12 peptides remain to be determined. If specific antagonists of these peptides can be found, they will greatly assist in elucidating the peptides' physiological roles.

Animals↗

Effect of dialysate glucose load on plasma glucose and glucoregulatory hormones in CAPD patients.

The effect of a dialysate exchange with both 1.5 and 4.25% glucose solutions on plasma levels of glucose, insulin, gastric inhibitory polypeptide (GIP), and glucagon has been investigated in 5 continuous ambulatory peritoneal dialysis (CAPD) patients. Only in the case of the 4.25% solution did plasma glucose levels rise above 100 mg/dl. 4 of the 5 patients responded to this change with a marked insulin secretion. Employing the 1.5% solution, plasma glucose remained stable and only a slight insulin stimulation was observed in 2 patients. It is concluded that provided the 4.25% dialysates are used only occasionally, there will be no continuous stimulation of the pancreatic beta-cells due to absorption of glucose from the dialysate alone during CAPD treatment. GIP levels are highly elevated in CAPD patients. A dialysate exchange with either a 1.5 or a 4.25% glucose solution had no effect on this gastrointestinal hormone. Hyperglucagonemia was also observed in this collective. An initial suppression of glucagon levels occurred in 4 of the patients after a 4.25% dialysate exchange. The 5th patient demonstrated an initial rise followed by a later decrease in glucagon, a response similar to that reported in adult onset diabetes after an oral glucose tolerance test.

Adult↗

Experimental studies of intestinal ion and water transport.

A major advance in transport physiology was H. H. Ussing's development of the voltage-clamp method, and later the Koefoed-Johnsen-Ussing model for Na+ transport. In the same decade, J. C. Skou identified the Na(+)-K(+)-ATPase, which maintains the Na+ and K+ gradients that drive most epithelial transport processes. With this foundation, Danish scientists have pursued the mechanism of ion transport and the resulting solute-linked water flow. Recent contributions have been on isosmotic transport, suggesting solute recycling, and KCl-water cotransport in the basolateral epithelial cell membrane. Efficient small intestinal nutrient absorption is dependent on coupling to the Na+ gradient. Cotransport of Na+ and glucose is quantitatively the most important absorptive mechanism in the small intestine, as illustrated by the success of oral rehydration solutions in diarrhoea. The majority of amino acids are likewise transported by Na+ dependent carriers, but recent experiments have identified a concomitant Cl- dependency for some. Regulation of intestinal secretion, both under normal digestive processes, and in response to enterotoxins, has turned out to be very complex. It involves local and central neuronal regulation through an array of neurotransmitters and local actions of gastrointestinal hormones. Major effectors are the submucosal neurons and the main transmitters serotonin, vasoactive intestinal peptide, acetylcholine, substance P, and neurotensin. Development of antisecretagogues is impeded by the existence of several receptor subtypes and significant species differences. The Na+ and water-conserving properties of the large intestine have been shown to be regulated by adrenocortical hormones, with aldosterone as a potent stimulator of colonic Na+ absorption. A major colonic function is the symbiosis with the anaerobic bacterial population. The fermentation of carbohydrate to short-chain fatty acids, which can be absorbed, supplements small intestinal digestive function.

Animals↗

Antacids and hormones.

Antacids are neutralizing compounds which have been shown to hasten ulcer healing and to prevent bleeding from stress ulcerations. Owing to gastric alkalinization, gastrin will be released following antacid ingestion, a condition similar to that following the ingestion of a meal. Gastrin release and, more important, acid rebound also occur when the gastric mucosa comes into contact with calcium chloride. These findings indicate that acid rebound is independent of antral neutralization. Acid rebound and gastrin release will also be induced in duodenal ulcer patients by magnesium hydroxide. The magnitude of acid rebound represents one fourth to one third of the peak acid response to pentagastrin and is more marked following calcium than magnesium antacid intake. The mechanism of acid rebound may be in part due to gastrin release, but may also be due to the direct effect of calcium on the parietal cell. In the duodenum, calcium and magnesium evoke pancreatic enzyme secretion and gall bladder emptying. This effect of both cations is attributed to the release of cholecystokinin. Owing to their chemical composition, antacids stimulate the release of gastrointestinal hormones, cause acid secretion and stimulate pancreatic enzyme secretion and gall bladder concentration. So far, it has not been proven that these effects of antacids and of their chemical constituents will limit their therapeutic use.

Antacids↗

The endocrine polypeptide cells of the human stomach, duodenum, and jejunum.

Thirty specimens of stomach, duodenum, and jejunum, removed at operation, were examined by optical microscopical, cytochemical, and electron microscopical techniques. The overall distribution of four types of endocrine polypeptide cell in the stomach, and three in the intestine, was determined. The seven cell types are described by names and letters belonging to a scheme for nomenclature agreed upon at the 1969 Wiesbaden conference on gastrointestinal hormones. The gastrin-secreting G cell was the only cell for which firm identification with a known hormone was possible. Although there was wide variation in the distribution of the various cells, from one case to another, striking differences were nevertheless observable, with respect to the G cell, between antra from carcinoma and from ulcer cases.

Bile Duct Neoplasms↗