Surgical management of reflux oesophagitis.
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Esophagitis, Peptic↗
Biomedical subjects
H T Debas
Publications and source records attributed to H T Debas.
Metabolism of gastrin and cholecystokinin by endopeptidase 24.11 from the pig stomach.
The purpose of this investigation is to examine the metabolism and inactivation of human and porcine gastrin 17 (nonsulfated) (G-17) and cholecystokinin octapeptide (sulfated) (CCK-8) by gastric endopeptidase 24.11. Endopeptidase 24.11 was isolated by immunoaffinity chromatography using a monoclonal antibody to the kidney enzyme. Peptides were incubated with endopeptidase 24.11. The digests were either fractionated by reverse-phase high-pressure liquid chromatography and the products identified by amino acid analysis or they were used for bioassays. Digests of human gastrin were assayed for stimulation of acid secretion in the anesthetized rat, and cholecystokinin digests were assayed for the stimulation of amylase secretion from isolated rat pancreatic acini. Human G-17 was degraded by cleavage of the Trp4-Leu5,Ala11-Tyr12,Gly13-Trp14,Trp14 -Met15, and Asp16-Phe17-NH2 bonds, and the fragments (1-16), (1-13), (1-11), (1-4), (5-11), (5-13), (12-13), (12-14), (14-16), and (17-NH2) were identified. Porcine G-17 was degraded by hydrolysis of the Ala11-Tyr12,Gly13-Trp14, and Asp16-Phe17-NH2 bonds producing (1-16), (1-13), (1-11), (12-13), (14-16), and (17-NH2) fragments. CCK-8 was degraded by hydrolysis of the Gly4-Trp5 and Asp7-Phe8-NH2 bonds, and the fragments (1-7), (1-4), (5-7), (5-8), and (8-NH2) were identified. There was a progressive decline in the biological activity with incubation time.
Amino Acid Sequence↗
Physiology and pathophysiology of gastrin: a review.
Recent advances in understanding the physiology and pathophysiology of the gastrointestinal hormone, gastrin, are reviewed. Details of gastrin biosynthesis, secretion, and cellular actions may have broad implications for other peptide hormones. Potentially useful antigastrin drugs are described. Areas of future development are suggested.
DNA Replication↗
Clinical significance of gastrointestinal hormones.
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Apudoma↗
Advances in drug therapy for peptic ulcer disease.
Recently, three new drug types have emerged to treat peptic ulceration. We compared the mechanism of action of omeprazole and somatostatin-14, both inhibitors of gastric acid, with that of tetraprenylacetone, a drug thought to be cytoprotective in the upper gut. Omeprazole and somatostatin-14 caused potent inhibition of meal-stimulated acid secretion in the dog (92% +/- 6% and 97% +/- 1%, respectively). On the other hand, tetraprenylacetone had no significant inhibitory effect on acid secretion (4% +/- 17%). In separate studies, tetraprenylacetone was shown to be a stimulant of gastric bicarbonate secretion in the rabbit, increasing bicarbonate secretion from a basal level of 0 to 86 +/- 28 pmol/2 h. Tetraprenylactone was also found to be a strong stimulant of canine pancreatic bicarbonate secretion. The ability of tetraprenylacetone to stimulate endogenous bicarbonate secretion may explain its ability to heal ulcers both experimentally and clinically.
Animals↗
Chronic duodenal and gastric ulcer.
During the past two decades, major advances have been made in our understanding of basic gastric physiology. Appreciation of cellular biology has contributed to rapid progress in gastric pharmacology. Clinicians may choose from a large and rapidly growing list of antiulcer drugs. The proper choice of medical or surgical therapy depends on knowledge of the pathophysiology of peptic ulceration and of the inherent limitations of each approach. Selective drug use, tailoring of medical regimens to individual clinical situations, and the combination of medical and surgical treatments will play prominent roles in the future management of peptic ulceration.
Duodenal Obstruction↗
Gastrin.
Gastrin is the most important peptide in the regulation of gastric acid secretion. This communication reviews important new developments in our knowledge of its synthesis, action, and pathophysiology. The gene for human gastrin has been isolated, and it encodes a pre-pro-gastrin which is a 101-aminoacid peptide containing within it the structure of big gastrin (G34) with a C-terminal glycine extension. Post-translational processing by alpha-amidation of the glycine-extended progastrin results in generation of the active forms of the peptide (G34, G17). When gastrin binds to its receptor on the parietal cell, phosphatidylinositol biphosphate (IP2) in the plasma membrane is converted to inositol 1,4,5-triphosphate (IP3), which acts as the secondary intracellular messenger to increase intracellular calcium and initiate the process that eventually leads to acid secretion. Although an abnormality in gastrin release or action is not thought to be crucially important in the genesis of duodenal ulcer, these patients nevertheless demonstrate increased postprandial gastrin release, and a greater sensitivity of their parietal cells to gastrin. Hypergastrinemia is the cause of peptic ulceration in the Zollinger-Ellison syndrome, in primary gastrin cell hyperplasia or hyperfunction, and in the retained antrum syndrome. Ulcerogenic hypergastrinemia must be distinguished from hypergastrinemia that is secondary to hypoacidity or anacidity, as is seen in atrophic gastritis or postvagotomy.
Female↗
Recent advances in the treatment of duodenal ulcer disease. A surgical perspective.
Chronic peptic ulceration is a disease process in transition. During the past two decades, the disease has changed in its incidence, in its presentation and in its medical consequences. The pathogenesis of acid-peptic disease has been the major focus of numerous investigations, and major advances in understanding basic gastric physiology have led to specific and increasingly effective therapeutic approaches. With the introduction of H(2)-receptor antagonists, the treatment of peptic ulceration has been radically altered, and many new therapies await clinical trial. Surgeons treating gastroduodenal ulceration will require greater knowledge of gastric physiology and an increasingly refined appreciation of both the power and limitations of various medical and surgical therapies.
Duodenal Ulcer↗
Partial purification of a novel stimulant of gastric acid secretion from canine non-antral mucosa.
A novel stimulant of gastric acid secretion was extracted and purified from the non-antral gastric mucosa of the canine stomach and some of its biological properties were examined. Tissue was boiled in water and extracted in 2% trifluoroacetic acid. The stimulatory activity was purified by a combination of reverse-phase high pressure liquid chromatography (HPLC) and gel filtration. Fractions were assayed for a stimulation of basal, pentagastrin- and histamine-stimulated gastric acid secretion in the anaesthetized rat. Stimulatory activity was eluted from reverse-phase HPLC columns with acetonitrile and its elution from Sephadex G-10 and G-50 columns suggested a molecular weight of 1,000 to 3,000. The highly purified extracts enhanced basal, pentagastrin- and histamine-stimulated acid secretion in the rat. A stimulatory fraction was purified which was devoid of immunoreactive gastrin and gastrin-releasing peptide and contained only small amounts of histamine. Its chromatographic properties differed from those of histamine and acetylcholine. On two occasions the stimulant was purified to homogeneity and found to contain amino acids. Insufficient pure material was obtained for full characterization. The stimulant has been tentatively called oxyntin.
Amino Acids↗
Effect of increased intracranial pressure on gastric acid secretion.
The effects of intracranial pressure on gastric acid secretion were studied in 30 rabbits. Intracranial pressure was increased in a graded and controlled fashion using a barostat connected to a cannula in the lateral cerebral ventricle. Eighteen rabbits were studied under urethane anesthesia with a background subthreshold intravenous infusion of bethanechol. Twelve rabbits were studied in the conscious state. Increases in intracranial pressure led to immediate and significant increases in gastric acid output in a dose-related manner in both conscious and anesthetized animals. Serum gastrin levels did not increase in either group of animals. Vagotomy only partially abolished the increase in acid outputs seen with increased intracranial pressure, whereas atropine completely blocked the response. We conclude that increased intracranial pressure causes stimulation of acid secretion by a gastrin-independent cholinergic mechanism that is only partially mediated by the vagus.
Animals↗
New horizons in the pharmacologic management of peptic ulceration.
Greatly improved understanding of the cellular basis for gastric acid secretion and gastroduodenal mucosal defense has led to a dramatic improvement in the pharmacologic treatment of peptic ulcer disease. The advances produced by cimetidine and ranitidine are being continued by a new generation of histamine receptor antagonists, as well as by other anti-ulcer agents. These new drugs, when used appropriately, will greatly expand the surgeon's ability to treat patients with peptic ulcer disease. A knowledge of the pathophysiologic characteristics of peptic ulceration and of the inherent limitations of each agent will become increasingly important for surgeons who treat these patients.
Acetylcholine↗
Peptide YY release by fatty acids is sufficient to inhibit gastric emptying in dogs.
Peptide YY is a candidate enterogastrone localized to endocrine cells of the ileocolonic mucosa. The purpose of the present study was to determine if blood levels of peptide YY observed after perfusion of the intestine with fatty acids are capable of slowing gastric emptying. Gastric emptying of a 300-ml saline meal was monitored during intravenous infusion of normal saline or graded doses of peptide YY. Gastric emptying was significantly inhibited by infusion of peptide YY in doses of 200 and 400 pmol/kg X h. During the saline control study, 229 +/- 12 ml of the 300-ml saline meal emptied by 10 min. This figure was reduced (p less than 0.01) to 110 +/- 28 ml by the infusion of peptide YY at a dose of 200 pmol/kg X h. This dose of peptide YY produced plasma concentrations (delta PYY = 239 +/- 50 pM) that were lower than those seen in response to intestinal perfusion of oleic acid (delta PYY = 395 +/- 55 pM) in the same animals. We conclude that perfusion of the intestine with oleic acid releases peptide YY in amounts sufficient to slow gastric emptying.
Animals↗
Trophic effect of amniotic fluid on fetal gastrointestinal development.
To determine if amniotic fluid or its constituent trophic factors influence fetal gastrointestinal tract development we developed models of fetal esophageal ligation to prevent swallowing of amniotic fluid and fetal esophageal cannulation with infusion of various substances to mimic fetal swallowing. A total of 43 fetuses was studied. Esophageal ligation resulted in a 32% reduction in gastric weight and a 40% reduction in serum gastrin level, compared to unoperated controls, whereas intestinal and liver weights were unchanged. Gastric acid concentration averaged 43.4 +/- 7.7 mumole/ml in control fetuses, but only 0.5 +/- 0.5 mumole/ml following esophageal ligation. Infusion of Ringer's lactate solution intragastrically did not prevent the changes in gut development seen after esophageal ligation. In contrast, infusion of bovine amniotic fluid resulted in relatively normal gut development, with a gastric acid concentration of 28.5 +/- 6.9 mumole/ml and liver and gastric weights and serum gastrin levels no different from control. Epidermal growth factor had a potent trophic effect on both somatic and gastrointestinal fetal growth and resulted in a mean gastric acid concentration of 35.2 +/- 6.6 mumole/ml. In contrast, pentagastrin, although restoring gastric weight to control values, had no effect on gastric acid secretion, with a mean of 0.1 +/- 0.1 mumole/ml. We conclude that fetal swallowing of amniotic fluid is essential in fetal gastrointestinal development, possibly via luminal trophic actions of peptides such as epidermal growth factor and gastrin.
Amniotic Fluid↗
Calcitonin gene-related peptide-induced selective inhibition of gastric acid secretion in dogs.
Calcitonin gene-related peptide (CGRP) is a 37-residue peptide recently characterized in the brain and found in high concentrations in the gut, particularly in the stomach and pancreas. The effects of intravenous infusion of human and rat CGRP (260 pmol . kg-1 . h-1) on gastric secretion and emptying and pancreatic exocrine secretion were studied in conscious dogs. CGRP inhibited by 60-75% gastric acid secretion stimulated by a meal, sham feeding, or step doses of bombesin but did not modify acid response to step doses of histamine or bethanechol. The inhibitory effect of CGRP is not due to blockage of postprandial or bombesin-stimulated gastrin release. CGRP did not influence basal or meal-stimulated pancreatic exocrine secretion or the rate of gastric emptying of a saline meal. These results indicate that CGRP is a potent and selective inhibitor of gastrin-mediated acid secretion in dogs and, under these conditions, did not alter other gastrointestinal functions such as gastric emptying or pancreatic exocrine secretion.
Animals↗
Contrasting cholinergic dependence of pancreatic and gallbladder responses to cholecystokinin.
Cholinergic receptors for cholecystokinin (CCK) have been identified on neurons of the enteric nervous system, including those of the gallbladder. To determine whether any differences exist in the extent to which CCK action depends on muscarinic cholinergic receptors in the pancreas and gallbladder, 11 dogs with pancreatic and 7 dogs with biliary fistulas were given increasing doses of intravenous CCK-8 (15-250 ng X kg-1 X h-1) or intraduodenal sodium oleate (0.1-9 mmol/h) with and without atropine pretreatment. Pancreatic protein response to CCK-8 was dose dependent, reaching a maximal of 448 +/- 76 mg/15 min at the highest dose. Atropine pretreatment caused nonsignificant reduction in the response to the lowest dose but had no effect on the responses to the other doses, with the response to the highest dose of CCK being 473 +/- 82 mg/15 min. In contrast, gallbladder contraction as measured by bile fistula bilirubin output was very sensitive to inhibition by atropine. Bilirubin responses to 16, 32, 62.5, 125, and 250 ng X kg-1 X h-1 were 14 +/- 5, 18 +/- 5, 28 +/- 5, 36 +/- 6, and 52 +/- 12 mg/h, respectively, without atropine and 0 +/- 0, 6 +/- 2, 7 +/- 2, 18 +/- 4, and 18 +/- 4 mg/h with atropine pretreatment. Similarly, pancreatic responses to sodium oleate infusion were less susceptible to inhibition by atropine than were the gallbladder responses. With respect to pancreatic protein secretion, the response to only the lowest dose of sodium oleate was significantly inhibited by atropine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Enterogastrone-like effect of peptide YY is vagally mediated in the dog.
Intraluminal fat inhibits gastric secretion through as yet undetermined mechanisms which involve release of one or more hormonal enterogastrones. As intraluminal fat releases Peptide YY (PYY) in amounts sufficient to inhibit meal-stimulated acid secretion, this ileo-colonic peptide exhibits the characteristics required of an enterogastrone. The present study seeks to determine the mechanism by which PYY inhibits acid secretion by examining the effects of PYY on gastric acid stimulated by pentagastrin, histamine, and bethanechol. In addition, effects of PYY on the acid response to sham feeding and distention of a denervated gastric pouch were examined. A dose of PYY (400 pmol X kg-1 X h-1) was employed that reproduced blood levels observed after intestinal perfusion with oleic acid and inhibited the acid secretory response to an intragastric meal by 35 +/- 6%. This same dose of PYY maximally inhibited histamine- and pentagastrin-stimulated acid secretion by 28 +/- 7% (P less than 0.05), and 17 +/- 4% (P less than 0.05), respectively. Although PYY had no effect on bethanechol-stimulated secretion it markedly inhibited the secretory response to sham feeding, maximally reducing secretion by 90 +/- 4% (P less than 0.01). We speculate that PYY acts by inhibiting acetylcholine release from vagal nerve fibers rather than by inhibiting acetylcholine's action on the parietal cell. The demonstration that PYY virtually abolishes cephalic phase acid secretion while having little if any effect on the response to exogenous secretogogues gives PYY unique characteristics among the known hormonal inhibitors of gastric secretion.
Animals↗
The use of somatostatin and its analogs in the treatment of surgical disorders.
Somatostatin is a naturally occurring peptide with a wide spectrum of biologic actions, most of which are inhibitory in nature. It has wide distribution, and within the gastrointestinal tract is is found in the pancreas, the stomach, intestinal mucosa, and myenteric neurons. It appears to function as a classic circulating hormone, as well as both a paracrine or locally acting agent and a neurocrine agent. Because of its inhibitory actions on gut endocrine, secretory, and motor functions, it has potential applicability in the treatment of a variety of disorders of interest to the surgeon. Indeed, it has been used successfully in the management of upper gastrointestinal hemorrhage, secretory diarrhea, short bowel syndrome, pancreatitis, gastrointestinal fistulas, and peptide-secreting tumors of the gut (apudomas). This review discusses physiology, pathophysiology, and therapeutic applications of somatostatin that may be important in surgical practice.
Diarrhea↗
Interactions of vasoactive intestinal polypeptide and cholecystokinin octapeptide on the control of gallbladder contraction.
The gallbladder is supplied by three types of vagal fibers: cholinergic, cholecystokinin (CCK)-ergic, and vasoactive intestinal polypeptide (VIP)-ergic. Most previous studies on the interaction of VIP and CCK on gallbladder contraction have been in vitro. In this study we evaluate this interaction more fully in vivo using six dogs with chronic bile fistula. Dose-response curves were constructed to CCK-8 alone and to VIP alone. The effect of graded doses of VIP on maximal response to CCK-8 was also studied. CCK-8 caused the expected dose-related stimulation of gallbladder contraction, while graded doses of VIP had the opposite effect. VIP also caused a dose-related inhibition of the maximal response to CCK-8, decreasing bilirubin output from 39 +/- 8 to 15 +/- 3 mg/hr (p less than 0.05). The corollary to these findings is that gallbladder tone and contraction is regulated by the interplay of stimulatory cholinergic-CCK-ergic and inhibitory VIP-ergic fibers. Further, a plausible explanation for the variable effects of vagotomy on gallbladder contraction is that variable proportions of these opposing fibers are cut.
Animals↗