Gastrointestinal hormones and apudomas

Interest and developments in gastrointestinal hormones "exploded" since was isolated by Gregory et al1 in 1964. Progress in radioim- Avram M. Cooperman, M.D. munoassay and chromatography had been re- sponsible for the "unleashing" of peptides Department of General Surgery whose nomenclature and properties are scarcely defined before newer peptides are identified and reported. It sometimes seems that there are more peptides than chemical effects attributed to them. Coupled with advances in the chemistry of peptides has been their identification in several clinical syndromes. These syndromes are now more easily recognized than previously because of increasing awareness and the availability of specific therapy (e.g., cimetidine for Zollinger- Ellison syndrome). Basic information about these hormones has been summarized in three recent reviews.2-4 In this paper, the three identified hormones (gas- trin, , and -pancreo- zymin) are discussed, and also several of the candidate hormones (peptides that await fur- ther clarification before classification as hor- mones), their sites of origin, mechanism of ac- tion, and relation to clinical syndromes. 83

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. 84 Cleveland Clinic Quarterly Vol. 44, No. 3 ' Cells of origin involve cyclic AMP, cyclic GMP, and 7 8 Many peptides and hormones may adenylcyclase. ' The association be- share a common cell of origin. This tween cyclic nucleotides and gastroin- testinal hormones was suggested by concept was popularized by Pearse et 9 al5*6 who noted the structural and Sutherland and Rail in 1958. A small chemical similarities of these cells. heat-stable compound found in cellu- Anatomically, the cells are similar to lar membranes capable of stimulating ganglion cells of the neural crest. glycogenolysis was isolated. This was These cells also share chemical simi- 3',5'-cyclic AMP, and it is likely the larities (demonstrated by histochemi- cellular or "second" messenger (the cal techniques). Five of these proper- circulating hormone is the first mes- ties are high fluorogenic amine con- senger). An important component in tent, amine precursor uptake, amino this system is adenylcyclase, an en- acid decarboxylase, side-chain car- zyme that catalyzes the conversion of boxyl groups, and specific immuno- adenosine triphosphate (ATP) to chemical properties. These common cyclic AMP and pyrophosphate. characteristics have led to the acro- Some hormones can penetrate the nym APUD cells for amine precursor cell membrane directly (steroids, es- uptake and decarboxylase cells. The trogens, androgens), but most pep- current list of these cells includes at tides cannot. For these hormones a least 24 specific cells in the , specific binding site is present on the thyroid, islets of Langerhans (pan- cell. Little is known about the sites or creas), and small intes- numbers of receptors except they are tine, large intestine and anterior pi- numerous (600 to 1000 beta-adrener- tuitary . gic receptors may exist on each tur- key erythrocyte).7 The binding site Early investigations showed the or- and affinity for receptors are spe- igin of APUD cells to be from the cific. Little is understood about the neural crest. These cells have been coupling between hormone and re- shown to migrate to the foregut, mid- ceptor, although phospholipids may gut, and hindgut. If this hypothesis is participate. Cations as Mg+ and Ca++ correct, the origins date back 500 mil- may influence adenylcyclase activity lion years in lower vertebrates. Not as well. Abnormalities in adenylcy- all peptide secreting cells are APUD clase are more than theoretical as dis- cells. Those from the parathyroid eases associated with defects in this and most cells of the anterior pitui- system. These include cholera, tary are not included in this classifica- pseudo-hypoparathyroidism, neph- tion. These totipotential cells may be- rogenic diabetes insipidus, and glyco- come overactive and by hyperplasia, gen storage disease. neoplasia, or dedifferentiation se- crete one or more peptides and cause While enzymatic action of adenyl- a variety of syndromes. cyclase can activate ATP to cyclic AMP, this is the first of the intracellu- lar steps necessary before a cellular Mechanism of action enzymatic function can be produced. The mechanism of action for most Cyclic AMP activates a specific pro- hormones in man has not been de- tein kinase which has two subunits, fined. The most popular hypotheses regulatory and catalytic. It is postu-

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. Summer 1977 Gastrointestinal hormones and apudomas 85 lated that a joined subunit is inactive ter two molecules await chemical and but cyclic AMP dissociates these biological definition. units, liberating a free catalytic com- Most circulating gastrin in man is ponent, the activated enzyme. There produced in the antrum. Less is pro- are many effects of cyclic AMP in- duced in the duodenum and upper cluding contraction of the myocar- (the antrum contains 5 to 10 dium, relaxation of smooth muscle, times more gastrin than the duo- aggregation of platelets, stimulation denum). The pancreatic islets have of exocrine pancreatic secretion, and little gastrin. Ninety percent of antral perhaps increasing secre- mucosal gastrin is G17 and this pre- tion (through one or more mecha- dominates in man. In pernicious ane- nisms). mia and the Zollinger-Ellison syn- In vitro studies have shown that drome G34 is predominant. Walsh13 secretin, glucagon, vasopressin, ste- studied plasma clearance and gastric roids, and vasoactive intestinal poly- secretory activity of G17, G34, and peptide (VIP) increase 3',5'-cyclic G13. G34 was cleared more slowly AMP levels. Gastrin, CCK-PZ, pan- than G17 or G13 and was as potent as creatic polypeptide, and prostaglan- G17 in stimulating gastric acid secre- dins do not increase cyclic AMP sug- tion; G13 was half as potent. Catabo- gesting another mechanism of ac- lism of the molecule is dependent on tion.8 its size. The half life of infused G17 and G34 in dogs was 3" and 15", re- Gastrin spectively. The larger forms are less Most basic and clinical research has readily metabolized. The kidneys been with gastrin. In 1905 Edkins10 play a major role in gastrin catabo- 14,15 presented a paper "On the Chemical lism. Several chemicals as well as Mechanism of Gastric Secretion" in mechanical stimuli release gastrin. which he reported that antral mu- Some of this work is based on animal cosal extracts in anesthetized cats experiments in which the stimulus stimulated gastric acid secretion. He and effect differ from man. In man named the hormone gastrin (for gas- the natural stimulus for gastrin tric secretin). This work was repro- release is food. High protein meals duced and clarified by Komarov11 in and the amino acid glycine are potent 1938. A significant advance was made releasers of gastrin. Fat, carbohy- by Gregory et al1 in 1964 when they drates, and intragastric alcohol are isolated a pure gastrin extract from poor stimulants. hog antral mucosa. This extract was a Mechanical distention of the stom- polypeptide containing 17 amino ach may release gastrin and cause acids in two peptide molecules (gas- acid hypersecretion; this work was in trin I and II). Many refinements and animals and not man. Recently, purifications have followed. There Olbe16 showed that mechanical dis- are at least five gastrin molecules. tention of the antrum caused acid hy- These include minigastrin (G13), lit- persecretion, but the mechanism was tle gastrin (G17), big gastrin (G34), through a pyloro-oxyntic reflux not consisting of at least six molecules, gastrin. big big gastrin and a larger molecule The vagal release of gastrin has 12 (component I of Rehfeld). The lat- been demonstrated by sham feeding

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. 86 Cleveland Clinic Quarterly Vol. 44, No. 3 ' in animals and duodenal ulcer pa- stomach and the release of acetylcho- tients. When sham feeding was tested line . Blockage of acetylcholine or his- in normal man there was no gastrin tamine will diminish these effects of release. It is likely that the mecha- gastrin. The increased secretion of nism of acid secretion is direct vagal by gastrin is secondary to acid stimulation. This variation in behav- secretion. ior may be due to a vagal inhibitor The third effect of pepsin by gas- that is present in normal man but trin on the stomach is trophic.19 This lacking in duodenal ulcer patients. action is confined to the oxyntic area Other hormones and chemicals may of the stomach, duodenum, and pan- release gastrin (calcium, epineph- creas. Cellular integrity and mucosal rine, and calcitonin).17,18 blood flow in hypergastrinemic states Inhibition of gastrin release is pri- are better maintained. Experimen- marily due to gastric acid. Con- tally, when continuous infusions of versely, any disease with decreased gastrin were given, oxyntic mitosis, acid secretion, e.g., pernicious ane- increased DNA and RNA synthesis mia, may be accompanied by in- was noted. In comparison no similar creased levels of serum gastrin. Of effect was seen after infu- increasing importance has been hor- sion. Furthermore, rat stomachs per- monal inhibition of gastrin secretion fused with pentagastrin showed a by other peptides —VIP, glucagon, 100% to 200% increase in incorpora- and secretin. tion of amino acids. Other pharmacologic actions of Actions of gastrin gastrin include stimulation of water The effects of gastrin on the gas- and electrolyte secretion from stom- trointestinal tract in man are phar- ach, , liver, ; macologic and physiologic. A phar- stimulation of the lower esophageal macologic effect is one that may not sphincter, decrease in gastric empty- be present with ordinary concentra- ing, relaxation of the pyloric sphinc- tions of circulating hormone. There ter and ileocecal valve. Gastrin also is disagreement about what is a phar- potentiates the release of gastrin in- macologic effect of gastrin and what hibitory polypeptide (GIP), VIP, in- is a physiologic one. At least three sulin, and calcitonin. actions of gastrin are physiologic: (1) stimulation of gastric acid secretion, Clinical application (2) stimulation of pepsin secretion, The major impact of serum gastrin and (3) a trophic effect on the stom- determinations done by radioimmu- ach. noassay has been to diagnose the Zol- The major effect of gastrin is to linger-Ellison syndrome. Although increase gastric acid secretion. The gastrin levels are elevated in many mechanism of action which ulti- diseases, there are few in which levels mately involves the is four to five times normal are found. complex, but probably involves an in- These include the Zollinger-Ellison teraction between acetylcholine, his- syndrome, retained antrum, perni- tamine, and gastrin. Gastrin injec- cious anemia, and hypergastrinemic tions in rats are followed by a de- hyperchlorhydric duodenal ulcer.20 crease in histamine content of the Normal values of serum gastrin

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. Summer 1977 Gastrointestinal hormones and apudomas 87 will vary at each laboratory, but as cent study of the "G" cells is posi- specificity of the assay and experi- tive.23 ence increase, the values decrease. The role of gastrin in duodenal ul- Normal values in our laboratory are cer disease is unclear; high, low, and 100 ± 50 pg/ml. Values depend on normal values have been reported.24 the laboratory, age of the subject, When increased absolute values may and obviously the amount of acid in be difficult to demonstrate in duo- the stomach. denal ulcer patients a defect in inhibi- While absolute values of gastrin in tion may be present. Lastly, disease the Zollinger-Ellison syndrome vary, which impairs gastrin catabolism levels four times normal should be (e.g., renal disease), may also be asso- suspected.21 The importance is ob- ciated with increased levels of serum vious. When the Zollinger-Ellison gastrin. syndrome is untreated or unrecog- nized, the mortality is still high Secretin (78%). Most effects of this syndrome Secretin was the first hormone are due to gastrin overproduction. identified by Bayliss and Starling25 in These include increased pancreatic 1902. A denervated loop of jejunum output, increased lower esophageal in an anesthetized dog was isolated sphincter pressure, and massive gas- and a small amount of hydrochloric tric hypersecretion. acid was placed in the lumen. This Sixty percent of patients with the was followed by an increased flow of Zollinger-Ellison syndrome have ma- . Despite this early lignant pancreatic tumors and nearly work nearly 60 years elapsed before half have metastasized at the time of this hormone was synthesized by surgery. Fewer patients have benign Bodanszky et al26 in 1966. A reliable, tumors, hyperplasia, or tumors of ec- reproducible radioimmunoassay for topic gastrin production.21 When the secretin is still difficult. Many early diagnosis is clear, total gastrectomy is assays may have been contaminated mandatory, except in the rare in- by other members of the secretin stance when isolated duodenal wall family (VIP, glucagon). Much work or ectopic tumors are present. When on this assay has been done by the diagnosis is in doubt stimulatory Bloom27 who, in addition to establish- tests with secretin and calcium are ing normal values in man, has de- done.18'22 These tests stimulate gas- fined some of the physiologic effects trin release in Zollinger-Ellison syn- of secretin. drome, but not in duodenal ulcer or The site of production of secretin "G" cell hyperplasia. The other dis- is the S cell in the duodenal mucosa. eases that are marked by high levels The molecule has 27 amino acids and of serum gastrin should be differen- it is strongly basic because of arginine tiated by careful history, biopsy, and and histidine units. stimulatory tests. Although a variety of properties Antral or "G" cell hyperplasia is a and effects have been attributed to controversial syndrome that is secretin, it is difficult to know what is marked by high levels of serum gas- a pharmacologic effect and what is trin but no rise in serum gastrin with physiologic. The presumed major ef- antral stimulation. Immunofluores- fects of secretin are thought to be an

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. 8 Cleveland Clinic Quarterly Vol. 44, No. 3 ' increased volume of pancreatic bicar- syndrome. As the radioimmunoassay bonate, increase in pancreatic blood becomes available and more specific, flow, decrease in gastric acid output its applications will increase and pre- to food and gastrin, and insulin re- cise data will be available. leasing effect inhibition of glucagon release, increase in pepsin output, Cholecystokinin-pancreozymin and perhaps lowering of the esopha- Ivy and Oldberg31 noted the fat in geal sphincter pressure. the intestine stimulated gallbladder Because of difficulties in secretin contraction. Fifteen years later, in assay it is difficult to know what stim- 1943, Harper and Raper32 noted in- ulates its release and what are its creased pancreatic secretion in simi- physiologic actions. The strongest lar experiments. It is now recognized stimulus for secretin release is acid in that both actions are hormonal, and the duodenum, particularly a pH of because of its first activity it is called 4.5 or less. Lowering the pH below cholecystokinin or CCK-PZ. 3.0 does not increase pancreatic bi- The amino acid sequence has been carbonate output (assuming titratable determined, but the hormone has acid is constant).28 Vagal stimulation not yet been synthesized. CCK has does not increase secretin output, but two molecules, one of 33, the other 39 vagotomy, atropine, or local anes- amino acids. The potency of CCK lies thetics applied to the duodenal mu- in its eight terminal amino acids.33 cosa do diminish the release of secre- Immunofluorescent studies have tin. Sugar in the duodenum, oral localized the cell of production to the feeding, and products of fat and pro- mucosa of the jejunum and duo- tein and amino acids are not, as was denum. Measurement of CCK has previously thought, effective stimuli been difficult due to limited methods 29 for secretin release in man. and a limited amount of pure CCK- The probable physiologic actions PZ available to develop a radioimmu- of secretin include an increase in noassay.33, 34 Go and Reilly33 have pancreatic output of water, electro- cautioned against over-interpretation lytes, trypsin and insulin, an in- or over-reliance on the present CCK creased volume and electrolyte out- assays. put of by the liver, decreased Stimuli to CCK release include gastric emptying in the stomach, re- duodenal, amino acids, food, fatty duced resting and gastrin stimulated acids, and hydrochloric acid. Duo- pressure of the lower esophagus and denal perfusions of amino acids have decreased motility of the duodenum. been followed by CCK release, par- These effects are subject to modifica- ticularly phenylalanine and trypto- tion as techniques to measure secre- phan.35 tin improve. Fatty acids longer than eight chains The clinical applications of secretin are effective releasers of CCK-PZ. In assay are presently limited. In duo- contrast hydrogen ions are weak re- denal ulcer disease impaired secretin leasers of CCK-PZ. The mechanism release to duodenal acidification has of action of CCK may be through been shown. Elevated tumor levels cyclic guanosine 3',5' monophos- have been reported by Schmitt et al30 phate. in a patient with the watery diarrhea Clinical applications of CCK-PZ

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. Summer 1977 Gastrointestinal hormones and apudomas 89 are limited because of the problems mone. With this assay it will be possi- in its measurement and availability. ble to better define the actions of Elevated levels have been found in each.38 the Zollinger-Ellison syndrome and Both forms of gut glucagon are in one patient with watery diarrhea.30 glycogenolytic and stimulate mobili- There may be practical applications zation of carbohydrate stores. Enter- of CCK because of its latter proper- oglucagonoid increases rapidly after ties. As a powerful stimulant to small the ingestion of food. This response bowel contractibility it may have a is enhanced by gastric resection or role in ileus. In contrast to the above bypass of the pylorus. The release of three hormones, the remaining pep- enteroglucagonoid is accompanied tides await promotion to hormonal by a rise in serum insulin. These ac- status. Many are newly described or tions may be responsible for lowering discovered and will be of value in the blood glucose and lessening symp- years ahead. toms of the dumping syndrome (ele- vated levels have been found in Gut glucagon (enteroglucagon) dumping). Increased levels have also Enteroglucagon is a hormone dif- been present in the watery diarrhea ferent and separate from pancreatic syndrome. Even more unusual has glucagon. The term gut glucagon is been the syndrome of necrolytic mi- descriptive and includes at least three gratory erythema, hyperglycemia, di- peptides that arise from the mucosa lated bowel, and benign or malignant of the small intestine.4,36 Two of pancreatic tumors that secrete gluca- 39 these molecules have a molecular gon. Cure may follow resection of a weight of 3500 (enteroglucagon) and solitary pancreatic tumor. the third has a molecular weight of 2900 (glucagon-like immunoreactivity VIP Gil). The existence of enterogluca- VIP is a 28-amino acid peptide resi- gon was suggested by Unger et al37 in due with broad biological activities on 1961 and eluted by chromatography the cardiovascular, respiratory, and in 1968. gastrointestinal systems. The biochemical structure of gut This peptide was first isolated by glucagon is similar to secretin and Said and Mutt.40 It is distributed VIP. Fourteen amino acids are iden- throughout the intestinal tract with tical and in similar positions to the highest concentrations in the ileum, secretin molecule. Two molecular jejunum, and colon. Most studies of forms of enteroglucagon exist in avi- the biological actions of VIP have ans. The cells of glucagon produc- been in animals. Its peripheral vaso- tion in many species (rat, baboon, dilatory actions resulted in its name. man, dog, and cat) are the gastric In the guinea pig it dilates the tra- fundus; Gil arises from cells of the chea and pulmonary vessels. In the intestine (many of which are in the it inhibits hista- ileum). mine and pentagastrin stimulated Radioimmunoassay techniques acid secretion; it inhibits pepsin se- have been developed that differen- cretion and relaxes smooth muscle. tiate pancreatic glucagon, gut gluca- Its effects on the pancreas include gon, and enteroglucagonoid hor- electrolyte and water secretion and

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. 90 Cleveland Clinic Quarterly Vol. 44, No. 3 ' an increase in bile flow. In the small cal applications of GIP are limited. intestine it stimulates secretion, in- Earlier reports of elevated GIP levels creases mucosal levels of cyclic AMP in watery diarrhea were probably in- and stimulates glycogenolysis, lipoly- accurate.46 sis and increases insulin release.41-43 The clinical importance and rele- Bombesin and other candidate hor- vance of VIP have been in its isola- mones tion in serum and tissue of patients A peptide isolated from the skin of with the watery diarrhea syndrome frogs that stimulated gastrin release and more recently in a patient with from the antrum stimulates pan- carcinoid syndrome.44 The watery creatic secretion and contraction of diarrhea syndrome is caused by be- the gallbladder (all in dogs).47, 48 Its nign or malignant pancreatic tumors, activities in man are unknown. Mo- islet cell hyperplasia, adrenal medul- tilin is an 11-amino acid polypeptide lary, or retroperitoneal tumors. The with a molecular weight of 2700. Its syndrome is characterized by severe cell of origin is the enterochromaffin watery diarrhea, hypokalemia and cells of the intestine. This peptide hypochlorhydria or achlorhydria. At enhances motility of transplanted least 75 cases have been reported, and denervated fundic pouches. Ra- many in the past few years. The diag- dioimmunoassay is available but clini- nosis should be suspected from the cal effects and activities are un- history, particularly when other known. more common causes of diarrhea are Chymodenin is a basic polypeptide excluded. Stool potassium levels are with a molecular weight of 5000 iso- elevated, hypokalemia is present, lated from impure secretin and cho- and gastric acid may be absent or the lecystokinin.49 Studies in rabbits have levels low. When benign tumors are shown a rise in pancreatic secretion present cure may follow resection. rich in chymotrypsinogen. This sug- For malignant tumors that have me- gests that specific pancreatic enzymes tastasized, steroids, streptozotocin, 5- may be controlled by a specific regu- fluorouracil, or radiation therapy lator. The implications of this con- may relieve symptoms. cept are both intriguing and uncon- ventional. GIP Avian pancreatic polypeptide (APP) GIP was isolated from the CCK-PZ was isolated by Kimmel et al50 during molecule by Brown et al45 in 1969 and the purification of insulin. The bio- was named because it inhibited stom- logical actions may vary with species. ach motility and secretion. This pep- In dogs it stimulated basal secretion tide has 43 amino acids and a molecu- of acid and inhibited pentagastrin lar weight of 5100. In humans GIP stimulated secretion. Also in dogs has been localized to the duodenum low doses of APP relaxed the gall- and jejunal mucosa. bladder without affecting gastric acid Glucose may release GIP and there or bile flow. A radioimmunoassay may be a lesser peak with fat stimula- species specific is available. APP has tion. GIP may now be measured by been isolated by immunofluorescence radioimmunoassay. The levels in studies in apudomas. normal man are 250 pq/ml. The clini- Coherin is a polypeptide isolated

Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. Summer 1977 Gastrointestinal hormones and apudomas 91 from posterior pituitary glands; it is cretion following portosystemic chemically distinct from oxytocin and shunts or small bowel resection. vasopressin.51 When injected into There is indirect evidence for this. dogs it inhibited jejunal contractions The variety of peptides and hor- followed by propagated contractions mones that arise from the intestinal lasting 2 to 5 hours. tract has rapidly increased in the past Urogastrone is an inhibitory sub- 10 years. I suspect radioimmunoassay stance found in the urine of man and will be developed for all of these pep- animals capable of inhibiting gastric tides and clinical applications or acid secretion.52 Pepsin response or physiologic functions then identified. cholinergic stimulation is also re- Perhaps the next step will be synthe- duced. This hormone may be active sis of these substances so that clinical in man. It may be measured by ra- use may stimulate deficient biochemi- dioimmunoassay but the site of pro- cal actions or treat clinical syndromes duction is unknown. caused by excess production of circu- Bulbogastrone is released from the lating peptides. duodenal bulb by acidification.53 It has not been chemically identified References but its mechanism of action is be- 1. Gregory H, Hardy PM, Jones DS, et al: lieved to be inhibition of acid secre- The antral hormone gastrin. Nature 204: 931-934, 1964. tion. Experimentally the duodenal 2. Grossman MI, and others: Candidate hor- bulb is the specific site of acid inhibi- mones of the gut. Gastroenterology 67: tion as postbulbar duodenal seg- 730-755, 1974. ments do not have these inhibitory 3. Walsh JH, Grossman MI: Gastrin (first of properties. Inhibition of gastrin stim- two parts). N Engl J Med 292: 1324-1334, 1975; Gastrin (second of two parts). N Engl ulated acid secretion by all stimuli fol- J Med 292: 1377-1384, 1975. lows bulbogastrone injection. Fur- 4. Rayford PL, Miller TA, Thompson JC: ther studies are needed to define its Secretin, cholecystokinin and newer gas- structure and physiological proper- trointestinal hormones (first of two parts). ties. N Engl J Med 294: 1093-1101, 1976; Secre- tin, cholecystokinin and newer gastrointes- Enteroxyntin, a humoral mecha- tinal hormones (second of two parts). N nism caused by the introduction of Engl J Med 294: 1157-1164, 1976. food into the small intestine resulting 5. Pearse AG, Coulling I, Weavers B, et al: in gastric acid secretion was observed The endocrine polypeptide cells of the hu- by Gregory and Ivy in 1941.54 The man stomach, duodenum, and jejunum. Gut 11: 649-658, 1970. nature of this substance has not been 6. Pearse AG, Polak JM, Heath CM: Poly- identified positively. Much work has peptide hormone production by "carci- 55 been done by Orloff et al. The sub- noid" apudomas and their relevant cyto- stance does not appear to be hista- chemistry. Virchows Arch (Zellpathol) 16: mine or gastrin, extra antral gastrin 95-109, 1974. 7. Steer ML: Adenyl cyclase. Ann Surg 182: or CCK-PZ. Because this substance 603-609, 1975. arises from the small intestine and 8. Steer ML: Cyclic AMP. Ann Surg 184: 107- stimulates the oxyntic cells, Gross- 115, 1976. man56 suggested the name entero-ox- 9. Sutherland EW, Rail TW: Fractionation yntin. It may arise from the mucosa and characterization of a cyclic adenine of the small intestine. It may be the ribonucleotide formed by tissue particles. J Biol Chem 232: 1077-1091, 1958. humoral mediator of acid hyperse- 10. Edkins JS: The chemical mechanism of

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gastric secretion. J Physiol 34: 133-144, gastrin in duodenal ulcer. Gut 12: 899-902, 1906. 1971. 11. Komarov SA: Gastrin. Proc Soc Exp Biol 25. Bayliss WM, Starling EH: The mechanism Med 38: 514-516, 1938. of pancreatic secretion. J Physiol 28: 325- 12. Rehfeld JF, Stadil F, VikelsOeJ: Immuno- 353, 1902. reactive gastrin components in human se- 26. Bodanszky M, Ondetti MA, Levine SD, et rum. Gut 15: 102-111, 1974. al: Synthesis of a hepatacosapeptide amide 13. Walsh JH: Biologic activity and disappear- with the hormonal activity of secretin. ance rates of big, little and mini- in Chem Industr 42: 1757-1758, 1966. dog and man, in Gastrointestinal Hor- 27. Bloom SR: The development of a radioim- mones; a Symposium. Thompson JC, ed. munoassay for secretin, in Gastrointestinal Austin, Univ Texas Press, 1975, pp 75- Hormones; a Symposium. Thompson JC, 83. ed. Austin, Univ Texas Press, 1975, pp 14. Korman MG, Laver MC, Hansky J: Hy- 257-268. pergastrinaemia in chronic renal failure. 28. Bloom SR, Ward AS: Secretin release in Br Med J 1: 209-210, 1972. man after intraduodenal acid. (Abstr) Gut 15. Booth RA, Reeder DD, Hjelmquist UB, et 15: 338, 1974. al: Renal inactivation of endogenous gas- 29. Boden G, Saraga W, Murthy S, et al: Ef- trin in dogs. Arch Surg 106: 851-854, 1973. fect of intraduodenal fatty acids, amino 16. Olbe L: Gastric acid secretory mecha- acids, and sugars on secretin levels. (Abstr) nisms. Effects of vagotomy on gastric acid Clin Res 22: 354A, 1974. secretion, in Vagotomy; Latest Advances. 30. Schmitt MG Jr, Soergel KH, Hensley GT, Holle F, Anderson S, eds. Berlin, Heidel- et al: Watery diarrhea associated with pan- berg, New York, Springer-Verlag; 1974, creatic islet cell carcinoma. Gastroenterol- pp 38-52. ogy 69: 206-216, 1975. 17. Dockray GJ: Patterns of serum gastrin at 31. Ivy AC, Oldberg E: A hormone mecha- rest and after stimulation in man and nism for gallbladder contraction and evac- dogs, in Gastrointestinal Hormones; a uation. Am J Physiol 86: 599-613, 1928. Symposium. Thompson JC, ed. Austin, 32. Harper AA, Raper HS: Pancreozymin, a Univ Texas Press, 1975, pp 59-73. stimulant of the secretion of pancreatic 18. Passaro E Jr, Basso N, Walsh JH: Calcium enzymes in extracts of the small intestine. J challenge in the Zollinger-Ellison syn- Physiol 102: 115-125, 1943. drome. Surgery 72: 60-67, 1972. 33. Go LW, Reilly WM: Problems encoun- 19. Johnson LR: Trophic action of gastroin- tered in the development of the cholecys- testinal hormones, in Gastrointestinal tokinin radioimmunoassay, in Gastrointes- Hormones; a Symposium. Thompson JC, tinal Hormones; a Symposium. Thomp- ed. Austin, Univ Texas Press, 1975, pp son JC, ed. Austin, Univ Texas Press, 215-230. 1975, pp 295-299. 20. Ebeid AE, Fisher JE: Gastrin and ulcer 34. Go VL, Ryan RJ, Summerskill WH: Ra- disease: what is known. Surg Clin North dioimmunoassay of porcine cholecystoki- Am 56: 1249-1265, 1976. nin-pancreozymin. J Lab Clin Med 77: 21. IsenbergJI, WalshJH, Grossman MI: Zol- 684-689, 1971. linger-Ellison syndrome. Gastroenterol- 35. Debas HT, Grossman MI: Pure cholescys- ogy 65: 140-165, 1973. tokinin: pancreatic protein and bicarbon- 22. IsenbergJI, WalshJH, Passaro E Jr, et al: ate response. 9: 469-481, 1973. Unusual effect of secretin on serum gas- 36. Sasaki H, Rubalcava B, Srikant CB, et al: trin, serum calcium, and gastric acid secre- Gut glucagonoid (GLI) and gut glucagon, tion in a patient with suspected Zollinger- in Gastrointestinal Hormones; a Sympo- Ellison syndrome. Gastroenterology 62: sium. Thompson JC, ed. Austin, Univ 626-631, 1971. Texas Press, 1975, pp 519-528. 23. Welbourn RB, Pearse AG, Polak JM, et al: 37. Unger RJ, Eisentraut AM, McCall MS, et The APUD cells of the alimentary tract in al: Glucagon antibodies and an immunoas- health and disease. Med Clin North Am say for glucagon. J Clin Invest 40: 1280- 58: 1359-1374, 1974. 1289, 1961. 24. Korman MG, Soveny C, Hansky J: Serum 38. Holst JJ, Rehfeld JF: Human circulating

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gut glucagon; binding to liver cell plasma 791-793, 1972. membranes, in Gastrointestinal Hor- 47. Erspamer V, Melchiorri P: Actions of mones; a Symposium. Thompson JC, ed. bombesin on secretions and motility of the Austin, Univ Texas Press, 1975, pp 529- gastrointestinal tract, in Gastrointestinal 536. Hormones; a Symposium. Thompson JC, 39. Mallinson CN, Bloom SR, Warin AP, etal: ed. Austin, Univ Texas Press, 1975, pp A glucagonoma syndrome. Lancet 2: 1-5, 575-589. 1974. 48. Erspamer V, Melchiorri P, Sopranzi N: 40. Said SI, Mutt V: Polypeptide with broad The action of bombesin on the kidney of biological activity; isolation from small in- the anaesthetized dog. Br J Pharmacol 48: testine. Science 169: 1217-1218, 1970. 438-455, 1973. 41. Said SI: Vasoactive intestinal peptide 49. Adelson JW: Chymodenin; an overview, in (VIP). Gastroenterology 67: 735-737, 1974. Gastrointestinal Hormones; a Symposium. 42. Said SI: Vasoactive intestinal polypeptide Thompson JC, ed. Austin, Univ Texas (VIP); current status, in Gastrointestinal Press, 1975, pp 563-574. Hormones; a Symposium. Thompson JC, 50. KimmelJR, Hayden LJ, Pollock HG: Iso- ed. Austin, Univ Texas Press, 1975, pp lation and characterization of a new pan- 591-597. creatic polypeptide hormone. J Biol Chem 43. Makhlouf GM, Said SI: The effect of vaso- 250: 9369-9374, 1975. active intestinal peptide (VIP) on digestive 51. Goodman, I, Hiatt RB: Coherin: a new and hormonal function, in Gastrointes- peptide of the bovine neurohypophysis tinal Hormones; a Symposium. Thomp- with activity on gastrointestinal motility. son JC, ed. Austin, Univ Texas Press, Science 178: 419-421, 197?, 1975, pp 599-610. 52. Gerring EL, Gregory H: Urogastrone. 44. Bloom SR, Polak JM: The role of VIP in Gastroenterology 67: 739-740, 1974. pancreatic cholera, in Gastrointestinal 53. Andersson S: Bulbogastrone. Gastroenter- Hormones; a Symposium. Thompson JC, ology 67: 742-743, 1974. ed. Austin, Univ Texas Press, 1975, pp 54. Gregory RA, Ivy AC: The humoral stimu- 635-642. lation of gastric secretion. QJ Exp Physiol 45. Brown JC, Dryburgh JR, Moccia P, et al: 31: 111-128, 1941. The current status of GIP, in Gastrointes- 55. Orloff MJ, Villar-Valdes H, Rosen H, et tinal Hormones; a Symposium. Thomp- al: Humoral mediation of the intestinal son JC, ed. Austin, Univ Texas Press, phase of gastric secretion and of acid hy- 1975, pp 537-547. persecretion associated with portacaval 46. Elias E, Bloom SR, Welbourn RB, et al: shunts. Surgery 66: 118-130, 1969. Pancreatic cholera due to production of 56. Grossman MJ, Entero-oxyntin. Gastroen- gastric inhibitory polypeptide. Lancet 2: terology 67: 754, 1974.

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