cholecystokinin and Stomach-Ulcer

The patient with gastric ulcer (GU) has abnormal reflux of bile-containing duodenal contents into the stomach. Antral gastritis is prominently associated with GU and is more extensive with severe reflux and with ulcer chronicity and probably when bile salts are accompanied by other constituents of duodenal fluids. Smoking is significantly associated with GU, and it produces reflux in normal subjects and in patients with duodenal ulcer, which in turn is commonly associated with GU. Reflux has not been shown to precede either the gastritis or the gastric ulcer and probably persists despite ulcer healing. The pyloric spincter in the patient with GU probably contracts subnormally to endogenous or exogenous secretin or CCK. This can be explained by associated hypergastrinemia since antral acidification improves the response. Because the pylorus may be usually open, abnormal reflux may be related as much or more to disturbances of other gastroduodenal functions known to control the movement of chyme through what may be a relatively passive pyloric zone. Speculation from animal models implicates bile reflux in aspirin-induced and shock-related gastric ulceration and assigns to bile a possible explanation, in part at least, for the apparent therapeutic efficacy of a carbenoxalone derivative and an antipepsin agent. Similar speculation warrants a search in the patient with GU for abnormalities of gastroduodenal peristalsis-related electric activity and for impaired release of secretin, possibly from antral cells of production. Possible abnormal purinergic inhibition of the gastric fundus and pylorus also warrants further study.

Topics: Animals; Bile; Cholecystokinin; Disease Models, Animal; Duodenum; Gastric Mucosa; Gastrins; Gastritis; Gastroesophageal Reflux; Humans; Pyloric Antrum; Pylorus; Secretin; Stomach Ulcer

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Duodenal Ulcer; Gastrins; Gastrointestinal Hormones; Humans; Secretin; Stomach Ulcer

Topics: Animals; Cholecystokinin; Dogs; Duodenal Ulcer; Esophagus; Gallbladder; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Pancreatic Juice; Secretin; Secretory Rate; Stimulation, Chemical; Stomach Ulcer; Vagotomy; Vagus Nerve; Zollinger-Ellison Syndrome

Topics: Animals; Cats; Ceruletide; Cholecystokinin; Digestive System; Digestive System Physiological Phenomena; Dogs; Duodenal Ulcer; Gastric Juice; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Gastrointestinal Motility; Glucagon; Guinea Pigs; Humans; Pancreas; Secretin; Stomach Ulcer

This study was done to examine the role of CCK in gastric mucosal defense and to assess the gastroprotective roles of nitric oxide and blood flow. In rats, the CCK secretagogues oleate and soybean trypsin inhibitor augmented gastric mucosal blood flow and prevented gastric injury from luminal irritants. Type A CCK receptor blockade negated CCK secretagogue-induced gastroprotection and exacerbated gastric injury from bile and ethanol but did not block adaptive cytoprotection. CCK secretagogue-induced gastroprotection and hyperemia were negated by nonselective nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester) but not by selective inducible NOS inhibition (aminoguanidine). Gastric mucosal calcium-dependent NOS activity, but not calcium-independent NOS activity, was increased following CCK and CCK secretagogues. The release of endogenous CCK plays a role in the intrinsic gastric mucosal defense system against injury from luminal irritants. The protective mechanism appears to involve increased production of nitric oxide from primarily the constitutive isoforms of NOS and a resultant increase in blood flow.

Topics: Acids; Animals; Blotting, Western; Cholecystokinin; Enzyme Inhibitors; Ethanol; Female; Gastric Mucosa; Guanidines; Hyperemia; Irritants; Isoenzymes; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oleic Acid; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Regional Blood Flow; Stomach Ulcer; Trypsin Inhibitors

CCK exhibits a potent cytoprotective activity against acute gastric lesions, but its role in ulcer healing has been little examined. In this study we determined whether exogenous CCK or endogenously released CCK by camostate, an inhibitor of luminal proteases, or by the diversion of pancreatico-biliary secretion from the duodenum, could affect ulcer healing. In addition, the effects of antagonism of CCK-A receptors (by loxiglumide, LOX) or CCK-B receptors (by L-365,260), an inhibition of NO-synthase by N(G)-nitro-L-arginine (L-NNA), or sensory denervation by large neurotoxic dose of capsaicin on CCK-induced ulcer healing were examined. Gastric ulcers were produced by serosal application of acetic acid and animals were sacrificed 9 days after ulcer induction. The area of ulcers and blood flow at the ulcer area were determined. Plasma levels of gastrin and CCK and luminal somatostatin were measured by RIA and mucosal biopsy samples were taken for histological evaluation and measurement of DNA synthesis. CCK given s.c. reduced dose dependently the ulcer area; the threshold dose of CCK being 1 nmol/kg and the dose inhibiting this area by 50% being 5 nmol/kg. This healing effect of CCK was accompanied by a significant increase in the GBF at ulcer margin and the rise in luminal NO production, plasma gastrin level and DNA synthesis. Concurrent treatment with LOX, completely abolished the CCK-8-induced acceleration of the ulcer healing and the rise in the GBF at the ulcer margin, whereas L-365,260 remained without any influence. Treatment with camostate or diversion of pancreatic juice that raised plasma CCK level to that observed with administration of CCK-8, also accelerated ulcer healing and this effect was also attenuated by LOX but not by L-365,260. Inhibition of NO-synthase by L-NNA significantly delayed ulcer healing and reversed the CCK-8 induced acceleration of ulcer healing, hyperemia at the ulcer margin and luminal NO release, and these effects were restored by the addition to L-NNA of L-arginine but not D-arginine. Capsaicin denervation attenuated CCK-induced ulcer healing, and the accompanying rise in the GBF at the ulcer margin and decreased plasma gastrin and luminal release of somatostatin when compared to those in rats with intact sensory nerves. Detectable signals for CCK-A and B receptor mRNAs as well as for cNOS mRNA expression were recorded by RT-PCR in the vehicle control gastric mucosa. The expression of CCK-A receptor mRNA and cNOS mRNA wa

Topics: Animals; Cholecystokinin; DNA Replication; Dopamine Agents; Esters; Gabexate; Gastric Mucosa; Gastrins; Guanidines; Hormone Antagonists; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pancreatin; Proglumide; Protease Inhibitors; Rats; Rats, Wistar; Receptors, Cholecystokinin; Regional Blood Flow; RNA, Messenger; Sensory Receptor Cells; Sincalide; Somatostatin; Stomach; Stomach Ulcer

Duodenal fat such as oleate is known to influence gut functions by release of cholecystokinin (CCK), but the contribution of CCK endogenously released by duodenal fat or by diversion of pancreatic juice from the duodenum in the mechanism of mucosal integrity and gastroprotection has been little studied. This study was designed to compare the effect of CCK-8 and intraduodenal (i.d.) instillation of sodium oleate, or diversion of the pancreatic biliary secretions that are known to release CCK, on the gastric mucosal lesions induced by topical application of 100% ethanol or acidified aspirin (ASA) in rats with or without the pretreatment with a CCK-A receptor antagonist, loxiglumide, or with L-365,260 to block CCK-B receptors. In addition, the effect of suppression of prostaglandin (PG) biosynthesis by indomethacin (5 mg/kg i.p.), inhibition of nitric oxide (NO)-synthase by L-NAME (5 mg/kg i.v.), or blockade of sensory nerves by capsaicin (125 mg/kg s.c.) on the protective activity of sodium oleate was determined. Sodium oleate (50-200 mM i.d.), or diversion of pancreatic juice from the duodenum for 3 h that produced significant rise in plasma CCK levels, significantly reduced gastric lesions induced by 100% ethanol to an extent similar to that induced by exogenous CCK-8 (5 nmol/kg s.c.). The protective effect of oleate or diversion of pancreatic juice was accompanied by an increase in gastric blood flow (GBF). Both protection and accompanying hyperemia were completely abolished by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an antagonist of CCK-B receptors, had no effect. Oleate given i.d. significantly attenuated acidified ASA-induced gastric lesions and gastric secretion while increasing the luminal concentration of somatostatin. These effects were significantly reduced by loxiglumide but not by L-365,260. In contrast, CCK-8, which stimulated gastric acid secretion, failed to affect the lesions induced by acidified ASA and the decrease in the GBF produced by this ulcerogen. Indomethacin, which suppressed PG generation by approximately 90%, failed to influence the protective activity of oleate or CCK-8 against ethanol-induced lesions, whereas L-NAME, vagotomy, or sensory denervation significantly attenuated this protection and accompanying hyperemia. Addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK-8 and duodenal oleate against gastric lesions induced by ethanol or acidified ASA

Topics: Animals; Capsaicin; Cholecystokinin; Denervation; Dinoprostone; Dopamine Agents; Enzyme Inhibitors; Gastric Acid; Gastric Mucosa; Hormone Antagonists; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oleic Acid; Pepsin A; Proglumide; Rats; Rats, Wistar; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Sincalide; Somatostatin; Stomach Ulcer; Vagotomy

Cholecystokinin (CCK) shows a potent influence on gastric secretion and motility but its role in gastric mucosal integrity has been little examined. In this study we found that exogenous CCK octapeptide protected gastric mucosa against ethanol-induced gastric injury but was ineffective against aspirin-induced damage. The protective effects of CCK were dose-dependent and almost completely reversed by pretreatment with the specific CCKA receptor antagonist, loxiglumide, while the CCKB receptor antagonist, L-365,260, was not effective. The CCK-induced protection against ethanol injury was accompanied by a significant increase in gastric blood flow. The inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester attenuated the gastroprotection and gastric hyperemia induced by CCK while the concurrent treatment with L-arginine, but not D-arginine restored the protective activity of CCK and the accompanying increase in gastric blood flow. Endogenous CCK released by intraduodenal instillation of oleate prevented the formation of acute gastric lesions induced by both ethanol and aspirin and the protective effects were abolished by pretreatment with loxiglumide. We conclude that CCK exerts protective activity against ethanol-induced damage and that this effect is mediated through specific CCKA receptors and hyperemia involving NO.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Aspirin; Cholecystokinin; Dose-Response Relationship, Drug; Duodenum; Ethanol; Gastric Mucosa; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Proglumide; Rats; Rats, Wistar; Receptors, Cholecystokinin; Regional Blood Flow; Stomach Ulcer

In a follow up study 19 patients after Billroth-I, 22 patients after Billroth-II-resection and 38 patients after total gastrectomy (23 with Roux-Y-reconstruction and 15 with Longmire-Gütgemann) underwent a stool fat determination and an indirect pancreatic function test with fluorescein dilaurate in serum und urine. In 9 of 19 cases (47.3%) after B-I-resection and 14 of 22 patients (63.5%) after B-II-resection there were pathological results of the PLT-test in urine. After total gastrectomy as well with reconstruction of the duodenal passage as with its exclusion the PLT-test results were pathological in 60% resp. 87%. These results indicate a secondary pancreatic insufficiency following gastric resection.

Topics: Adult; Aged; Anastomosis, Roux-en-Y; Cholecystokinin; Exocrine Pancreatic Insufficiency; Female; Fluoresceins; Follow-Up Studies; Gastrectomy; Humans; Male; Middle Aged; Neurotensin; Pancreatic Function Tests; Postoperative Complications; Stomach Neoplasms; Stomach Ulcer

We examined in male Sprague-Dawley rats the effects of nicotine at doses of 50 (0.31 mM) and 200 mg/L (1.23 mM) given for a period of 16 weeks on body weight gain, food and fluid intake, plasma CCK, glucose and insulin levels, amylase secretory responses of isolated pancreatic acinar cells to CCK-8 and carbachol, and histopathology (gross and light microscopy) of stomach and pancreas. These parameters were re-examined further in animals treated with nicotine at doses of 200 mg/L (1.23 mM) for 12 weeks and given tap water for an additional 4 weeks to evaluate the effects of nicotine withdrawal. Metabolic data suggest that decreases in body weight gain, food and fluid intake, and plasma levels of glucose and insulin by nicotine are dose dependent. Endocrinological studies showed that the plasma levels of CCK were significantly increased with nicotine but the amylase secretory response of pancreatic acinar cells was inhibited in response to CCK-8 and carbachol. Histopathologic data revealed that treatment of animals with a high dose of nicotine enhanced the appearance of numerous vacuoles in the pancreatic acinar cell cytoplasm. When the pancreatic acinar cell morphology was closely examined, it showed evidence of pyknotic nuclei and fusion of vacuoles. Prominent loss of gastric mucosal surface was found in nicotine-treated animals with gross microscopic evidence of bleeding ulcers. All of the metabolic parameters except body weight gain were reversed upon nicotine withdrawal. In addition, plasma CCK levels and pancreatic enzyme secretion were reversed upon nicotine withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amylases; Animals; Blood Glucose; Body Weight; Cholecystokinin; Digestive System; Drinking; Eating; Insulin; Male; Nicotine; Pancreas; Peptic Ulcer Hemorrhage; Radioimmunoassay; Rats; Rats, Inbred Strains; Stomach Ulcer; Substance Withdrawal Syndrome

Cholecystokinin (CCK) is a polypeptid released postprandially by the upper intestinal mucosa. There are several biological active forms of CCK. Radioimmunological measurements of CCK may not detect all biological active forms or may have the disadvantage of crossreacting with gastrin. In the following we describe a modification of a bioassay for CCK which was first developed by Liddle et al. (J Clin Invest 1985). By means of this bioassay pre- and postprandial plasma CCK-levels of healthy male volunteers are compared with CCK-levels of patients with partial gastric resections and excluded duodenum. Both groups showed similar basal CCK-values (about 1 pM) and a food induced increase of this hormone by reaching maximal values after 15 to 30 min (control: 4.30 +/- 0.65 vs. operated: 13.37 +/- 2.83 pM). Patients with gastric resections, however, had about three times more CCK released over the 60 min time period studied as compared to controls. Thus exclusion of the duodenum, the supposed main place of CCK production, does not cause a lower but rather higher increase of postprandial CCK release.

Topics: Adult; Aged; Anastomosis, Roux-en-Y; Cholecystokinin; Duodenal Ulcer; Gastrectomy; Gastric Emptying; Gastrins; Humans; Intestinal Absorption; Middle Aged; Peptic Ulcer Hemorrhage; Postoperative Complications; Radioimmunoassay; Stomach Ulcer

Using 99mTc diethyl HIDA, a gamma camera was used to assess duodenogastric reflux of bile in the supine position in control patients and patients with active duodenal ulceration. Cholecystokinin was injected intravenously during the test to contract the gall bladder. Patients with benign gastric ulcers, and a group of age matched controls, were investigated for duodenogastric bile reflux in the sitting position by a nasogastric aspiration technique after a 10% dextrose meal. Of 60 patients with duodenal ulceration 32 (53%) were reflux positive, and of 13 control patients 6 (46%) were positive. Of 30 patients with gastric ulceration 17 (53%) were reflux positive, and 8 out of 15 (53%) control subjects were positive. The incidence of duodenogastric reflux assessed supine in the fasting state, and seated after a liquid meal, was similar in patients with peptic ulceration and in normal controls.

Topics: Cholecystokinin; Duodenal Ulcer; Duodenogastric Reflux; Humans; Imino Acids; Intubation, Gastrointestinal; Posture; Radionuclide Imaging; Stomach Ulcer; Technetium; Technetium Tc 99m Diethyl-iminodiacetic Acid

Duodenogastric reflux was assessed scintigraphically in normal subjects (n = 20) and in patients with duodenal (n = 15) or gastric ulcers (n = 14). Reflux was graded 0-4 according to degree and was minimal in the control group (0.25 +/- 0.12) (mean +/- SEM), but significantly increased in 11 out of 15 patients with duodenal ulceration (1.33 +/- 0.25) and in 12 out of 14 patients with gastric ulceration (1.86 +/- 0.29) (P less than or equal to 0.0025). Gastric mucosal biopsies taken at endoscopy showed changes of gastritis which correlated well with the degree of reflux. It is suggested therefore that duodenogastric reflux may play a significant role in the pathogenesis of some peptic ulcers, and may be responsible for many of the pathophysiological changes seen in these patients.

Topics: Biopsy; Cholecystokinin; Duodenal Ulcer; Duodenogastric Reflux; Gastric Mucosa; Humans; Imino Acids; Organotechnetium Compounds; Radionuclide Imaging; Stomach Ulcer; Technetium

We studied reflux of duodenal contents into the stomach in patients with gastric ulcers, patients with duodenal ulcers, and normal subjects. Duodenogastric reflux was assessed in the fasting state and after cholecystokinin octapeptide administration (0.02 micrograms/kg intravenously). Slight reflux was observed in the fasting state in all three groups. However, after cholecystokinin octapeptide administration, reflux was significantly greater in gastric ulcer patients than in control patients for pancreatic phospholipase A2 (p less than 0.01) and lysophosphatidylcholine (p less than 0.001). Also in gastric ulcer patients, the gastric contents were significantly more alkaline (pH 5.26 +/- 0.58, p less than 0.001) during duodenogastric reflux than in normal subjects (pH 3.65 +/- 0.50) or duodenal ulcer patients (pH 2.67 +/- 0.63). Our results suggest that reflux of both pancreatic and biliary secretions might contribute to the gastric mucosal injury in gastric ulcer patients and we postulate that pancreatic phospholipase A2 might have a greater role in this process than has been previously acknowledged.

Topics: Adult; Aged; Bile Acids and Salts; Cholecystokinin; Duodenogastric Reflux; Female; Gastric Juice; Hemolysis; Humans; Lysophosphatidylcholines; Male; Middle Aged; Phospholipases A; Phospholipases A2; Stomach Ulcer

Topics: Adolescent; Adult; Aged; Aprotinin; Cholecystokinin; Duodenal Ulcer; Female; Humans; Male; Middle Aged; Peptic Ulcer; Stomach Ulcer; Trypsin

99mTc-diethyl-IDA is completely excreted into the bile. When cholecystokinin is given after priming of the biliary tract with this tracer, gallbladder contraction leads to expulsion of bile into the duodenum. At the same time cholecystokinin causes contraction of the pylorus, which should normally prevent substantial reflux of tracer into the stomach. We have applied these physiological characteristics in a method to quantify biliary gastric reflux. Fourteen controls had a median reflux of 4.3% of the intravenous dose (93% of controls had values less than 9%). In 18 patients with Billroth II gastrectomies the median reflux was 46% (p less than 0.001). Patients with chronic gastritis (no. = 18) had also increased reflux (median 18.1%, p less than 0.001). The same was found in gastric ulcer (no. = 18, median 11.8%, p less than 0.003). In duodenal ulcer (no. = 7) increased reflux existed in only two patients with pyloric deformation. Patients with hiatal hernia did not show increased reflux (no. = 10, median 2.2%). Bilirubin measurements tended to underestimate reflux in pathological cases, whereas bile acid measurements and reflux percentages of tracer showed a close relationship (r = 0.87, p less than 0.001).

Topics: Bile Reflux; Biliary Tract Diseases; Cholecystokinin; Gastrectomy; Gastritis; Humans; Imino Acids; Methods; Stomach Ulcer; Technetium; Technetium Tc 99m Diethyl-iminodiacetic Acid

Topics: Cholecystokinin; Cholelithiasis; Duodenal Ulcer; Esophageal Achalasia; Gastrins; Gastritis; Gastrointestinal Hormones; Humans; Pancreatic Diseases; Peptic Ulcer; Secretin; Stomach Neoplasms; Stomach Ulcer

Topics: Animals; Bethanechol Compounds; Cholecystokinin; Female; Glucagon; Humans; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Propantheline; Radioisotopes; Radionuclide Imaging; Rats; Selenium; Stomach Ulcer; Vasopressins

Topics: Aged; Amino Acids; Cholecystokinin; Duodenum; Female; Fluoroscopy; Gastric Juice; Gastrointestinal Motility; Humans; Hydrochloric Acid; Hydrogen-Ion Concentration; Intubation, Gastrointestinal; Male; Manometry; Middle Aged; Perfusion; Pressure; Pylorus; Secretin; Sodium Chloride; Stomach Ulcer

Topics: Animals; Cholecystokinin; Duodenal Ulcer; Eating; Electric Stimulation; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Hydrogen-Ion Concentration; Parasympatholytics; Peptic Ulcer; Pyloric Antrum; Radioimmunoassay; Secretin; Secretory Rate; Stomach Ulcer; Vagus Nerve; Zollinger-Ellison Syndrome

Topics: Bicarbonates; Celiac Disease; Cholecystokinin; Feces; Gastrectomy; Humans; Lipid Metabolism; Lipids; Male; Pancreas; Pentagastrin; Postgastrectomy Syndromes; Secretin; Stomach Ulcer; Trypsin

Duodeno-gastric reflux has been studied in normal subjects and patients with duodenal and gastric ulceration during the responses to parenteral secretin and cholecystokinin-pancreozymin and to acidification of the small intestine. Reflux was absent or slight in normal subjects and most patients with duodenal ulcer but was appreciable in most patients with gastric ulcer. Duodeno-gastric regurgitation may occasionally resultin a misleading assessment of pancreatic exocrine secretory capacity.

Topics: Bicarbonates; Bile Pigments; Cholecystokinin; Duodenal Diseases; Duodenal Ulcer; Gastric Juice; Humans; Intestinal Secretions; Intestine, Small; Pancreas; Pylorus; Secretin; Stomach Diseases; Stomach Ulcer; Trypsin; Vagotomy

Topics: Cholecystokinin; Duodenal Ulcer; Duodenum; Gastric Juice; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Humans; Intestinal Secretions; Pepsin A; Peptic Ulcer; Secretin; Stomach Ulcer

Topics: Animals; Cholecystokinin; Duodenum; Female; Gastric Juice; Male; Mineral Oil; Rats; Secretin; Stomach Ulcer; Tissue Extracts

Topics: Bicarbonates; Cholecystokinin; Enteritis; Gallbladder Diseases; Gastric Acidity Determination; Gastrins; Gastritis; Pancreas; Pancreatitis; Pyrazoles; Secretin; Stimulation, Chemical; Stomach Ulcer

Topics: Afferent Loop Syndrome; Cholecystokinin; Chronic Disease; Gastrectomy; Gastrins; Humans; Methods; Recurrence; Secretin; Stomach Ulcer