Duodenum In Response Research Articles

Imaging of Ampullary and Periampullary Conditions

AbstractThe ampulla of Vater is formed by the union of the pancreatic duct and the common bile duct and is also known as hepatopancreatic ampulla or hepatopancreatic duct. The ampulla is surrounded by a muscular valve known as the sphincter of Oddi, which controls the flow of bile and pancreatic juices into the duodenum in response to food. The ampulla is also an important embryological landmark as it marks the anatomical transition from foregut to the midgut. Because of this, it is a watershed zone where the blood supply changes from the celiac axis to the superior mesenteric artery. Radiologic evaluation of the ampulla and the periampullary region is challenging because it requires an understanding of the embryology, the normal appearance, and different anatomic variants. Also, a wide variety of pathologies can occur in this region. The purpose of this review is to present the normal anatomy of the ampulla and the periampullary region on different imaging modalities and to summarize the imaging features of the common variants, and benign and malignant ampullary and periampullary conditions. Understanding of the normal anatomical appearance and variants along with the knowledge of common pathologic conditions affecting the ampulla and periampullary conditions can help radiologists in making accurate diagnosis resulting in optimum patient care.

Dietary fat stimulates pancreatic cancer growth and promotes fibrosis of the tumor microenvironment through the cholecystokinin receptor.

The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high-fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on the growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity. The high-fat diet significantly increased growth and metastasis of pancreatic cancer compared with the control diet, and the stimulatory effect was blocked by the CCK-receptor antagonist proglumide. We then selectively knocked out the CCK receptor on the pancreatic cancer cells using clustered regularly interspaced short palindromic repeats technology and showed that without CCK-receptors, dietary fat was unable to stimulate cancer growth. We next demonstrated that dietary fat failed to influence pancreatic cancer xenograft growth in genetically engineered CCK peptide knockout mice. The tumor-associated fibrosis that is so prevalent in the pancreatic cancer microenvironment was significantly decreased with CCK-receptor antagonist therapy because fibroblasts also have CCK receptors. The CCK-receptor antagonist proglumide also altered tumor metalloprotease expression and increased tumor suppressor genes by a PCR array. Our studies confirm that a diet high in saturated fat promotes growth of pancreatic cancer and the action is mediated by the CCK-receptor pathway. NEW & NOTEWORTHY Diets high in long-chain saturated fats promote growth of pancreatic cancer independent of obesity. The mechanism through which dietary fat promotes cancer is mediated through the cholecystokinin (CCK) receptor pathway. Therapy with a CCK-receptor antagonist altered the tumor microenvironment by reducing fibrosis, increasing cluster of differentiation 8+ lymphocytes, increasing tumor suppressor genes, and thus decreasing metastases. Use of CCK-receptor antagonist therapy with standard chemotherapy for pancreatic cancer may improve response by altering the tumor microenvironment.

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OBJECTIVES/SPECIFIC AIMS: Epidemiologic studies have found that the incidence of pancreatic cancer is greatest in countries that consume diets high in fat. The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat. CCK has also been shown to stimulate growth of pancreatic cancer through the CCK receptor that is over-expressed on pancreatic cancer cells. The aim of this investigation was to determine if dietary fat promotes growth of pancreatic cancer through the actions of CCK at its receptor. METHODS/STUDY POPULATION: The effects of dietary fat on growth of murine Panc02 pancreatic cancer xenografts were studied in 3 different systems with immune competent mice: (1) pharmacologic blockade with a CCK receptor antagonist, (2) genetic knockout of the CCK receptor by CRISPR, and (3) in genetically engineered mice lacking the CCK peptide (CCK-KO). After injection of 2×106 Panc02 cells subcutaneously, mice were fed either a high-fat diet or a control diet for 37–42 days. Tumor volumes and weights were measured and histology performed. RESULTS/ANTICIPATED RESULTS: Dietary fat significantly increased the size of pancreatic cancer xenografts and this effect was reversed by CCK receptor blockade. Receptor antagonist therapy also significantly reduced tumor-associated fibrosis and increased the influx of CD8+ lymphocytes in the micro-environment. Panc02 cancer cells lacking CCK receptors failed to respond exogenous administration of CCK in vitro and to dietary fat in vivo. Dietary fat did not stimulate Panc02 tumor growth in CCK-KO mice. DISCUSSION/SIGNIFICANCE OF IMPACT: The mechanism by which dietary fat stimulates growth of pancreatic cancer is by CCK and this effect is independent of obesity. This is a significant finding because of the potential beneficial effects of medications which can block the effects of CCK in populations at risk for pancreatic cancer consuming a high-fat diet.

Deep-sea water containing selenium provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.

Deep-sea water (DSW), which is rich in micronutrients and minerals and with antioxidant and anti-inflammatory qualities, may be developed as marine drugs to provide intestinal protection against duodenal ulcers. We determined several characteristics in the modified DSW. We explored duodenal pressure, oxygenation, microvascular blood flow, and changes in pH and oxidative redox potential (ORP) values within the stomach and duodenum in response to tap water (TW, hardness: 2.48 ppm), DSW600 (hardness: 600 ppm), and DSW1200 (hardness: 1200 ppm) in Wistar rats and analyzed oxidative stress and apoptosis gene expressions by cDNA and RNA microarrays in the duodenal epithelium. We compared the effects of drinking DSW, MgCl2, and selenium water on duodenal ulcers using pathologic scoring, immunohistochemical analysis, and Western blotting. Our results showed DSW has a higher pH value, lower ORP value, higher scavenging H2O2 and HOCl activity, higher Mg2+ concentrations, and micronutrients selenium compared with TW samples. Water infusion significantly increased intestinal pressure, O2 levels, and microvascular blood flow in DSW and TW groups. Microarray showed DSW600, DSW1200, selenium water upregulated antioxidant and anti-apoptotic genes and downregulated pro-apoptotic gene expression compared with the TW group. Drinking DSW600, DSW1200, and selenium water but not Mg2+ water significantly enhanced Bcl-2 and thioredoxin reductase 1 expression. Bax/Bcl-2/caspase 3/poly-(ADP-ribose)-polymerase signaling was activated during the pathogenesis of duodenal ulceration. DSW drinking reduced ulcer area as well as apoptotic signaling in acetic acid-induced duodenal ulcers. DSW, which contains selenium, provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.

Role of distension on duodenal and colonic contractility in mice: a novel myograph for intestines

The role of mechanical distension (stretch and tension) on intestinal contractility is poorly understood. We introduce a novel isovolumic myograph to quantify the intestinal contractility in response to mechanical stimulation. To evaluate the role of distension on contractility, an external restraint was used to restrict intestinal distension or stretch induced by inflation pressure. The amplitude of intraluminal pressure at isovolumic condition was defined as an index of intestinal contractility. The in situ maximal contraction (1.42 ± 0.39 mmHg) of duodenum in response to inflation pressure was similar to the in vitro maximal contraction (1.39 ± 0.37 mmHg). As the pressure was increased, the in situ duodenal contraction attenuated faster than the in vitro one. The in situ maximal contraction (4.86 ± 1.32 mmHg) of distal colon in response to inflation pressure was significantly larger than the in vitro maximal contraction (2.31 ± 0.67 mmHg). With increase of pressure, the in situ colonic contractility (1.82 ± 0.87 mmHg) became similar to the in vitro counterpart (1.61 ± 0.98 mmHg). With restraint, the maximal contraction of duodenum and distal colon decreased from 4.86 ± 1.32 and 1.42 ± 0.39 mmHg to 2.91 ± 0.87 and 0.97 ± 0.29 mmHg, respectively. Finally, a significant linear relation was found between strain and amplitude of contraction for both duodenum and colon which became non-significant with restraint. Our results suggest that distension is an important stimulus for intestinal contractility and nervous regulation is implicated in the intestinal contractility response to mechanical stimulus.

Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations

Pancreatic exocrine insufficiency (PEI) occurs when the amounts of enzymes secreted into the duodenum in response to a meal are insufficient to maintain normal digestive processes. The main clinical consequence of PEI is fat maldigestion and malabsorption, resulting in steatorrhoea. Pancreatic exocrine function is commonly assessed by conducting a 3-day faecal fat test and by measuring levels of faecal elastase-1 and serum trypsinogen. Pancreatic enzyme replacement therapy is the mainstay of treatment for PEI. In adults, the initial recommended dose of pancreatic enzymes is 25,000 units of lipase per meal, titrating up to a maximum of 80,000 units of lipase per meal. In infants and children, the initial recommended dose of pancreatic enzymes is 500 units of lipase per gram of dietary fat; the maximum daily dose should not exceed 10,000 units of lipase per kilogram of bodyweight. Oral pancreatic enzymes should be taken with meals to ensure adequate mixing with the chyme. Adjunct therapy with acid-suppressing agents may be useful in patients who continue to experience symptoms of PEI despite high-dose enzyme therapy. A dietitian experienced in treating PEI should be involved in patient management. Dietary fat restriction is not recommended for patients with PEI. Patients with PEI should be encouraged to consume small, frequent meals and to abstain from alcohol. Medium-chain triglycerides do not provide any clear nutritional advantage over long-chain triglycerides, but can be trialled in patients who fail to gain or to maintain adequate bodyweight in order to increase energy intake.

Dietary iron deficiency increases Zip14 expression in rats

Zip14 (Slc39a14) is a transmembrane protein that can transport iron and zinc. We have found that Zip14 expression is markedly up‐regulated in the liver, spleen, and duodenum of rats made anemic by repeated phlebotomy, suggesting that Zip14 responds to body iron status. The present study aimed to determine how Zip14 expression is affected by iron deficiency and overload. Weanling male Sprague‐Dawley rats (n=18) were randomized to 3 dietary groups: iron deficient (9 ppm Fe), control (215 ppm Fe), or iron‐loaded (2.9% carbonyl Fe). After 3 weeks, mean hemoglobin levels were 7.2, 13.2, and 14.5 g/dL, respectively, and mean liver non‐heme iron levels were 0.27, 1.56, and 93.5 μmol/g. Immunoblot analysis reveals that Zip14 protein levels increased dramatically in iron‐deficient liver, pancreas, and heart, tissues that express abundant Zip14. In iron‐deficient liver, zinc concentrations did not differ from controls, indicating that the marked increase in Zip14 levels did not result from altered zinc status. Zip14 expression also increased in duodenum in response to iron deficiency. The iron transport capacity of Zip14 along with its robust induction by iron deficiency strongly implicates Zip14 in physiologic iron metabolism. Supported by NIH grant DK065064 (MDK).

Dynamic regulation of mucus gel thickness in rat duodenum.

We examined the dynamic regulation of mucus gel thickness (MGT) in vivo in rat duodenum in response to luminal acid, cyclooxygenase (COX) inhibition, and exogenous PGE(2). An in vivo microscopic technique was used to measure MGT with fluorescent microspheres in urethan-anesthetized rats. Duodenal mucosa was topically superfused with pH 7.0 or pH 2.2 solutions with or without PGE(2) and indomethacin treatments. Glycoprotein concentration of duodenal loop perfusates was measured with periodic acid/Schiff (PAS) or Alcian blue (AB) staining. MGT and perfusate glycoprotein concentration were stable during a 35-min perfusion with pH 7.0 solution. Acid exposure increased MGT and PAS- and AB-positive perfusate glycoprotein concentrations. Indomethacin pretreatment increased both PAS- and AB-positive perfusate glycoprotein at baseline; subsequent acid superfusion decreased perfusate glycoproteins and gel thickness. PGE(2) (1 mg/kg iv) simultaneously increased MGT and PAS-positive perfusate glycoprotein concentrations followed by a transient increase in AB-positive glycoprotein concentration, suggesting contributions from goblet cells and Brunner's glands. Parallel changes in MGT and perfusate glycoprotein concentration in response to luminal acid and PGE(2) suggest that rapid MGT variations reflect alterations in the balance between mucus secretion and exudation, which in turn are regulated by a COX-related pathway. Luminal acid and PGE(2) augment mucus secretion from goblet cells and Brunner's glands.

Parallel increase in substance P and VIP in rat duodenum in response to irradiation

Irradiation was administered to the upper abdomen of rats, whereupon the duodenum was examined. Numerous vasoactive intestinal peptide (VIP)- and substance P (SP)-like immunoreactive nerve fibers were seen in the damaged mucosa, often in close association to each other. The intensity of the SP- and VIP-like immunoreaction was increased in several of the tissue compartments and, as measured with radioimmunoassay, the contents of SP- and VIP-like materials were increased after 30 Gray. The results show that SP and VIP levels increase after irradiation and suggest that SP and VIP are involved in interactive reactions in the reorganization and inflammatory processes in the gut after abdominal irradiation.

Electrogenic Ion Transport in Duodenum, an Aid in Cystic Fibrosis Diagnosis

Abnormality in chloride transport across epithelial tissues is a basic defect in cystic fibrosis (CF). Our aim was to compare the induced chloride secretion in duodenum in CF patients with different mutations. Duodenal biopsies from 9 patients were investigated in a modified Ussing chamber and the secretory response to prostaglandin E2 (PGE2) and acetylcholine (ACh) were measured. PGE2 and ACh induced no changes in chloride secretion in the AF508 homozygotes. In heterozygotes the induced change in chloride secretion corresponded to the severity of the known mutations. The secretory response in duodenum in CF is influenced by the patients genotype and mainly related to sweat chloride secretion.

Regulation of porcine biliary secretion by secretin.

The importance of physiological plasma levels of secretin in biliary bicarbonate secretion is not known. However, in anaesthetized pigs the substantial hepatic output of bicarbonate into the duodenum in response to low doses of secretin exceeds pancreatic bicarbonate output. The aim was therefore to study the relationship between duodenal acidification, secretin and hepatic biliary bicarbonate output in the conscious pig. Göttingen minipigs (n = 22) were cholecystectomized and the common bile duct catheterized. The biliary bicarbonate secretion in response to intraduodenal HCl, secretin or pentagastrin given intravenously, and to meal was studied. Intraduodenal HCl infusion, secretin and pentagastrin given intravenously augmented hepatic bicarbonate output and plasma secretin concentrations significantly. The secretin response to acidification was sufficient to explain the subsequent increase in biliary bicarbonate secretion. Hepatic bicarbonate secretion and concentrations of CCK and secretin in plasma increased postprandially. Exclusion of bile salts from the duodenum abolished postprandial increase in bile volume and increased release of CCK in fasting and fed pigs whereas secretin release was diminished. The results demonstrate that hepatic bicarbonate secretion is stimulated by endogenous secretin and therefore may have a physiological role in duodenal neutralization.

Failure of the nitric oxide synthase inhibitor to stimulate duodenal bicarbonate secretion in streptozotocin-diabetic rats

We examined the HCO 3- stimulatory effects of L-NAME (N G-nitro-L-arginine methyl ester) in the proximal duodenum of streptozotocin (STZ)-induced diabetic rats and compared with those of 16,16-dimethyl prostaglandin E2 (dmPGE2) and vagal electrical stimulation. Male SD rats were given STZ (70 mg/kg) i.p., and the experiments were done using 1–6 week STZ-diabetic rats with blood glucose levels of >300 mg/dl. Under urethane anesthesia the HCO 3- secretion was measured in the proximal duodenal loop using a pH-stat method and by adding 10 mM HCl. Hyperglycemic conditions appeared 1 week after STZ treatment and remained during 6 week-test period. The duodenal HCO 3- secretory response to L-NAME was significantly decreased in STZ-diabetic rats; the degree of reduction was dependent on the duration of diabetes, and the stimulatory effect disappeared completely in rats after 5–6 weeks of diabetes. Intravenous administration of L-NAME markedly increased arterial blood pressure with significant decrease in heart rate in normal rats, whereas in STZ-diabetic rats this agent caused only pressor response without any effect on heart rate. STZ-diabetic rats also secreted significantly less amount of HCO 3- from the duodenum in response to dmPGE2 and vagal electrical stimulation after 5–6 weeks of diabetes. These all changes observed in STZ-diabetic rats were significantly reversed by daily injection of insulin. These results suggest that 1) L-NAME failed to stimulate duodenal HCO 3- secretion in STZ-diabetic rats, and 2) impairment of the duodenal HCO 3- secretory ability in STZ-diabetic conditions is due to both vagal-dependent neuronal dysfunction and decreased sensitivity of the secreting cell.

The effects of feeding and secretin administration on the pancreaticoduodenal papilla of conscious dogs.

The aim of this study was to define the functional role of the pancreaticoduodenal papilla (PDP) in the regulation of pancreatic outflow into the duodenum in response to feeding and secretin administration in conscious dogs. The canine model we developed allowed for measurement of the pancreatic ductal pressure and pancreatic outflow simultaneously in a physiological state without interfering with the flow of pancreatic juice via the intact sphincter of the duodenal papilla. Feeding increased the pancreatic outflow from 2.8 +/- 0.2 to 13.4 +/- 1.3 ml/15 min with a slight increase in the pancreatic ductal pressure from 8.5 +/- 0.6 to 13.7 +/- 1.4 cmH2O. The administration of secretin increased the pancreatic outflow from 2.8 +/- 0.2 to 12.7 +/- 1.0 ml/15 min without increasing the pancreatic ductal pressure. The viscosity of the pancreatic juice increased during exposure to food, but decreased following food intake and secretin administration, after which the PDP seemed to dilate by about 40% of the fasting value. The results suggest that PDP changes its opening to maintain the pancreatic ductal pressure below a certain level, even if pancreatic secretion into the pancreatic duct increases due to food intake and secretin administration.

Tests of exocrine pancreatic function.

Pancreatic disease is broadly categorized into acute and chronic forms. Acute pancreatitis is a potentially life-threatening disorder characterized by the autodigestion of the pancreas by its own enzymes, accompanied by local or generalized peritonitis. Exocrine and endocrine dysfunction during acute pancreatitis is usually transient and reversible, and if patients survive an acute episode the recovery of the pancreas is usually complete; the development of chronic pancreatitis is an unusual complication. Chronic disorders of the pancreas may affect both the endocrine and exocrine functions of this organ. In this review, tests of exocrine function are evaluated as to their usefulness in the investigation of chronic exocrine pancreatic diseases, where damage to the acinar cells impairs the release of digestive enzymes, bicarbonate and fluid into the duodenum in response to a meal. This can eventually progress to 'pancreatic malabsorption' characterized by an inability to digest proteins and lipids. Some patients with chronic pancreatic exocrine disease will also develop diabetes mellitus as the damage extends to the {j-islet cells. Diseases associated with exocrine pancreatic dysfunction are relatively uncommon (Table I), and present with various symptoms which influence the choice and order of investigations. Pancreatic disorders can be explored by looking for both structural abnormalities and exocrine dysfunction and several techniques, often used in combination, are available to investigate putative disease. Imaging methods visualize the anatomy and structure of the gland, and difficulties in interpretation do not occur in advanced disease:

The role of intracellular calcium stores in motilin induced contractions of the longitudinal muscle of the rabbit duodenum

The contraction of longitudinal muscle strips of the rabbit duodenum in response to motilin and acetylcholine was investigated in normal and high K+-solutions in the presence and absence of external calcium, in order to demonstrate the existence of pharmaco-mechanical coupling for motilin and to examine whether the peptide mobilizes calcium from an intracellular store. In depolarized smooth muscle (140 mM K+), motilin (3.2 x 10(-9)-1 x 10(-7) M) and acetylcholine (1 x 10(-5) M) were still capable of causing a considerable, transient, concentration-dependent contraction in the presence of Ca2+. The 'extra'-contraction to motilin was not blocked by tetrodotoxin (1 microgram/ml) nor by atropine (10(-7) M), but acetylcholine (10(-5) M) was blocked by atropine. Verapamil (10(-7) M) could selectively block the K+ contraction without affecting the extra agonist contraction. Nitroprusside was ineffective up to 10(-4) M in high K+-solutions, but in normal Hepes-buffer it caused a concentration-dependent rightward shift of the concentration-response curve of motilin and acetylcholine contractions. In a calcium-depleted medium, high K+-depolarized muscle strips were still responsive to motilin and acetylcholine, but higher concentrations (10(-6) M) were needed than in the presence of calcium and the contractions reached only 57 +/- 11% and 74 +/- 9% respectively of the maximal contraction in 1.2 mM Ca2+ containing solutions. The response to motilin (10(-6) M) was not only smaller than that to acetylcholine (10(-5) M), it also faded more rapidly with time.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the sympathetic nervous system in cysteamine-induced gastric lesions in rats.

Cysteamine.HCl, when administered subcutaneously at 350 mg/kg, consistently induced severe gastric lesions in Wistar Kyoto rats (WKY), but not in spontaneously hypertensive rats (SHR). In both WKY and SHR, visible ulcers could not be induced in the duodenum in response to cysteamine. It appears that the stomach and duodenum of SHR are resistant to cysteamine due to hyperfunctioning of the sympathetic nervous system.

Pathogenesis of the Earliest Epithelial Cell Damage Induced by Mepirizole and Cysteamine in the Rat Duodenum

AbstractMepirizole (200 mg/kg) and cysteamine (100 mg/kg) induced epithelial cell damage in the proximal duodenum of rats within 30 min after s.c. administration. The injury induced was severe 60 min later. Gastric acid secretion determined in intact animals was stimulated by these agents 30 and 60 min later when the intraluminal pH of the duodenum was significantly decreased. Duodenal blood flow was significantly decreased beginning 5 min after administration up to 60 mm. Oral treatment with sodium bicarbonate (300 mg/kg). Cimetidine (100 mg/kg). omeprazole or NC-1300 (gastric proton pump inhibitors. 30 mg/kg) and 16.16-dimethyl prostaglandin E2 (10 μg/kg) protected the epithelium from damage induced by the two duodenal ulcerogens. Epithelial cell damage in the duodenum in response to mepirizole and cysteamine appears to be related to the increased gastric acid secretion followed by lowered intraduodenal pH of the duodenum having decreased blood flow

Pathogenesis of the earliest epithelial cell damage induced by mepirizole and cysteamine in the rat duodenum.

Mepirizole (200 mg/kg) and cysteamine (100 mg/kg) induced epithelial cell damage in the proximal duodenum of rats within 30 min after s.c. administration. The injury induced was severe 60 min later. Gastric acid secretion determined in intact animals was stimulated by these agents 30 and 60 min later when the intraluminal pH of the duodenum was significantly decreased. Duodenal blood flow was significantly decreased beginning 5 min after administration up to 60 min. Oral treatment with sodium bicarbonate (300 mg/kg), cimetidine (100 mg/kg), omeprazole or NC-1300 (gastric proton pump inhibitors, 30 mg/kg) and 16,16-dimethyl prostaglandin E2 (10 micrograms/kg) protected the epithelium from damage induced by the two duodenal ulcerogens. Epithelial cell damage in the duodenum in response to mepirizole and cysteamine appears to be related to the increased gastric acid secretion followed by lowered intraduodenal pH of the duodenum having decreased blood flow.

The relaxing response of the isolated rat duodenum to nicotine

1. 1. The relaxing responses of the atropine-treated isolated rat duodenum to 12 μM nicotine (N) and transmural electrical stimulation (S) have been compared. 2. 2. The effects of both N and S were unaffected by 3–30 μM guanethidine or previous reserpinization (1 mg/kg, i.p. during 5 days). 3. 3. The effects of N and S were completely blocked by 0.5–2.0 mM procaine, 0.1 mM butacaine or 0.3–1.2 μM tetrodotoxin. 4. 4. The relaxing response to N but not that to S was blocked by 0.3 mM hexamethonium or 3 μM mecamylamine and absent in the nicotine-desensitized preparation. 5. 5. The effects of both N and S were unaffected in the adenosine-5′-triphosphate (ATP)-desensitized preparation. 6. 6. It is suggested that the nonadrenergic and noncholinergic (NANC) relaxation of the rat duodenum in response to N and S is also nonpurinergic.

Pathogenic Mechanisms Involved in Mepirizole-lnduced Duodenal Damage in the Rat

Mepirizole (60 and 200 mg/kg) administered s.c. induced damage in the surface epithelial cells of the rat proximal duodenum as early as 2 hr after the treatment. 16,16-Dimethyl prostaglandin E2 (dmPGE2, 30 μg/kg) administered s.c. significantly protected the duodenal mucosa against mepirizole-induced damage for up to 6 hr. Gastric acid secretion in acute fistula preparations was significantly reduced 1 hr after administration of mepirizole (60 and 200 mg/kg). The secretion reverted to the control level 2 hr later. In the 60 mg/kg-treated group, however, there was a significant increase in the acid output for up to 6 hr. Duodenal HCO3− secretion stimulated with 10 mM HCl was significantly inhibited with mepirizole (60 and 200 mg/kg). Mepirizole (60 and 200 mg/kg) significantly increased the amount of acid in the duodenum for 2 to 6 hr after the treatment. dmPGE2 (30 μg/kg) significantly inhibited gastric acid secretion, stimulated duodenal HCO3− secretion, and reduced the increased amount of acid in the duodenum in response to mepirizole. Endogenous prostaglandin E2 and 6-keto prostaglandin F1α in the duodenal mucosa were significantly reduced by mepirizole (200 mg/kg) 1 to 2 hr later. Mepirizole-induced duodenal damage appears to be caused by the increased amount of acid in the duodenum.