Pathogenesis Of Duodenal Ulcer Research Articles

Role of local motility changes in the pathogenesis of duodenal ulcers induced by cysteamine in rats.

The possible role of local motility in the pathogenesis of duodenal ulcers was investigated in rats using cysteamine. Duodenal motor activity was measured as intraluminal pressure recordings by means of a balloon positioned in the proximal duodenum. Subcutaneous administration of cysteamine (100 mg/kg) produced two linear bandlike lesions in the proximal duodenum within 6 hr. This dose of cysteamine significantly increased gastric acid secretion in acute fistula rats, and decreased duodenal HCO3- secretion caused by acid. During this period, this agent inhibited gastric motility but did produce markedly enhanced contractions in the duodenum. The changes in duodenal motility appeared within 5-10 min and were dose-dependent for cysteamine (10-100 mg/kg). Pretreatment with subcutaneously administered atropine (10 mg/kg), 16,16-dmPGE2 (30 micrograms/kg) or dopamine (10 or 30 mg/kg) significantly reduced the development of duodenal lesions caused by cysteamine, the inhibition being 86.8%, 49.7%, 54.5% or 67.8%, respectively. In the presence of cysteamine, dopamine had minimal effect on both acid and HCO3- secretion, while atropine or 16,16-dmPGE2 markedly inhibited acid secretion or increased HCO3- secretion, respectively. The enhanced duodenal motility induced by cysteamine was blocked partially by atropine and only slightly by 16,16-dmPGE2. Dopamine showed a dose-dependent inhibition on the duodenal hypermotility following cysteamine, and at 30 mg/kg almost completely abolished the development of contractions. These results suggest that abnormal hypermotility in the duodenum may be partly involved in the pathogenesis of cysteamine-induced duodenal ulcers.

Development and significance of cysteamine and propionitrile models of duodenal ulcer.

Cysteamine is widely used in rodents to induce duodenal ulcer. Herein, the pathogenesis of duodenal ulceration in its earliest stages was reviewed using findings from cysteamine- and propionitrile-induced duodenal ulcer in rodent models, especially taking into account changes in the secretion of gastric acid, duodenal and pancreatic bicarbonate as well as gastroduodenal motility. The effect of cysteamine-HCl in inducing ulcers in rats is circadian rhythm-dependent. The effect is greatest from just before the end of diurnal rest to just after the start of nocturnal activity. The chronobiologic effect may be in part due to the circadian rhythm-dependent increased gastric acid production from cysteamine. Titratable acidity was found to be twice as great in the gastric juice of rodents when cysteamine was given by injection at 2000 (just after the start of nocturnal activity) in comparison to when given at 0800 or 1200 (at the beginning or middle span of daily rest). Further studies have shown that adrenalectomy of rats 7 days before cysteamine administration obliterated the observed circadian susceptibility to ulcer formation. Duodenal ulceration, at least in the cysteamine model, appears to be under chronobiologic neuroendocrine control or influence, seemingly mediated by the adrenal glands.

Development and Significance of Cysteamine and Propionitrile Models of Duodenal Ulcer

Cysteamine is widely used in rodents to induce duodenal ulcer. Herein, the pathogenesis of duodenal ulceration in its earliest stages was reviewed using findings from cysteamine-and propionitrile-induced duodenal ulcer in rodent models, especially taking into account changes in the secretion of gastric acid, duodenal and pancreatic bicarbonate as well asgastroduodenal motility. The effect of cysteamine-HCl in inducing ulcers in rats is circadian rhythm-dependent. The effect is greatest from just before the end of diurnal rest to just after the start of nocturnal activity. The chronobiologic effect may be in part due to the circadian rhythm-dependent increased gastric acid production from cysteamine. Titratable acidity was found to be twice as great in the gastric juice of rodents when cysteamine was given by injection at 2000 (just after the start of nocturnal activity) in comparison to when given at 0800 or 1200 (at the beginning or middle span of daily rest). Further studies have shown that adrenalectomy of rats 7 days before cysteamine administration obliterated the observed circadian susceptibility to ulcer formation. Duodenal ulceration, at least in the cysteamine model, appears to be under chronobiologic neuroendocrine control or influence, seemingly mediated by the adrenal glands.

胃膵分泌相関からみた十二指腸潰瘍の発生病理

胃膵分泌相関からみた十二指腸潰瘍の発生病理

The Inhibition of Nocturnal Gastric Acid Secretion by Omeprazole in Patients with Duodenal Ulcer

Omeprazole is a substituted benzimidazole which has been shown to act by selective inhibition of the H+K+ATPase proton pump within the parietal cell. It has a prolonged duration of action, raising the possibility of a once-a-day treatment regime. Therefore, we have investigated the effects of single morning doses of enteric-coated omeprazole on gastric acid secretion during the following night, in the knowledge that excessive night-time gastric secretion has been implicated in the pathogenesis of duodenal ulcer. The control of nocturnal secretion with bedtime doses of H2-receptor antagonists has been successful in preventing ulcer recurrence.

RANITIDINE 150 mg TWICE DAILY VS 300 mg NIGHTLY IN TREATMENT OF DUODENAL ULCERS

102 patients with endoscopically proven duodenal ulcers were randomly allocated to treatment with ranitidine either 150 mg twice a day or 300 mg every evening for 4 weeks in a prospective double-blind study. The two groups were similar. 48/57 (84%) healed on ranitidine 150 mg twice daily and 43/45 (96%) healed on 300 mg every evening (p = 0 ·9)—that is, ranitidine 300 mg as a single night time dose is as effective as 150 mg twice daily. The results also indicate the importance of overnight gastric acidity in the pathogenesis of duodenal ulcers.

Somatostatin depletion of the gut and pancreas induced by cysteamine is not prevented by vagotomy or by dopamine agonists

The role of endogenous somatostatin in the pathogenesis of duodenal ulceration was investigated in the present study by using the cysteamine animal model of the disease. Our previous studies showed a rapid and multiorgan depletion of somatostatin immunoreactivity (SIR) in rats given a single dose of duodenal ulcerogen cysteamine. We now determined whether acetylcholinergic and dopaminergic modulation (both known to influence the development of duodenal ulcer) are accompanied by modification of cysteamine-induced SIR depletion in rat organs. Vagotomy performed either 1 or 18 h before cysteamine administration did not interfere with the chemically induced SIR decrease in pancreas, gastric and duodenal mucosa. Vagal denervation alone had no marked influence on SIR levels but if combined with cysteamine, the SIR depletion in the stomach was significantly more pronounced than after the duodenal ulcerogen alone. Pretreatment with the dopamine agonists bromocriptine or lergotrile (known to prevent the chemically induced duodenal ulcers) did not influence the SIR depletion by cysteamine. Thus cysteamine depletes endogenous somatostatin in peripheral organs (e.g., stomach, duodenum, pancreas) by mechanisms independent of both vagus nerve and dopamine agonists. A role of central somatostatin depletion leading to disinhibition of vagus is also considered in the pathogenesis of experimental duodenal ulcer.

Exogenous and endogenous acid and pepsins in the pathogenesis of duodenal ulcers in the rat.

A continuous subcutaneous infusion for 24 hr of the gastric secretagogues, pentagastrin (4 micrograms/kg/min) together with carbachol (0.8 micrograms/kg/min) produced a 100% incidence of duodenal ulcers (DU) in male albino Wistar rats. The mean acid output producing these duodenal ulcers was 2.3 mmol/24 hr, with a gastric secretory volume of 25 (+/- 1) ml/24 hr at an acid concentration of 91 (+/- 2) mmol/liter. The pepsin activity in the gastric juice was 185 micrograms/ml. To simulate this acid-pepsin hypersecretion, acid and/or pepsin was infused intragastrically for 24 hr. The intragastric infusion of hydrochloric acid (0.1 M, 0.2 M, 0.5 M) alone and hog purified pepsin (2.5, 5, 10 mg/24 hr) at a constant rate of 1 ml/hr for 24 hr failed to produce duodenal ulcers in rats although gastric lesions in the body of the stomach were produced. The infusion of 0.2 M HCl with 5 mg pepsin over 24 hr produced DU in two of 10 rats. However, pooled secretagogue-stimulated gastric juice, infused intragastrically, produced DUs in 11 of 12 rats. Acid alone does not produce DU experimentally in rats at the rate of infusion used in these experiments. Acid and exogenous procine pepsin (similar to human pepsin 3 on agar gel electrophoresis) rarely produced duodenal ulcers. However, acid and endogenous rat pepsin are needed together for the duodenal ulcerogenesis. This pepsin may be an obligatory ulcerogenic factor in the rat.

DOPAMINE DISORDER IN DUODENAL ULCERATION

Cysteamine-induced duodenal ulcers in rats were prevented by the dopamine agonists bromocriptine, lergotrile, and apomorphine, whereas both the severity of duodenal ulcers and the mortality among cysteamine-treated rats were raised by the dopamine receptor antagonist, haloperidol. Bromocriptine and lergotrile greatly reduced gastric-acid output in cysteamine-treated rats. A review of the literature shows a high incidence of duodenal ulcers in patients with Parkinson's disease (associated with dopamine deficiency) and a low occurrence in schizophrenics (associated with dopamine excess and/or hyperactivity). Thus, changes in peripheral and/or central dopamine concentrations and/or receptor activity may have a role in the pathogenesis of duodenal ulceration.

Gastric emptying in normal subjects and patients with peptic ulcer

Gastric emptying in patients with peptic ulcer and normal subjects was studied using the acetaminophen method. The subjects consisted of 15 normal subjects, 52 gastric ulcer patients and 65 duodenal ulcer patients, who were studied in active stage of the ulcer. As an indicator of gastric emptying, the plasma acetaminophen concentration was measured by dye method (diphenylhydrazyl), as mcg/ml, at 45 minutes after ingestion of a high calory pasty test meal (200 ml) with 1.5 gr of acetaminophen. In normal subjects, the plasma acetaminophen concentration was 9.4 +/- 3.6 mcg/ml. In gastric ulcer patients, the concentration was 7.4 +/- 3.2 mcg/ml, which showed significantly delayed gastric emptying (P less than 0.05). In duodenal ulcer patients, the concentration was 11.6+/-3.3 mcg/ml, which suggested significantly rapid gastric emptying (P less than 0.05). In consideration of gastric secretion, gastric ulcer cases with lower acid secretion have more delayed gastric emptying. In duodenal ulcer cases with hypersecretion, gastric emptying is more rapid than normo-and/or hyposecretory cases (P less than 0.005). The delayed gastric emptying may play a role in etiology of gastric ulcer. On the other hand, the rapid gastric emptying with gastric acid hypersecretion may be important in the pathogenesis of duodenal ulcer.

Duodenal-ulcer disease associated with elevated serum pepsinogen I: an inherited autosomal dominant disorder.

To delineate genetic factors involved in the pathogenesis of duodenal ulcer, serum pepsinogen I levels were determined by radioimmunoassay in two large kindreds with multiple members affected with duodenal ulcer. An elevated serum immunoreactive pepsinogen I concentration (greater than 100 ng per milliliter) segregated as an autosomal dominant trait in these families. Furthermore, 10 of 11 patients with clinical ulcer disease in these families had hyperpepsinogenemia. An elevated serum pepsinogen I concentration appears to be a subclinical marker of the ulcer diathesis in families with this autosomal dominant form of peptic-ulcer disease.

Gastric emptying of ingested acid and its effects on plasma gastrin and secretin in duodenal ulcer subjects.

Abnormal acid production or handling is thought to be involved in duodenal ulceration. Gastric emptying of 25 mmol hydrochloric acid (250 ml 0.1 M solution) was studied by using an isotopic method in control and ulcer subjects. Plasma gastrin and secretin levels were simultaneously measured. Gastric emptying was significantly faster in ulcer subjects using several parameters. Plasma gastrin levels were suppressed in both groups, with equivocal differences between them. Mean plasma secretin levels showed no significant elevation in controls and at only one point in ulcer subjects. Mean elevation in plasma secretin levels during intermediate phase of gastric emptying (T30-70) correlated with rate of acid loss from stomach in both groups. Regression lines were significantly different in position, however, and indicated a higher threshold for secretin release in ulcer subjects. The significance of this in the pathogenesis of duodenal ulcer is discussed.

Effect of nicotine on serum secretin and exocrine pancreatic secretion

The effect of nicotine (100 mug/kg hr-1) on serum secretin and pancreatic secretions was studied in dogs with chronic pancreatic fistulas. Release of immunoreactive secretin (IRS) was stimulated by intraduodenal infusion of HCl (9.6 mEq/30 min). Pancreatic flow rate and bicarbonate and protein secretions were stimulated either by intestinal acidification or infusion of exogenous secretin (1.0 IU/kg hr-1). It was found that nicotine delayed the appearance of peak IRS concentrations in response to intraduodenal HCl by about 20 min. However, nicotine had no effect on the total amount of IRS released nor was this delay accompanied by a similar delay in the appearance of peak bicarbonate output. Furthermore, nicotine did not affect pancreatic secretory function stimulated by either HCl or exogenous secretin. These data do not support the thesis that nicotine plays an important role in the pathogenesis of duodenal ulcers in smokers by inhibiting the pancreatic secretion of bicarbonate.

The carbohydrate and ester sulfate content of mucosal biopsies in health and in patients with duodenal ulcer

The carbohydrate and ester sulfate contents of duodenal mucosal biopsies from patients with duodenal ulcer and from control subjects have been determined by gas—liquid chromatography. The net amounts and molar ratios (to glucosamine) of fucose, galactose, mannose, glucose, N-acetylglucosamine, N-acetylgalactosamine and sulfate were similar in both groups. These findings suggest that sulfated glycoproteins, which inhibit the proteolytic activity of pepsin, are not involved in the pathogenesis of duodenal ulcer.

Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer.

New methods are described by which the buffer content and the rate and pattern of net gastric acid secretion in human subjects fed normal meals can be measured by use of sodium bicarbonate infusion to control intragastric pH. With these techniques, it was shown that the rate of acid secretion in response to a steak meal in seven duodenal ulcer patients was twice the rate achieved in six control subjects and that the amount of acid secreted after eating exceeded the peak histamine response in the ulcer patients but not in the controls. Meal-stimulated acid secretion, expressed as a function of the peak histamine response, was roughly correlated with the serum gastrin concentration (r = 0.45), but it was concluded that other factors must also contribute to the higher than normal secretory responses to a meal found in duodenal ulcer patients. Measurement of buffer content of the stomach revealed that the duodenal ulcer patients emptied the meal buffer at a much more rapid rate than the normal subjects. By 2 h after eating, the ulcer subjects had less than half as much buffer in their stomachs as the controls. The combination of acid hypersecretion and rapid buffer emptying leads to abnormally high gastric acidity after a meal in duodenal ulcer patients. These results suggest that, in addition to a large parietal cell mass, parietal cell responsiveness to a meal and the rate of buffer emptying may be important in the pathogenesis of duodenal ulcer.

Hydrochloric acid secretion capacity of the stomach as an inherited factor in the pathogenesis of duodenal ulcer.

The HCl response to maximal histamine stimulation was investigated in 428 subjects: 160 DU patients, 113 healthy persons from ulcer families, and 155 controls. The data obtained were correlated with blood group status and secretor status as determined in the saliva. Both DU patients and healthy members of ulcer families showed a highly significant increase of HCl output when compared with the control subjects. Increased gastric acid production in relation to blood Group O and nonsecretion was noted in DU patients and in nonulcerated members of ulcer families. The combined effect of Group O and nonsecretion effaces the difference between duodenal ulcer patients and their relatives in terms of HCl values. The association of blood Group O and nonsecretion genes with an increased capacity for HCl secretion in duodenal ulcer subjects and their healthy relatives might suggest a pleiotropic effect of these genes.

Metal Sensitivity and Duodenal Ulcer

To the Editor:— Recently I have been impressed with a series of cases in which the presenting complaint was the common problem of metal sensitivity. These patients are for the most part sensitive to nickel, which is alloyed into a large number of metallic products which contact the skin, eg, jewelry, buckles, garters, and snaps. I have been impressed by the considerable number who have a history of active or healed duodenal ulcer (x-ray-proven). Whether this observation is true to the point of being able to withstand controlled study is difficult to say. Since our knowledge of the pathogenesis of duodenal ulcer is incomplete, conjecture regarding something more than a coincidence between the metal sensitivity and the ulceration could be useful and worthy of presentation. Cross sensitivity reactions between contact dermatitis of the skin and the mucosa have been demonstrated, as in acrylic dermatitis due to dentures. Whether this mucosal

Relation of Duct of Santorini to the Pathogenesis of Duodenal Ulcer

Relation of Duct of Santorini to the Pathogenesis of Duodenal Ulcer

DISTAL ANTRECTOMY WITH VAGECTOMY FOR DUODENAL ULCER; REVIEW OF 450 CASES.

Introduction The surgical pendulum is swinging toward universal adoption of the recent more conservative type surgical procedures which have been developed in a number of surgical centers during the past 20 years. As a result of the findings of several investigators, particularly the monumental work of Dragstedt and associates, the basic altered gastric physiology in the pathogenesis of duodenal ulcer is now known and understood. By the clinical application of these basic physiologic principles, several surgeons have patterned conservative surgical procedures to control duodenal ulcer without affecting, to any serious degree, the normal gastric functions or nutritional status of the patients. In addition, several of these procedures have reduced the incidence and severity of many of the undesirable postoperative sequelae associated with many of the older and time-tested surgical procedures for this chronic disease. It has been definitely established by careful research studies that there are two major physiologic phases

The Influence of Geography on Duodenal Ulcers

This editorial is prompted by my reading of the paper entitled "Peptic Ulcer in Africa" by Clarence A. Snyder and Merton J. Alexander in this issue of theArchivesas well as by reflections on reported geographical factors influencing duodenal ulcer in India and in Norway. While there have been many significant contributions in recent years dealing with the pathogenesis of duodenal ulcer, some factors still remain obscure. One of these is the high incidence of ulcer reported in certain areas, while neighboring regions inhabited by the same race of people remain relatively free from the disease. In my own view a hypersecretion of gastric juice of nervous origin has been established as the sufficient cause of duodenal ulcer in the overwhelming majority of patients in the United States and in Europe. These patients regularly display a hypersecretion of gastric juice in the empty stomach which, if reproduced in the