J. W. Konturek

Role of reactive oxygen metabolites in aspirin‐induced gastric damage in humans: gastroprotection by vitamin C

The roles of active oxygen metabolites and anti‐oxidative defenses in aspirin (ASA)‐induced gastric damage have been little studied.

Infection of Helicobacter pylori in gastric adaptation to continued administration of aspirin in humans

BACKGROUND & AIMS Involvement of Helicobacter pylori in aspirin-induced gastropathy and adaptation to aspirin remains unclear. The aim of this study was to compare gastric damage and adaptation after repeated exposures to acetylsalicylic acid in the same subjects before and after eradication of H. pylori. METHODS Before and after H. pylori eradication, 8 volunteers were given aspirin, 2 g/day during 14 days. Mucosal damage was evaluated by endoscopy and histological analysis of biopsy samples. Gastric microbleeding, DNA synthesis, prostaglandin E2 generation, and luminal contents of transforming growth factor alpha and its immunohistochemical expression were determined on days 0, 3, 7, and 14 of aspirin course. RESULTS In all subjects, aspirin-induced gastric damage that reached maximum on day 3. In H. pylori-positive subjects, this damage was maintained at a similar level up to day 14. After H. pylori eradication, the damage was significantly lessened both in endoscopy and histology at day 14 and accompanied by increased mucosal expression and luminal release of transforming growth factor alpha. Prostaglandin E2 generation was significantly greater in H. pylori-positive subjects than after H. pylori eradication, but aspirin treatment resulted in >90% reduction of this generation independent of H. pylori status. CONCLUSIONS Gastric adaptation to aspirin is impaired in H. pylori-positive subjects, but eradication of this bacterium restores this process.

Diffuse esophageal spasm: a malfunction that involves nitric oxide?

Objective: As recently suggested, nitric oxide (NO) may play an important role in the regulation of esophageal motility, being partly responsible for the latency period and latency gradient between the onset of a swallow and contractions of esophageal circular smooth muscles. Diffuse esophageal spasm appears to be a classical example in which the mechanisms normally responsible for the physiologic timing of the contractions occurring in the esophageal body after swallowing are disturbed. Methods: Five patients (one male and four female; age, 18-48 years) with symptomatic esophageal spasm were given glyceryl trinitrate (GTN) intravenously in gradually increasing doses or L-arginine on two separate occasions and underwent manometric measurements of esophageal motility after wet swallows, using a multilumen perfused catheter system (Synectics Medical, Stockholm, Sweden). The amplitude, duration, and propagation of the contractions and the latency period were analyzed, using specially designed software. Addit...

Role of cholecystokinin in the control of gastric emptying and secretory response to a fatty meal in normal subjects and duodenal ulcer patients

BACKGROUND Exogenous cholecystokinin (CCK) is known to affect gastric motor and secretory activities, but its physiologic role in the control of gastric functions is unknown. METHODS In this study involving 10 young healthy subjects and 10 duodenal ulcer (DU) patients, 500 ml of a standard meal without or with addition of 15% soybean oil was given, and the gastric emptying rate and the pH profile and plasma levels of gastrin, CCK, pancreatic polypeptide (PP), and somatostatin were determined in separate tests with placebo or with antagonism of type-A CCK receptors (loxiglumide, 1200 mg orally). RESULTS In healthy controls and DU patients the emptying half-time was 44 and 34 min, respectively, and the addition of oil prolonged the emptying by about 50%. Pretreatment with loxiglumide significantly reduced fat-induced retardation of gastric emptying in both healthy controls and DU patients. A standard meal in healthy subjects resulted in an immediate rise in median gastric pH to about 6.0, and this was followed by gradual decrease within about 3 h to premeal values of about 2.0. After the meal, plasma gastrin rose by 57%, CCK by 177%, PP by 100%, and somatostatin by 39%. Addition of fat significantly attenuated and prolonged the pH decrease after the meal while reducing the increment in plasma gastrin and enhancing plasma CCK and PP levels. Loxiglumide significantly reduced the median postprandial pH (from control 4.8 to 2.5) and reversed the changes in the pH profile caused by the addition of fat. The increments in plasma gastrin and CCK were markedly augmented, whereas those of somatostatin and PP were significantly attenuated. DU patients showed lower postprandial pH (3.0) in tests with or without fat and higher increments in plasma gastrin. CCK antagonism failed to affect significantly the pH profile or the increments in plasma gastrin in DU patients. CONCLUSIONS These results indicate that endogenous CCK released by a fatty meal delays gastric emptying and inhibits gastric acid and plasma gastrin responses in healthy subjects, but in DU patients the inhibitory effect of CCK is less pronounced, suggesting a defect in the action of this hormone on gastrin release and gastric acid secretion.

Release and Action of Epidermal Growth Factor on Gastric Secretion in Humans

Epidermal growth factor (EGF) has recently been localized in salivary, pancreatic, and Brunners glands in humans, but little is known about its release and its action on gastric secretion. This study, performed on healthy subjects, was designed to determine the release of immunoreactive EGF in plasma and in salivary and gastric secretions under basal conditions and after modified sham feeding (MSF), ordinary feeding, and infusion of pentagastrin without and with addition of exogenous recombinant human EGF (hEGF). Under basal conditions the EGF concentrations in plasma and salivary and gastric secretions were 52 +/- 8 pg/ml, 2.5 +/- 0.3 ng/ml, and 0.12 +/- 0.03 ng/ml, respectively. MSF and ordinary feeding increased significantly EGF plasma level and salivary output but not gastric EGF output, and atropinization failed to effect these plasma and salivary EGF responses to MSF. Intravenous infusion of pentagastrin increased both plasma and salivary but not gastric EGF, and addition of exogenous hEGF in graded doses (0.25-1.0 micrograms/kg) resulted in a dose-dependent increase in the plasma level of EGF and in significant inhibition of gastric acid and pepsin outputs. The increment in plasma EGF, which resulted in significant inhibition of gastric secretion, was several times greater than that observed after MSF or feeding. EGF infused in a constant dose (0.12 or 1.0 micrograms/kg-h) resulted in an increment in plasma EGF similar to that observed after MSF alone.

Nitric oxide synthase inhibition and platelet function

Nitric oxide (NO), synthesized and released by endothelium, contributes to the regulation of vascular tone and platelet function (1,2). Platelets themselves generate NO, which acts as a negative-feedback mechanism to inhibit platelet adhesion and aggregation (3,4). The arginine analogue, NO-monomethyl-L-arginine (L-NMMA), competitively antagonizes the synthesis of NO from L-arginine (5). The aim of this study was to determine the platelet effects of L-NMMA in healthy subjects.

Leptin in the Control of Gastric Secretion and Gut Hormones in Humans Infected with Helicobacter pylori

BACKGROUND Leptin, a protein product of obese gene expressed primarily by adipocytes, provides feedback information on the size of energy stores to central OB receptors controlling the food intake, energy expenditure and body weight homeostasis. It has recently been detected in the rat stomach, especially after cholecystokinin (CCK) administration and in human stomach infected with Helicobacter pylori, but its role in gastric secretory functions in humans has not been revealed. This study was designed to determine the involvement of leptin in the control of basal, CCK- and meal-induced gastric H+ secretion and plasma gastrin and CCK levels in humans before and after an eradication of H. pylori. METHODS Two groups (A and B) of subjects were used; group A (n = 7), for comparison of the effects of CCK and leptin on basal gastric H+ and plasma hormone (leptin, gastrin and CCK) levels, and group B (n = 6), for studies on the involvement of leptin in gastric secretory and plasma hormonal responses to vagal stimulation and gastric peptone meal before and after H. pylori eradication. RESULTS In H. pylori-positive subjects, CCK (12-200 pmol kg(-1) h(-1)) given i.v. caused a dose-dependent increase of gastric H+ accompanied by a dose-dependent rise in plasma CCK and leptin levels. In contrast, leptin administered i.v. in graded doses (5-80 pmol kg(-1) h(-1)) resulted in a gradual inhibition of basal gastric H+ secretion and in adose-dependent increment in plasma leptin accompanied by an increase in plasma gastrin without alteration of plasma CCK level. Following eradication of H. pylori by 1-week triple therapy in group B patients, the infusion of CCK produced a significantly smaller increase in gastric H+ secretion and significantly smaller rise in plasma leptin as compared to those before the eradication. Cephalic phase stimulation of gastric secretion induced by modified sham-feeding in group B H. pylori-positive subjects increased gastric H+ secretion to about 40% of pentagastrin maximum without affecting plasma leptin, gastrin, or CCK level, while gastric peptone meal resulted in the increase in gastric H+ response reaching about 70% of pentagastrin maximum accompanied by a marked rise in plasma leptin, gastrin and CCK. The treatment with a standard dose of leptin (20 pmol kg(-1) h(-1)) failed to affect sham-feeding-induced gastric H+ secretion but reduced significantly the peptone meal-stimulated H+ secretion, while raising plasma gastrin in response to this meal. Plasma CCK under basal conditions and after sham-feeding was not affected, but plasma CCK response to gastric meal was significantly reduced by leptin infusion. Eradication of H. pylori did not affect basal or sham-feeding-induced H+ secretion but resulted in a significant fall in gastric meal-induced H+ and plasma leptin, gastrin and CCK levels. CONCLUSIONS 1) The gastric meal and CCK enhance the release of leptin in H. pylori-positive patients and this leptin is capable of inhibiting basal and meal-stimulated gastric H+ secretion, while raising plasma gastrin and reducing the plasma CCK levels, and 2) the eradication of H. pylori reduces the postprandial gastric H+ and plasmagastrin responses as well as the release of leptin in response to CCK and meal.Background: Leptin, a protein product of obese gene expressed primarily by adipocytes, provides feedback information on the size of energy stores to central OB receptors controlling the food intake, energy expenditure and body weight homeostasis. It has recently been detected in the rat stomach, especially after cholecystokinin (CCK) administration and in human stomach infected with Helicobacter pylori , but its role in gastric secretory functions in humans has not been revealed. This study was designed to determine the involvement of leptin in the control of basal, CCK- and meal-induced gastric H + secretion and plasma gastrin and CCK levels in humans before and after an eradication of H. pylori. Methods: Two groups (A and B) of subjects were used; group A ( n = 7), for comparison of the effects of CCK and leptin on basal gastric H + and plasma hormone (leptin, gastrin and CCK) levels, and group B ( n = 6), for studies on the involvement of leptin in gastric secretory and plasma hormonal responses to vagal stimulation and gastric peptone meal before and after H. pylori eradication. Results: In H. pylori -positive subjects, CCK (12-200 pmol kg -1 h -1 ) given i.v. caused a dose-dependent increase of gastric H + accompanied by a dose-dependent rise in plasma CCK and leptin levels. In contrast, leptin administered i.v. in graded doses (5-80 pmol kg -1 h -1 ) resulted in a gradual inhibition of basal gastric H + secretion and in adose-dependent increment in plasma leptin accompanied by an increase in plasma gastrin without alteration of plasma CCK level. Following eradication of H. pylori by 1- weektriple therapy in group B patients, the infusion of CCK produceda significantly smaller increase in gastric H + secretion and significantly smaller rise in plasma leptin as compared to those before the eradication. Cephalic phase stimulation of gastric secretion induced by modified sham-feeding in group B H. pylori positive subjects increased gastric H + secretion to about 40% of pentagastrin maximum without affecting plasma leptin, gastrin, or CCK level, while gastric peptone meal resulted in the increase in gastric H + response reaching about 70% of pentagastrin maximum accompanied by a marked rise in plasma leptin, gastrin and CCK. The treatment with a standard dose of leptin (20 pmol kg -1 h -1 ) failed to affect sham-feeding-induced gastric H + secretion but reduced significantly the peptone meal-stimulated H + secretion, while raising plasma gastrin in response to this meal. Plasma CCK under basal conditions and after sham-feeding was not affected, but plasma CCK response to gastric meal was significantly reduced by leptin infusion. Eradication of H. pylori did not affect basal or sham-feeding-induced H + secretion but resulted in a significant fall in gastric mealinduced H + and plasma leptin, gastrin and CCK levels. Conclusions: 1) The gastric meal and CCK enhance the release of leptin in H. pylori -positive patients and this leptin is capable of inhibiting basal and meal stimulated gastric H + secretion, while raising plasma gastrin and reducing the plasma CCK levels, and 2) the eradication of H. pylori reduces the postprandial gastric H + and plasma gastrin responses as well as the release of leptin in response to CCK and meal.

Disturbed Gastric Motor Activity in Patients with Human Immunodeficiency Virus Infection

BACKGROUND Human immunodeficiency virus (HIV) infection is accompanied by a wide spectrum of disorders that affect the central and peripheral nervous system. Damage to the peripheral and central nervous system, including its autonomic division, may become manifest at any stage of the disease. METHODS Twenty HIV-positive patients with abdominal complaints like dyspepsia, dysphagia, vomiting, and nausea underwent several function tests to determine oesophageal motility, gastric motor and electric activity, and gastric emptying rate. The CDC (Center for Disease Control) classification was used to determine the stage of the disease, which varied from B2 to C3. Before gastric motility examinations all patients underwent endoscopy of the upper gastrointestinal (GI) tract, and none of them showed any morphologic changes of the stomach or oesophagus. Biopsy specimens taken during upper GI endoscopy did not show any histologic alterations of the gastric or oesophageal mucosa. RESULTS Manometry of the antrum showed an unchanged postprandial (after 200 ml liquid, caloric meal) motility index (MI) when compared with the fasting period (mean fed MI, 174 +/- 43; mean fasting MI, 136 +/- 51). The same was seen for frequency, amplitude, and duration of antral contractions. The electrogastrographic recordings showed basal rhythm of 3 cpm, and no significant changes of the electric pattern were observed postprandially. The amplitude of electric oscillations (power content) significantly increased postprandially when compared with the fasting period. The gastric emptying rate of liquids, measured by means of the 13C-acetate breath test, was faster in HIV patients than in healthy controls. On the other hand, in HIV patients the scintigraphically determined emptying rate of solids was significantly delayed compared with the normal values. There were no significant differences in the oesophageal motility pattern with regard to the amplitude, duration, and propagation of peristaltic waves when compared with the values obtained from healthy volunteers. CONCLUSION Our results suggest that HIV-associated visceral neuropathy may present already in relatively early stages of infection and may contribute to abdominal symptoms that occur frequently in these patients.

Eradication of Helicobacter pylori restores the inhibitory effect of cholecystokinin on gastric motility in duodenal ulcer patients.

BACKGROUND Increased gastric emptying and defective action of endogenous cholecystokinin (CCK), that is known to inhibit this emptying, have been implicated in the pathogenesis of duodenal ulcer (DU). The aim of this double blind study was to assess whether CCK and somatostatin participate in the impairment of gastric motility in active DU patients before and after Helicobacter pylori eradication. METHODS Tests were undertaken in 10 DU patients without or with elimination of the action of endogenous CCK using loxiglumide, a selective CCK-A receptor antagonist, before and 4 weeks after eradication of H. pylori with 1 week triple therapy that resulted in healing of all DUs tested. The gastric emptying rate after feeding was determined using the 13C-acetate breath test. Before each test, samples of gastric juice were obtained by aspiration using a nasogastric tube for determination of somatostatin using specific radioimmunoassay. RESULTS Prior to H. pylori eradication gastric emptying half-time was 31 +/- 6 min in placebo-treated DU patients and this emptying rate was not significantly affected in tests after pretreatment with loxiglumide (10 mg/kg i.v.). Following eradication of H. pylori, in tests with placebo gastric emptying half-time was significantly longer (48 +/- 9 min) compared to that prior to H. pylori eradication. Pretreatment with loxiglumide in H. pylori eradicated DU patients significantly enhanced the gastric emptying rate with an emptying half-time of only 33 +/- 4 min. Eradication of H. pylori resulted in a significant increase in somatostatin concentration in gastric juice and loxiglumide significantly reduced this luminal somatostatin in H. pylori-eradicated subjects compared to values before anti-H. pylori therapy. CONCLUSIONS 1) H. pylori infection in DU patients is accompanied by enhanced gastric emptying and reduction in luminal release of somatostatin; 2) the failure of loxiglumide to affect gastric emptying in H. pylori-infected DU patients might be attributed, at least in part, to the failure of endogenous CCK to control gastric motility due to deficient release of somatostatin; and 3) H. pylori-infected patients appear to exhibit a deficient somatostatin release by endogenous CCK that can be reversed by the eradication of H. pylori indicating that both CCK and somatostatin may contribute to normalization of gastric emptying following H. pylori eradication in DU patients.

Expression of constitutive nitric oxide synthase in rat and human gastrointestinal tract.

The aim of this study was to determine the expression of constitutive NO synthases (ecNOS and bNOS) at the protein level in rat and human gastrointestinal tract. We established a quantitative Western blotting method for detection and quantification of ecNOS and bNOS in both species. Human gastric fundus was further analyzed by immunohistochemistry. EcNOS expression at the protein level could be quantified in different organs of the rat gastrointestinal tract and in human gastric mucosal biopsies. Immunohistochemistry of gastric fundus revealed that immunoreactivity for ecNOS was localized mainly in the endothelium of small vessels. In rats, expression of bNOS at the protein level was highest in esophagus. By means of immunohistochemistry of human gastric fundus, immunoreactivity was detected mainly in the plexus of Auerbach. We conclude that isoforms of constitutive nitric oxide synthase can be identified and quantified at the protein level both in rat and human gastrointestinal tract. The presence of bNOS in nerve tissue supports previous observations that NO serves as a transmitter in non-adrenergic, non-cholinergic nerves in human esophagus and stomach. The observation that ecNOS has been found mainly in endothelial cells suggests the involvement of NO in the regulation of mucosal blood flow.