Stanislaw J. Konturek

Inhibition of Acid Secretion in Dog by Metiamide, A Histamine Antagonist Acting on H2 Receptors

In dogs with Heidenhain pouches and gastric fistulae of the main stomach, metiamide, a histamine antagonist of the H2-blocking variety, in a dose of 12 µmoles kg-1 intravenously, inhibited gastric acid secretion during stimulation by histamine, pentagastrin, 2-deoxyglucose, and food (liver extract). Atropine sulfate (0.14 µmole kg-1 intravenously) also inhibited the response to all of these stimulants except histamine. To account for these findings, we speculate that the receptors on the parietal cell for histamine, gastrin, and acetylcholine interact.

Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers

We investigated the influence of inhibition of nitric oxide (NO) synthase, using NG-nitro-L-arginine (L-NNA) or NG-mono-methyl-L-arginine (L-NMMA), and the effects of exogenous donor of NO, such as glyceryl trinitrate (GTN), on the healing of chronic gastric ulcers induced by acetic acid, on gastric blood flow around the ulcer and on the number of capillaries in the granulation tissue at the ulcer bed. The inhibition of NO synthase resulted in a delay in ulcer healing and in a reduction in blood flow at the ulcer margin and in the number of capillaries in the granulation tissue at the ulcer bed. These effects of inhibition of NO synthase were antagonized, in part, by the administration of GTN or L-arginine but not D-arginine. We conclude that endogenous NO plays an important role in the maintenance of blood flow around the ulcer, in the angiogenesis in the granulation tissue and, thus, in the healing of gastric ulcers.

Distribution and release of epidermal growth factor in man.

Epidermal growth factor (EGF) is localised in man to salivary and Brunners glands. It is present in large concentrations in saliva and duodenal contents but the mechanisms of its release have been little studied. This study carried out on four groups of healthy subjects was designed to determine the distribution and the release of immunoreactive EGF (IR-EGF) in salivary, gastric, duodenal, and pancreatic secretions. Under basal conditions, the concentrations of IR-EGF in salivary, gastric, duodenal and pancreatic secretions were; 2.7 (0.4), 0.42 (0.12), 21 (5) and 8.5 (1.2) ng/ml, respectively. Chewing of Parafilm* significantly increased salivary but not gastric or duodenal EGF output while atropinisation led to the reduction in basal salivary and duodenal EGF output without affecting the increment in EGF release induced by chewing. Cigarette smoking caused a marked reduction in basal salivary and duodenal EGF output. Infusion of pentagastrin increased salivary and duodenal EGF output and this was blocked by the addition of somatostatin. Injection of secretin lead to an increase in pancreatic output of EGF. We conclude that in man the major sources of EGF are salivary glands, duodenum, and pancreas and that the release of EGF remains under neurohormonal control.

Role of locally generated prostaglandins in adaptive gastric cytoprotection

This study was designed to determine the role of mucosal generation of prostaglandins (PGs) in the ability of mild irritants (20% ethanol or 5% NaCl) to protect against the formation of mucosal lesions caused by necrotizing agents (100% ethanol or 25% NaCl) or acidified aspirin (ASA). Mild irritants protected against damage from necrotizing agents but not from ASA. This protection was accompanied by increased mucosal generation of PGE2 and PGI2-like substances. Exogenous PGE2 and PGI2 applied topically to the gastric mucosa in a nonantisecretory dose greatly inhibited the formation of lesions induced by either necrotizing agents or ASA. Pretreatment with indomethacin, which suppressed the generation of mucosal PGs augmented formation of lesions by necrotizing agents and partly counteracted the protective effect of mild irritants. We conclude that mild irritants, and exogenous PGs inhibit the formation of gastric lesions by necrotizing agents, at least in part, by mucosal generation of PGs.

Role of oxidative stress in the pathogenesis of caerulein-induced acute pancreatitis

In the last decade, the role of oxidative stress has been extensively evaluated in different experimental models of acute pancreatitis. This review shows that there is strong evidence that this stress occurs as an early phenomenon in pancreatic tissue in the course of caerulein-induced acute pancreatitis. Oxidative stress was documented in pancreatic tissue by means of methods showing generation of reactive oxygen species (e.g., chemiluminescence) and accumulation of products of reactive oxygen species-mediated lipid peroxidation. with concomitant depletion of enzymatic and low molecular weight antioxidants. Features of acinar cell injury and inflammation, especially pancreatic edema, show a marked improvement following treatment with a broad spectrum of antioxidants, platelet activating factor antagonists, or donors of nitric oxide (NO). Unfortunately, in most cases these beneficial effects are temporary and generally restricted to an early phase of the disease. However, results of well-designed clinical trials should finally evaluate the importance of oxidative stress-oriented treatment in acute pancreatitis in humans.

EFFECT OF GROWTH HORMONE RELEASE-INHIBITING HORMONE ON GASTRIC SECRETION, MUCOSAL BLOOD FLOW, AND SERUM GASTRIN

In dogs with gastric fistulae and Heidenhain pouches (HP) growth hormone release-inhibiting hormone (GH-RIH) infused intravenously in a dose of 2.5 mug per kg per hr inhibited almost completely acid and pepsin responses to pentagastrin, Urecholine, and a peptone. Histamine-induced acid secretion was more resistant to the inhibition by GH-RIH, and only acid secretion evoked by the lower doses of histamine was suppressed by this peptide. The inhibition of pentagastrin-induced gastric secretion was associated with a marked reduction in mucosal blood flow. The ratio of aminopyrine concentration in the gastric juice and blood plasma was not significantly changed by GH-RIH, indicating that the reduction in mucosal blood flow was secondary to an inhibition of gastric secretion. Gastric acid and serum gastrin responses to a peptone meal adjusted to pH 5.0 and kept in the main stomach at this same pH by intragastric titration were significantly decreased by GH-RIH, indicating that the observed acid inhibition could be attributed at least in part to the suppression of gastrin release. GH-RIH inhibited acid secretion from HP stimulated by liver extract in HP. The finding that GH-RIH inhibits gastric secretion induced by exogenous stimulants as well as by the direct chemical stimulation of the HP mucosa without changing serum gastrin level suggests that the major action of GH-RIH is a direct suppression of the oxyntic glands.

Effect of growth hormone-release inhibiting hormone on hormones stimulating exocrine pancreatic secretion.

The nature and extent of growth hormone-release inhibiting hormone (GH-RIH, somatostatin)-induced inhibition of pancreatic secretion of bicarbonate and protein, an index of enzyme secretion, were studied by administration of exogenous secretin or cholecystokinin (CCK) and of a number of stimulants for endogenous release of these hormones in fasted pancreatic fistula dogs with and without an infusion of GH-RIH. The results of this study show that GH-RIH inhibits the pancreatic fluid and bicarbonate secretion induced by duodenal acidification and exogenous secretion. The kinetic analysis shows that the interaction between GH-RIH and secretin affecting pancreatic bicarbonate secretion possesses the characteristics of competitive inhibition. GH-RIH does not change the pancreatic protein response to exogenous CCK, but profoundly inhibits pancreatic response to a variety of the endogenous stimulants of CCK release, including duodenal perfusion of sodium oleate, amino acid mixture, or feeding of a peptone meal. We conclude that GH-RIH is a very potent inhibitor of the endogenous release of CCK from the intestinal mucosa and inhibits competitively the action of secretin but not CCK on the exocrine pancreatic secretion.

The role of melatonin and L-tryptophan in prevention of acute gastric lesions induced by stress, ethanol, ischemia, and aspirin

Brzozowski T, Konturek PCh, Konturek SJ, Pajdo R, Bielanski W, Brzozowska I, Stachura J, Hahn EG. The role of melatonin and L‐tryptophan in prevention of acute gastric lesions induced by stress, ethanol, ischemia, and aspirin. J. Pineal Res. 1997; 23:79–89. ©Munksgaard, Copenhagen

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.

Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein overstimulation or ischemia/reperfusion

Abstract: Melatonin, a pineal secretory product, synthesized from l‐tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l‐tryptophan, on caerulein‐induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)‐provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 μg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l‐tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro‐inflammatory tumor necrosis factor α (TNFα) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4‐hydroxynonenal (4‐HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l‐tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFα and diminished pancreatic MDA + 4‐HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti‐inflammatory interleukin 10 (IL‐10). This was accompanied by a marked and dose‐dependent rise of plasma melatonin immunoreactivity. Gene expression of N‐acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l‐tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFα release combined with an increase of plasma anti‐inflammatory IL‐10 in rats with acute pancreatitis.