Artur Dembinski

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.

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.

Nitric oxide in pancreatic secretion and hormone-induced pancreatitis in rats.

SummaryThe aim of the present study was to determine the role of endogenous nitric oxide (NO) in pancreatic secretion in vivo and amylase release from pancreatic acini in vitro and in caerulein-induced acute pancreatitis in rats. Blockade of NO synthase byNG-nitro-L-arginine (L-NNA) (2.5 mg/kg iv) significantly reduced basal pancreatic protein secretion and that induced by the infusion of CCK (0.5 μg/kg-h), feeding, and the diversion of pancreatic juice in rats with pancreatic fistula. This inhibitory effect was partially reversed when L-arginine (50 mg/kg-h iv) was added to L-NNA. L-Arginine alone (50 mg/kg iv) did not affect basal or caerulein-induced pancreatic secretion. L-NNA, L-arginine, or their combination added in various concentrations to the incubation medium of dispersed acini failed to affect basal or secretagogue (caerulein or urecholine) stimulated amylase release. Infusion of caerulein (5 μg/kg-h) for 5 h produced histological changes of acute edematous pancreatitis accompanied by a marked increase in pancreatic protein content and about 50% reduction in tissue blood flow. L-NNA alone also reduced the pancreatic blood flow and caused a significant increase in pancreatic weight and protein content. L-NNA significantly potentiated the inflammatory changes in the pancreas caused by caerulein. Addition of L-arginine enhanced the pancreatic blood flow and ameliorated the pancreatitis induced by caerulein alone or that combined with L-NNA. We conclude that NO is involved in the stimulation of pancreatic secretion in vivo and exhibits a beneficial effect on pancreatitis, probably by improving the pancreatic blood flow.

Healing of Chronic Gastric Ulcerations by L-Arginine

This study was designed to determine the efficacy of L-arginine in healing of gastric ulcers induced by acetic acid and to assess the role of nitric oxide (NO), prostaglandins, gastrin and polyamines in the healing process. Intragastric administration of L-arginine (32.5-300 mg/kg/day) enhanced the healing rate of these ulcers in a dose-dependent manner, while D-arginine (300 mg/kg/day) was not effective. The acceleration of healing by L-arginine was accompanied by a marked increase in gastric blood flow (GBF) at the ulcer margin, and an enhancement of serum gastrin level, mucosal DNA synthesis, and DNA and RNA contents and angiogenesis in the granulation tissue in the ulcer bed. A similar increase in ulcer healing associated with hyperemia at the ulcer margin and enhanced angiogenesis but without alteration in serum gastrin were observed after treatment with glyceryl trinitrate, an NO exogenous supplier. Treatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, delayed ulcer healing and this was accompanied by a reduction of GBF at the ulcer margin and in angiogenesis in granulation tissue and by a decrease in serum gastrin level and mucosal growth. Addition of L-arginine to L-NNA restored ulcer healing, hyperemia at the ulcer margin and angiogenesis and prevented the fall in serum gastrin and mucosal growth caused by L-NNA. Pretreatment with indomethacin also delayed ulcer healing and this was reversed by the coadministration of L-arginine. Inhibition of polyamine biosynthesis by difluoro-methyl-ornithine completely abolished the acceleration of the healing and the increase in mucosal growth induced by L-arginine. Our findings indicate that L-arginine accelerates ulcer healing due to its hyperemic, angiogenic and growth-promoting actions, possibly involving NO, gastrin and polyamines.

Release of Cholecystokinin by Amino Acids

Summary The ability of essential and nonessential amino acids to stimulate the release of CCK was investigated in dogs using a bioassay procedure based on the perfusion of duodenojejunal Thiry-Vella loops and determining the increase of pancreatic protein response as well as the potentiation of pancreatic bicarbonate secretion induced by a background dose of secretin (0.2 units/kg/hr). All essential amino acids except threonine and all nonessential amino acids except cysteine and aspartic acid were effective in CCK release when perfused in equimolar concentration (50 mM) through the intestinal loop. The highest activity for release of CCK was exhibited by tryptophan and phenylalanine, which were also shown to release small amounts of secretin. The peak pancreatic protein response to tryptophan was 80% of the maximal response to exogenous CCK (25 units/kg/hr).

Dual, time-dependent deleterious and protective effect of anandamide on the course of cerulein-induced acute pancreatitis. Role of sensory nerves

Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 micromol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.

Comparison of Secretin and Vasoactive Intestinal Peptide on Pancreatic Secretion in Dogs

Vasoactive inhibitory peptide (VIP) and secretin were compared in regard to the stimulation of pancreatic bicarbonate secretion and the augmentation of pancreatic response to caerulein or a peptone meal in chronic gastric and pancreatic fistula dogs. Dose-response analysis showed that maximal bicarbonate response to VIP was about 17% of that to secretin. Both caerulein and endogenous cholecystokinin, released by a peptone meal, clearly potentiated pancreatic bicarbonate response to VIP in a manner similar to secretin. The interactions of these two peptides showed that VIP is a potent inhibitor of secretin-induced pancreatic secretion. From the dose-response curves to secretin alone and secretin plus VIP, Michaelis-Menten analysis showed typical competitive inhibition, which indicates that VIP and secretin share a common receptor site.

Comparison of Vasoactive Intestinal Peptide (VIP) and Secretin in Gastric Secretion and Mucosal Blood Flow

SummaryVIP and secretin were compared in regard to their effects on gastric acid and pepsin secretion induced by pentagastrin histamine or a peptone meal as well as on gastric mucosal blood flow and meal induced serum gastrin level in conscious dogs provided with gastric fistulas and denervated fundic pouches. Both VIP and secretin caused a dose-related stimulation of basal pepsin outputs and inhibition of pentagastrin-induced acid secretion. VIP, like secretin, inhibited pentagastrin and meal-induced gastric acid secretion but in contrast to secretin it caused inhibition of acid response to histamine. Inhibition of acid secretion by VIP or secretin was accompanied by secondary reduction in gastric mucosal blood flow in tests with pentagastrin or histamine and by depression of the serum gastrin level in tests with a peptone meal. This study indicates that in comparison with secretin, VIP has a wider spectrum of inhibition of stimulated gastric secretion and may be considered as one of the enterogastrones released in the small intestine.

Epidermal Growth Factor Protects against Pancreatic Damage in Cerulein-Induced Pancreatitis

Epidermal growth factor (EGF) exhibits gastroprotective and ulcer-healing action. These observations prompted us to determine the influence of EGF on cerulein-induced pancreatitis (CIP) in the rat. Acute pancreatitis was induced by subcutaneous infusion of cerulein (10 μg/kg/h) for 5 h. Initially EGF was administrated twice at doses of 1, 5, 10 or 100 μg/kg s.c. (first injection 30 min prior to cerulein infusion, and the second injection 2.5 h after the start of cerulein infusion) and from this part of study 10 μg/kg was chosen for the next experiments. CIP led to a significant decrease in DNA synthesis and a reduction in pancreatic blood flow (PBF) by 42 and 30%, respectively, as well as a significant increase in pancreatic weight, plasma amylase concentration, plasma interleukin-1β (IL-1β) level and the development of the histological signs of pancreatic damage with marked edema, leukocyte infiltration and vacuolization of acinar cells. Treatment with EGF attenuated the pancreatic tissue damage in CIP as manifested by partial reversal of the drop in DNA synthesis and improvement of pancreatic histology. Moreover, EGF administration attenuated the fall in PBF and significantly reduced the cerulein-evoked increase in pancreatic weight. Also plasma amylase and IL-1β were decreased in rats treated with EGF. We conclude that: (1) EGF exerts a protective effect against CIP, and (2) the beneficial activity of EGF in CIP seems to depend on the increase in pancreatic cell proliferation, the reduction in cytokine generation and the attenuation of the fall in PBF.

Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats

Summary Background Previous studies have shown that administration of ghrelin exhibits protective and therapeutic effects in the gut. The aim of the present investigation was to examine the influence of ghrelin administration on the course of cysteamine-induced duodenal ulcers, as well as effects on mucosal production of oxygen free radicals and duodenal antioxidant defense. Material/Methods Duodenal ulcers were induced in male Wistar rats by cysteamine administered intragastrically at the dose of 200 mg/kg in 1 ml of saline, 3 times at 4-h intervals. Starting 24 h after the first dose of cysteamine, rats were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 4, 8 or 16 nmol/kg/dose. Seven days after administration of the first dose of cysteamine, the study was terminated. Results Induction of ulcers by cysteamine was accompanied by a reduction in duodenal blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD); whereas mucosal concentration of interleukin-1β and malonyldialdehyde (MDA – an index of lipid peroxidation) were increased. Treatment with ghrelin increased healing rate of duodenal ulcers and enhanced duodenal blood flow, mucosal DNA synthesis and mucosal activity of SOD, and reduced mucosal concentration of interleukin-1β and MDA. Conclusions Treatment with ghrelin increases the healing rate of duodenal ulcers and this effect is related, at least in part, to improvement of duodenal mucosal blood flow, mucosal cell proliferation and antioxidant defense, as well as being related to reduction in mucosal oxidative stress and inflammatory response.