pH monitoring of gastro-oesophageal reflux before and after laparoscopic sleeve gastrectomy.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a common obesity-related co-morbidity that is assessed objectively by 24-h pH monitoring. Some concerns have been raised regarding the risk of de novo GORD or exacerbation of pre-existing GORD after laparoscopic sleeve gastrectomy. Here, 24-h pH monitoring was used to assess the influence of laparoscopic sleeve gastrectomy on postoperative GORD in obese patients with or without preoperative GORD. METHODS: From July 2012 to September 2014, all patients scheduled for laparoscopic sleeve gastrectomy were invited to participate in a prospective follow-up. Patients who underwent preoperative 24-h pH monitoring were asked to repeat the examination 6 months after operation. GORD was defined as an oesophageal pH < 4 for at least 4·2 per cent of the total time recorded. RESULTS: Of 89 patients, 76 had preoperative pH monitoring for GORD evaluation and 50 had postoperative reassessment. Patients without (group 1, 29 patients) or with (group 2, 21 patients) preoperative GORD were similar regarding age, sex ratio and body mass index. In group 1, the median (i.q.r.) total time at pH < 4 was significantly higher after surgery than before: 5·6 (2·5-9·5) versus 1·6 (0·7-2·9) per cent (P < 0·001). Twenty of the 29 patients experienced de novo GORD as determined by 24-h pH monitoring (P < 0·001). In group 2, total time at pH < 4 after surgery was no different from the preoperative value: 5·9 (3·9-10·7) versus 7·7 (5·2-10·3) per cent (P = 0·296). CONCLUSION: Laparoscopic sleeve gastrectomy was associated with de novo GORD in over two-thirds of patients, but did not seem to exacerbate existing GORD.

Quality control of colonoscopy procedures: a prospective validated method for the evaluation of professional practices applicable to all endoscopic units.

OBJECTIVES: To produce valid information, an evaluation of professional practices has to assess the quality of all practices before, during and after the procedure under study. Several auditing techniques have been proposed for colonoscopy. The purpose of this work is to describe a straightforward original validated method for the prospective evaluation of professional practices in the field of colonoscopy applicable in all endoscopy units without increasing the staff work load. METHODS: Pertinent quality-control criteria (14 items) were identified by the endoscopists at the Cochin Hospital and were compatible with: findings in the available literature; guidelines proposed by the Superior Health Authority; and application in any endoscopy unit. Prospective routine data were collected and the methodology validated by evaluating 50 colonoscopies every quarter for one year. RESULTS: The relevance of the criteria was assessed using data collected during four separate periods. The standard checklist was complete for 57% of the colonoscopy procedures. The colonoscopy procedure was appropriate according to national guidelines in 94% of cases. These observations were particularly noteworthy: the quality of the colonic preparation was insufficient for 9% of the procedures; complete colonoscopy was achieved for 93% of patients; and 0.38 adenomas and 0.045 carcinomas were identified per colonoscopy. CONCLUSION: This simple and reproducible method can be used for valid quality-control audits in all endoscopy units. In France, unit-wide application of this method enables endoscopists to validate 100 of the 250 points required for continuous medical training. This is a quality-control tool that can be applied annually, using a random month to evaluate any changes in routine practices.

[Chronic intestinal pseudo-obstruction in adults]. / Pseudo-obstruction intestinale chronique de l'adulte.

Chronic intestinal pseudo-obstruction is a rare disease stemming from numerous causes characterized by disturbances in gastrointestinal motility. Symptomatology is often misleading and topography is variable, thus putting the clinician in serious difficulty. Diagnosis is based on a body of arguments, ranging from the clinical examination to surgical biopsies in expert centers. Treatment is non-consensual and mostly symptomatic. It is based on the use of prokinetics and optimal nutritional support. In the most serious cases, surgery can be required. The etiological treatment should be that of the causal disease when it exists and when the etiology is identified. Results of such treatment are variable. Chronic intestinal pseudo-obstruction is a disease which remains poorly understood. Progress had been made in terms of diagnosis and treatment but it seems obvious that a better comprehension of physiopathological mechanisms is necessary in order to improve our practice.

[Medical practice on the Leeward Side]. / Maupiti: un exercice médical sous le vent.

The daily practice of medicine in the remote Leeward Islands of French Polynesia is a particularly gratifying experience. The population of 1200 inhabitants is eager to receive continuous medical services after many years of waiting for better care. Relatively good access to various specialists working in the hospitals of Raiatea or Papeete and to emergency and scheduled medical evacuation services make medical practice far more attractive on the Leeward Islands than in remote communities in underdeveloped countries of Third World. The first cause of morbidity is overweight associated with a high incidence of type II diabetes and attendant complications.

Treatment of unresectable hepatocellular carcinoma with a combination of human recombinant alpha-2b interferon and doxorubicin: results of a pilot study.

Based on the in vitro and in vivo potentiation of the cytotoxic activity of chemotherapeutic agents by the interferons, a pilot study combining human recombinant alpha-2b interferon (IFN) and doxorubicin was conducted for the treatment of unresectable, histologically proven hepatocellular carcinoma. Between March 1988 and May 1990, 21 patients (median age: 60 years, range: 29-76) entered the study. The dose of doxorubicin was fixed at 35 mg/m2, every 3 weeks. The dose of alpha-2b IFN was 6 million U/m2 per day, 5 days a week. 3 patients (14%) obtained a partial response lasting 11, 16 and 30 months, and 1 had a stable disease during 8 months. The other 17 patients died within a median survival time of 4 months. All patients experienced flu-like symptoms. 7 patients experienced WHO grade III-IV haematological toxicity. We conclude that the association of alpha-2b IFN and doxorubicin is feasible, with respect to the use of doxorubicin at an inferior dose level than the same agent used without IFN. The response rate is comparable to that observed with doxorubicin used alone. Further phase I studies and randomised trials are required to confirm the role of this regimen in the treatment of unresectable hepatocellular carcinoma.

Involvement of superoxide and xanthine oxidase in neutrophil-independent rat gastric damage induced by NO donors.

1. Nitric oxide (NO) and the superoxide anion can interact to form the cytotoxic moiety, peroxynitrite. The involvement and potential source of superoxide in the gastric mucosal damage induced by local infusion of NO donors, has now been investigated in the pentobarbitone-anaesthetized rat. 2. Local intra-arterial infusion of the NO donor, sodium nitroprusside (40 micrograms kg-1 min-1) for 10 min induced macroscopically apparent gastric mucosal injury. 3. This mucosal damage was dose-dependently reduced by prior administration of a systemically acting form of superoxide dismutase conjugated with polyethylene glycol (500-2000 iu kg-1, i.v.). 4. Likewise, the mucosal damage induced by nitroprusside was dose-dependently reduced by prior administration of the xanthine oxidase inhibitor, allopurinol (20-100 mg kg-1, i.p. or 100 mg kg-1, p.o.). 5. Pretreatment with allopurinol (100 mg kg-1, i.p.) also reduced the mucosal injury induced by local intra-arterial infusion of the nitrosothiol, S-nitroso-N-acetyl-penicillamine (40 micrograms kg-1 min-1), but not that induced by local infusion of endothelin-1 (5 pmol kg-1 min-1), indicating specificity of action. 6. Prior administration (4h) of rabbit anti-rat neutrophil serum (0.4 ml kg-1, i.p.), which reduced circulating neutrophils by 90%, did not significantly protect against mucosal injury induced by nitroprusside. 7. Intravenous administration of the platelet-activating factor receptor antagonists, WEB 2086 (1 mg kg-1) or BN 52021 (10 mg kg-1), or the thromboxane synthase inhibitor, OKY 15181 (25 mg kg-1), did not modify mucosal damage induced by nitroprusside, showing lack of involvement of these neutrophil-derived mediators. 8. These findings indicate the involvement of superoxide in the injurious actions of the NO donors, implicating a cytotoxic role of peroxynitrite. Xanthine oxidase, but not neutrophils, appears to be a source of the superoxide.

Cytotoxicity associated with induction of nitric oxide synthase in rat duodenal epithelial cells in vivo by lipopolysaccharide of Helicobacter pylori: inhibition by superoxide dismutase.

The products released by Helicobacter pylori (H. pylori) in the gastric antral and duodenal mucosa may be involved in mucosal ulceration by stimulating the local formation of cytotoxic factors such as nitric oxide (NO), superoxide or peroxynitrite. The present study investigates the ability of purified H. pylori lipopolysaccharide (LPS) to induce nitric oxide synthase (iNOS) in rat duodenal epithelial cells following in vivo challenge and its interaction with superoxide in promoting cellular damage and apoptosis. H. pylori LPS (0.75-3 mg kg(-1) i.v. or 3-12 mg kg(-1) p.o.) induced a dose - dependent expression of iNOS activity after 5 h in the duodenal epithelial cells, determined by [(14)C] arginine conversion to citrulline. The epithelial cell viability, as assessed by Trypan Blue exclusion and MTT conversion, was reduced 5 h after challenge with H. pylori LPS, while the incidence of apoptosis was increased. The iNOS activity and reduction in cell viability following H. pylori LPS challenge i.v. was inhibited by the selective iNOS inhibitor, 1400 W (0.2-5 mg kg(-1) i.v.). Concurrent administration of superoxide dismutase conjugated with polyethylene glycol (250 - 500 i.u. kg(-1), i.v.), which did not modify the cellular iNOS activity, reduced the epithelial cell damage provoked by i.v. H. pylori LPS, and abolished the increased incidence of apoptosis. These results suggest that expression of iNOS following challenge with H. pylori LPS provokes duodenal epithelial cell injury and apoptosis by a process involving superoxide, implicating peroxynitrite involvement. These events may contribute to the pathogenic mechanisms of H. pylori in promoting peptic ulcer disease.

Induction of nitric oxide synthase in vivo and cell injury in rat duodenal epithelium by a water soluble extract of Helicobacter pylori.

1. Helicobacter pylori (Hp) infection, which involves the gastric antrum and duodenal mucosa, may be involved in peptic ulceration by stimulating the local release of cytoxic or pro-inflammatory factors. 2. Nitric oxide (NO) is known to be cytotoxic at high concentration. The aim of the present study was therefore to investigate the ability of a water soluble extract of Hp to induce NO synthase in duodenal mucosa and epithelial cells following its administration in vivo in rats and determine its association with cell damage. 3. Administration of Hp water extract (4 ml kg(-1)) led to the expression of the calcium-independent inducible nitric oxide synthase (iNOS) after 4 h in the duodenum, determined as [14C]-arginine conversion to citrulline. 4. This iNOS activity was not reduced by pretreatment with anti-neutrophil serum (0.4 ml kg(-1), i.p., 3 h before challenge). However, dexamethasone pretreatment (1 mg kg(-1), i.v., 2 h before the extract), or administration of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 5 mg kg(-1), i.v., 2.5 h after the extract) reduced this activity. 5. Furthermore, iNOS was expressed in duodenal isolated epithelial cells 4 h after the i.v. challenge with the extract, at a time when the cellular viability was also reduced, as assessed by trypan blue exclusion. 6. Dexamethasone pretreatment, administration of L-NAME, or pretreatment with polymyxin B (1 mg kg(-1), i.v.) which binds endotoxin, reduced both the iNOS activity and epithelial cell damage. 7. The induction of NO synthase by the Hp extract thus results in duodenal epithelial cell injury and such actions could play a role in pathogenesis of peptic ulcer disease.

Maintenance of gastric pH above 6 with intravenous famotidine in patients with a bleeding duodenal ulcer.

BACKGROUND: The secondary prevention of bleeding from ulcers may be improved if antisecretory drugs are able to maintain a 24-h gastric pH close to neutral. AIM: To evaluate the effect of intravenous famotidine at a conventional dose of 40 mg/day on 24-h intragastric pH in patients with a bleeding duodenal ulcer, and to determine the dose required to maintain gastric pH > 6 by use of a Gastrojet (MIC, Switzerland) device (a pH meter-controlled programmable pump). METHODS: Twelve patients (nine men, three women), aged 24-78 years, admitted for a bleeding duodenal ulcer, were studied after active bleeding had stopped for at least 6 h. Gastric pH was recorded for two consecutive 24-h periods, each starting at 16.00 hours. The patients were fasted during these periods and received an infusion of 2.5 L of isotonic glucose. They were given famotidine, as a continuous i.v. infusion of 40 mg during one period, and at a rate determined by the Gastrojet during the other period (in a random sequence), with the aim of maintaining the gastric pH above 6. RESULTS: The 24-h median (interquartile range) pH and the mean (+/- S.E.M.) percentage of the 24-h period with a gastric pH > 6 were both significantly higher during the Gastrojet period than during the continuous infusion: 6.4 (6.3-6.5) vs. 5.7 (2.7-6.4) (P < 0.01) and 74 +/- 5% vs. 44 +/- 7% (P < 0.002), respectively. The mean dose of famotidine delivered by the Gastrojet was 172 mg (range: 101-200 mg). The entire available amount of famotidine (200 mg) was delivered in four of the 12 patients. The percentage of time at pH > 6 (mean +/- S.E.M.) was significantly higher at night (22.00 to 07.00 hours) than during the rest of the day (88 +/- 2 vs. 70 +/- 6%; P < 0.005) and the mean quantity of famotidine delivered per hour was significantly lower during the night (6.3 +/- 0.8 mg/h vs. 8.4 +/- 0.5 mg/h; P < 0.02). CONCLUSION: We conclude that 40 mg of famotidine delivered as a continuous i.v. infusion is not sufficient to maintain gastric pH > 6 for 24 h in duodenal ulcer patients. Our study with the Gastrojet device shows that it may be possible to achieve this goal by using a much larger dose, preferably delivered during the day.

Impact of Helicobacter pylori resistance to clarithromycin on the efficacy of the omeprazole-amoxicillin-clarithromycin therapy.

BACKGROUND: Helicobacter pylori resistance to clarithromycin is relatively frequent in France and is assumed to be the main cause of failure of the proton pump inhibitor-amoxicillin-clarithromycin (proton pump inhibitor-AC) therapy, which is the first-line regimen in France. AIM: To determine the respective effects of clarithromycin primary and secondary resistances on efficacy of the proton pump inhibitor-AC regimen and to determine whether failures are associated with persistence of the same strain or with emergence of a new one. METHODS: A total of 123 H. pylori-infected patients were treated for 7 days with omeprazole 20 mg b.d., amoxicillin 1 g b.d., and clarithromycin 500 mg b.d. Eradication was assessed by breath test in 102 patients. Minimal inhibitory concentrations of clarithromycin were determined by E-test. Strain genotyping was performed by random amplified polymorphic DNA. RESULTS: The pre-treatment and post-treatment prevalences of clarithromycin resistance were 19% (23 out of 123) and 69% (nine out of 13), respectively. The rates of eradication were 68% (69 out of 102), 79% (67 out of 85), and 12% (two out of 17) for all, susceptible and resistant strains, respectively. The post-treatment isolate was available for six patients with a susceptible pre-treatment isolate and a persistent infection. Resistance emerged in two patients and was associated with persistence of the pre-treatment strain in one and with selection of a new strain in the other. CONCLUSIONS: In our hospital, failures of the proton pump inhibitor-AC therapy are related to both clarithromycin primary and secondary resistances, but the emergence of secondary resistance does not explain all of the failures in the initial clarithromycin-susceptible group. In that group a new strain can emerge after failure.

Twenty-four-hour intragastric acidity and plasma gastrin during 3-month treatment with omeprazole in healthy subjects.

BACKGROUND: Prolonged treatment with omeprazole 20 or 40 mg/day is sometimes required, especially for severe oesophagitis. However, information about long-term effects on intragastric acidity and plasma gastrin response with such drug regimens is scarce. METHODS: Sixteen healthy subjects (11 men, 5 women, mean age 29 years) randomly received either 20 or 40 mg of omeprazole once daily (at 08.00 h) for 3 months. Gastric pH was recorded every 6 s for 24 h from noon to noon under standardized conditions, and blood samples were collected hourly in order to determine the 24-h plasma gastrin response on day 0 (pre-entry), day 7, day 28 and day 90. RESULTS: From day 0 to day 7, 24-h median pH increased from 1.7 to 4.6 and mean percentage of time at pH < 4 decreased from 89% to 35% with omeprazole 20 mg. Respective values with omeprazole 40 mg were 1.9 to 4.3, and 89% to 34%. Inhibition of gastric acidity remained unchanged during the 3 months of treatment. Despite similar effects on the basis of 24-h analysis, the decrease in daytime acidity was slightly higher with omeprazole 40 mg than with omeprazole 20 mg. Twenty-four-hour integrated plasma gastrin significantly increased with both drug regimens between day 0 and day 7 (P < 0.01), and between day 7 and day 28 (P < 0.01) with omeprazole 40 mg; there was no significant increase between day 28 and day 90 with either of the drug regimens. CONCLUSION: Omeprazole 20 and 40 mg/day provides long-term stable acid suppression with a progressive increase in gastrin response, stabilizing after 2 months of treatment.

Co-detection of Helicobacter pylori and of its resistance to clarithromycin by PCR.

Our aim was to develop a rapid molecular test based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and making it possible to detect Helicobacter pylori directly from gastric biopsy samples, and to test its susceptibility to clarithromycin. A 629-bp fragment of the 23S rRNA gene of H. pylori was amplified by PCR and the mutations responsible for clarithromycin resistance were detected with Bsa1 and Bbs1 restriction endonucleases. Thirty-five gastric samples were tested in parallel by standard microbiologic methods (culture and clarithromycin susceptibility testing with E-test strips) and by PCR-RFLP. The 10 culture-negative samples were also PCR-negative. Sixteen out of the 25 culture-positive samples (64%) were PCR-positive. RFLP analysis could be done in 12 cases and the results were in agreement with those of the E-test: susceptibility in five cases, resistance in seven (six A2144G mutations and one A2143G mutation).

Capsaicin-sensitive mechanisms in the modulation of rat colonic vascular permeability under physiological and pathological conditions.

Inflammatory bowel disease (IBD) causes a prolonged life-quality reduction of patients and high costs for health services. The aim of this study was to explore the possible involvement of peptidergic capsaicin-sensitive afferent nerves (CSN) in the pathogenesis of IBD. For the defunctionalization of colonic CSN, the lower part of the colon (1-4 cm from the anus) was exposed through a midline laparotomy and small pieces of gelfoam moistened with a solution of capsaicin (1%, 100 microL) was applied onto the serosal surface for 30 min in male Wistar rats. Colonic vascular permeability was assessed by measuring the extravasation of [125I] human serum albumin (2 microCi/kg, i.v., 2 h prior to killing). Two months after capsaicin treatment a significant increase in albumin extravasation was found in the lower (P < 0.005), but not in the upper (5-8 cm from the anus) part of the colon as compared to the sham-operated control. Intrarectal (8 cm from anus) administration of trinitrobenzene-sulphonic acid (TNBS; 30 mg/rat) induced similar plasma leakage in the lower and upper colon of control (CSN-intact) rats (P < 0.001) 1 week later. TNBS + ethanol (50%) produced further extravasation throughout the colon (P < 0.001) of CSN-intact animals. In the lower colon of capsaicin-pretreated rats TNBS-alone provoked an increase in plasma extravasation (P < 0.001) similar to that caused by TNBS + ethanol in CSN-intact rats. In the upper colon there was no difference in the effect of TNBS-alone on plasma leakage between control (CSN-intact) and CSN-depleted rats. The results suggest that capsaicin-sensitive nerves may play a significant protective/anti-inflammatory role in the colon under normal and pathological conditions.

Attenuation of Helicobacter pylori endotoxin-provoked rat intestinal inflammation by selective inhibition of the inducible nitric oxide synthase.

We studied the actions of purified Helicobacter pylori endotoxin (3 mg kg(-1), i.v.) on rat intestinal vascular permeability (assessed by the radiolabelled human serum albumin leakage technique) and on nitric oxide synthase induction (assessed by the citrulline assay) 4 h later. We found increased albumin leakage and expression of the inducible nitric oxide synthase in jejunum and colon, effects reversed by a selective inducible nitric oxide synthase inhibitor N-(8-(aminomethyl)benzyl)-acetamidine (1400W; 0.2-1 mg kg(-1), s.c., concurrently with endotoxin). Thus, H. pylori endotoxin seems to be capable of provoking an inflammatory response in the rat intestinal tissue. Systemic liberation of H. pylori endotoxin might possibly attenuate jejunal and colonic mucosal barrier function, a process mediated by the expression of the inducible nitric oxide synthase.

Role of oxygen-derived metabolites in the rat gastric mucosal injury induced by nitric oxide donors.

Local intra-arterial infusion of high doses of the nitric oxide (NO) donor, nitroprusside (10-40 micrograms kg-1 min-1 for 15 min) induced dose-dependent haemorrhagic injury to the rat gastric mucosa and reduced systemic arterial blood pressure, whereas intragastric nitroprusside (10-50 mg ml-1), which caused similar falls in blood pressure, failed to induce such injury. The mucosal damage induced by nitroprusside was reduced by local concurrent infusion of superoxide dismutase (500-4000 i.u. kg-1). Local superoxide dismutase also abolished the mucosal injury induced by local infusion of the NO donor, S-nitroso-N-acetyl-penicillamine (40 micrograms kg-1 min-1), but not that induced by local infusion of endothelin-1 (5 pmol kg-1 min-1) indicating specific actions. Intravenous infusion of the iron chelator and peroxyl scavenger, desferrioxamine (0.25-1 mg kg-1 min-1) or the hydroxyl radical scavenger, dimethylthiourea (20 mg kg-1 min-1) also reduced the mucosal damage induced by the local administration of the NO donors, but not that induced by endothelin-1. These findings implicate the involvement of superoxide and possibly other oxygen-derived free radicals in the injurious actions of high levels of nitric oxide generated from NO donors, and may reflect a role of the cytotoxic peroxynitrite moiety.

Involvement of peroxynitrite in the lipid peroxidation induced by nitric oxide in rat gastric mucosa.

Local intra-arterial infusion of high doses of nitric oxide (NO) donors, such as S-nitroso-N-acetyl-penicillamine or nitroprusside cause extensive gastric mucosal damage. The involvement of lipid peroxidation of mucosal tissue in the mechanism of such gastric damage has been investigated in the pentobarbitone-anaesthetised rat. Local intra-arterial infusion of nitroprusside (40 micrograms.kg-1.min-1) or S-nitroso-N-acetyl-penicillamine (40 micrograms.kg-1.min-1) induced macroscopically apparent injury and provoked a dose-dependent peroxidation of lipid in gastric tissue. By contrast, endothelin-1 infusion provoked mucosal injury of the mucosa, yet did not produce lipid peroxidation. Local co-infusion of superoxide dismutase (2000-4000 IU.kg-1) reduced both the lipid peroxidation and the mucosal damage provoked by S-nitroso-N-acetyl-penicillamine and nitroprusside. These findings indicate that lipid peroxidation accompanies the mucosal tissue damage induced by NO donors, while the action of superoxide dismutase implicates the involvement of peroxynitrite, formed from superoxide and NO, in this process.

Time-dependent actions of nitric oxide synthase inhibition on colonic inflammation induced by trinitrobenzene sulphonic acid in rats.

The time-dependent actions following pretreatment or delayed administration of the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) on colonic inflammation and inducible NO synthase activity following the intrarectal administration of trinitrobenzene sulphonic acid (TNBS) were evaluated in the rat. Intracolonic instillation of TNBS (30 mg in 0.25 ml of 50% ethanol) led to macroscopic injury, an increase of mucosal myeloperoxidase activity and the expression of the Ca2+-independent inducible NO synthase over 8 days. The inflammatory response following TNBS reached maximum levels between 12 and 72 h and then it declined until 14 days. Oral administration of L-NAME (25 mg/kg per 24 h in the drinking water) 2 days before TNBS augmented macroscopic damage and increased colonic inducible NO synthase activity 6, 12, 24 and 72 h after TNBS administration. In contrast, when L-NAME was administered 6 h after TNBS instillation, at time of expression of inducible NO synthase, the macroscopic lesions were reduced, as well as the enhanced inducible NO synthase activity, determined, over 72 h. Delayed (6 h after TNBS) administration of L-NAME also attenuated the colonic myeloperoxidase activity provoked by TNBS, after 24 h. This activity was not affected by pretreatment (2 days before TNBS) with L-NAME. These findings indicate that the timing of administration of non-selective NO synthase inhibitors such as L-NAME, in models of colitis is critical to the eventual outcome. Thus, pretreatment with L-NAME, which will inhibit constitutive NO synthase, exacerbates the subsequent damage following challenge. In contrast, delayed administration of L-NAME at the time of inducible NO synthase expression, has a beneficial action on the colonic injury and inflammation.

Endogenous vasopressin increases acute endotoxin shock-provoked gastrointestinal mucosal injury in the rat.

Administration of a low dose of endotoxin (from Escherichia coli, 3 mg kg(-1), i.v.), which does not affect vascular permeability or blood pressure over 1 h, leads to the release of endogenous vasopressin and damage to the mucosal microvasculature. Thus, endogenous vasopressin could be involved in septic shock. In the present study, we investigated the role of endogenous vasopressin in gastrointestinal mucosal injury induced by acute endotoxin shock, which was generated in rats by administering a high dose of E. coli endotoxin (50 mg kg(-1), i.v.). Tissues were removed 15 min after endotoxin. The vasopressin V1 receptor antagonist, d[CH2]5Tyr[Me]arginine-vasopressin (0.2-1 microg kg(-1), i.v.), was injected 10 min before endotoxin. Monastral blue (30 mg kg(-1), i.v.), which stains damaged vasculature, was injected 10 min before autopsy. Endotoxin reduced systemic arterial blood pressure (from 115+/-5 to 42+/-4 mmHg), generated macroscopic and microvascular injury, and elevated plasma vasopressin levels (from 3.4+/-0.2 to 178+/-16 pg ml(-1)). The vasopressin V1 receptor antagonist reduced this macroscopic injury, and in the vasopressin-deficient Brattleboro rat a similar reduction of gastrointestinal mucosal damage was found. Substantial decreases in endotoxin-induced microvascular damage were observed in each tissue, e.g., the gastric Monastral blue staining was reduced by 47+/-3% and 96+/-3% (P < 0.01) after vasopressin V1 receptor antagonist treatment and in Brattleboro rats, respectively. Vasopressin, acting through its V1 receptors, thus appears to be involved in acute endotoxin shock-provoked gastrointestinal injury.

Helicobacter pylori lipopolysaccharide-provoked injury to rat gastroduodenal microvasculature involves inducible nitric oxide synthase.

The actions of a purified Helicobacter pylori lipopolysaccharide (3 mg x kg(-1), i.v.) on rat gastric antral and duodenal microvascular integrity (determined as radiolabelled albumin leakage) and the expression of the inducible nitric oxide (NO) synthase (iNOS; assessed by the citrulline assay) were investigated 4 h after challenge. Significant increases of albumin leakage and expression of iNOS in both antral and duodenal tissues were observed following challenge. Concurrent administration of the selective iNOS inhibitor, 1400W (N-(8-(aminomethyl)benzyl)-acetamidine; 0.2-1 mg x kg(-1), s.c.), with lipopolysaccharide, caused a dose-dependent attenuation of the gastric and duodenal albumin leakage. Thus, H. pylori lipopolysaccharide can initiate the expression of iNOS in the stomach and duodenum following systemic challenge, which can provoke gastroduodenal microvascular dysfunction.

Inducible nitric oxide synthase attenuates chronic colitis in human histocompatibility antigen HLA-B27/human beta2 microglobulin transgenic rats.

Rats transgenic for HLA-B27/human beta2-microglobulin develop a spontaneous multisystem inflammatory disorder that closely mimics human spondyloarthropathies. Prominent features of this disorder are gut inflammation that predominates in the colon, and arthritis. Several mediators such as IFN-gamma, IL-1beta, TNF-alpha, and inducible nitric oxide synthase (iNOS) have been found increased in the inflamed colonic mucosa. In the colon of HLA-B27 transgenic rats, iNOS is predominantly expressed by epithelial cells, and iNOS transcripts are detected in the hip cartilage of those rats, but not in nontransgenic littermates. The role of iNOS in this disorder was evaluated by administering the corticosteroid dexamethasone, or the NOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL) to HLA-B27 transgenic rats with established disease. Treatment with dexamethasone attenuated some aspects of gut inflammation, although it had no effect on iNOS expression. In contrast, treatment with L-NIL effectively inhibited iNOS activity, and resulted in an increase in colitis. Cytokine transcripts in the colon were modified by these treatments: IFN-gamma and IL-1beta were decreased after dexamethasone treatment, whereas administration of L-NIL resulted in decreased IFN-gamma, and TNF-alpha. A trend towards increased IL-1b expression was observed which could have contributed to the L-NIL pro-inflammatory effect. These results suggest that iNOS exerts a protective effect on colitis, in the inflammatory disorder of HLA-B27 transgenic rats.