Á Király

Otilonium bromide enhances sensory thresholds of volume and pressure in patients with irritable bowel syndrome

UNLABELLED Visceral hyperalgesia has been suggested to play a role in the development of symptoms presented by irritable bowel syndrome patients. Otilonium bromide was developed to block smooth muscle Ca release to control cramping pain of these patients. AIMS to determine whether otilonium bromide can influence sensory thresholds of patients suffering from irritable bowel syndrome. METHODS 15 patients with Rome-II positive IBS were tested by Synectics Visceral Stimulator Barostat using rapid phasic distension (870 ml/min). The sensory threshold for first sensation, stool, pain and maximum tolerable volume and pressure were measured. All of the parameters were tested before and 1 week after the initiation of otilonium bromide (Spasmomen, Berlin Chemie, 3x40 mg) therapy. RESULTS The perceptual thresholds for first sensation, stool, pain and maximum tolerable distention were, 8.8+/-1.7 Hgmm, 19.2+/-2.1 Hgmm, 26.3+/-2.8 Hgmm, 28.7+/-2.8 Hgmm for pressure, 90+/-21 ml, 145+/-28 ml, 208+/-25 ml, 213+/-28 ml for volume, before treatment, respectively. Otilonium bromide treatment did not influence the thresholds for first sensation and stool, 7.4+/-1.4 Hgmm, 20.7+/-4.6 Hgmm and 83+/-21 ml, 178+/-35.8 ml, respectively. The pressure threshold of pain was significantly higher 1 week after treatment (26.3+/-2.8 Hgmm vs. 29.1+/-5.5 Hgmm, P<0.05), but the volume threshold of this sensation remained unchanged (208+/-25 ml vs. 234+/-39 ml, not significant). The pressure (28.7+/-2.8 Hgmm vs. 38.1+/-3.4 Hgmm, P<0.05) and volume (213+/-28 ml vs. 278+/-27 ml, P<0.05) thresholds for maximum tolerable volume were increased by 7 days otilonium bromide treatment. CONCLUSION These data suggest that otilonium bromide enhances sensory thresholds to recto-sigmoideal distention.

Failure of capsaicin-containing red pepper sauce suspension to induce esophageal motility response in patients with Barrett’s esophagus

UNLABELLED The physiologic importance of afferent sensory pathways in the esophageal motor functions has been recently recognised. Capsaicin-sensitive sensory afferents were shown to play a role in the maintenance of mucosal integrity of the GI tract, and regulation of human esophageal motility. The aim of this study was to investigate the effect of topical application of capsaicin-containing red pepper sauce (Tabasco, 25%v/v, pH:7.0) suspension on the phasic activity of the human esophagus of healthy volunteers and patients with Barretts esophagus. METHODS The diagnosis of Barretts esophagus was based on the findings of esophagoscopy and histology taken from the squamocolumnar junction of the esophagus. Esophageal motility was measured by perfusion manometry before and after application of red pepper sauce. RESULTS Capsaicin containing red pepper sauce increases the motility response (LES tone, contraction amplitude, propagation velocity) of the human esophagus in healthy volunteers. This response failed in patients with Barretts esophagus. CONCLUSION Impaired esophageal sensory motor function may serve as one etiologic role in the development of Barretts esophagus.

The key-role of vagal nerve and adrenals in the cytoprotection and general gastric mucosal integrity.

BACKGROUND Our laboratory group observed earlier that the gastric mucosal cytoprotective effect of prostacyclin (PGI(2)) disappeared after surgical vagotomy in rats. Similarly to this, the beta-carotene induced gastric cytoprotection disappeared in adrenalectomized rats too. AIMS In these studies we aimed to investigate the possible role of vagal nerve and adrenals in the development of gastric mucosal lesions induced by exogenously administered chemicals (ethanol, HCl, NaOH, NaCl and indomethacin), and on the effects of cytoprotective and antisecretory drugs (atropine, cimetidine), and scavengers (vitamin A and beta-carotene). METHODS The observations were carried out in fasted CFY strain rats. The gastric mucosal lesions were produced by intragastric (i.g.) administration of narcotising agents (96% ethanol; 0.6 M HCl; 0.2 M NaOH; 25% NaCl) or subcutaneously (s.c.) administered indomethacin (20 mg/kg) in intact, surgically bilaterally vagatomized, and adrenalectomized rats without or with glucocorticoid supplementation (Oradexon, 0.6 mg/kg given i.m. for 1 week). The gastric mucosal protective effect of antisecretory doses of atropine (0.1-0.5-1.0 mg/kg i.g.) and cimetidine (10-25-50 mg/kg i.g.), and vitamin A and beta-carotene (0.01-0.1-1.0-10 mg/kg i.g.) was studied. The number and severity of mucosal gastric lesions was numerically or semiquantitatively measured. In other series of observations the gastric acid secretion and mucosal damage were studied in 24 h pylorus-ligated rats without and with acute bilateral surgical vagotomy. RESULTS It was found that: (1) the chemical-induced gastric mucosal damage was enhanced in vagotomized and adrenalectomized rats, meanwhile the endogenous secretion of gastric acid, and the development of mucosal damage can be prevented by surgical vagotomy; (2) the gastric cyto- and general protection produced by the drugs and scavengers disappeared in vagotomized and adrenalectomized rats; (3) the gastric mucosal protective effects of drugs and of scavengers returned after sufficient glucocorticoid supplementation of the rats. CONCLUSION It has been concluded that the intact vagal nerve and adrenals have a key role in the gastric mucosal integrity, and in drugs- and scavengers-induced gastric cyto- and general mucosal protection.

Vagal nerve and the gastric mucosal defense

An essential role for an intact vagal nerve has been proven in the development of gastric mucosal cyto- and general protection. On the other hand, chemically-induced (ethanol, HCl, indomethacin) gastric mucosal damage is enhanced after acute surgical vagotomy. The aims of this paper were to study the possible mechanisms of the vagal nerve in the development of gastric mucosal defense. The following questions were addressed: 1) effect of surgical vagotomy on the development of ethanol- (ETOH), HCl-, and indomethacin (IND)-induced gastric mucosal damage: 2) changes in the gastric mucosal defense by scavengers, prostacyclin and other compounds (small doses of atropine and cimetidine; 3) changes in the gastric mucosal vascular permeability due to chemicals; 4) effect of indomethacin in the ETOH and HCl models with and without surgical vagotomy; 5) changes in the gastric mucosal content of prostacyclin and PGE2 in the ETOH and HCl models after surgical vagotomy; and 6) changes in the role of SH-groups in gastric mucosal defense after surgical vagotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of vagal nerve in gastric mucosal defense: unchanged gastric emptying and increased vascular permeability.

Gastric cytoprotection in response to different agents (prostaglandins, carotenoids, etc.) failed to occur after surgical vagotomy. Decreased gastric emptying and the increased vascular permeability were tested in ethanol-treated rats without and with bilateral surgical vagotomy. The experiments were carried out on Sprague–Dawley rats. The animals were fasted for 24 h before experiments. Bilateral surgical vagotomy or only laparatomy were carried out at 30 min before administration of ethanol (96%, 1 ml). The animals were killed at 0, 1, 5, 15, and 60 min after ethanol administration, when the number and severity of gastric mucosal lesions were noted. In another series of experiments, the animal received Evans blue (1 mg/100 g) i.v. 15 min before killing. The gastric contents were collected and the glandular mucosa was scraped. Evans blue was extracted in chloroform, and its concentration was spectrophotometrically measured. It has been found that (a) both number of lesions and severity of ethanol-induced gastric mucosal damage were larger at each time period in surgically vagotomized rats than in rats with intact vagal nerves; (b) the increased vascular permeability was significantly higher in gastric mucosa at an early period in surgically vagotomized rats compared to rats with intact vagal nerve; (c) the increased vascular events preceded the development of macroscopic appearance of gastric mucosa damage in both groups of animals; and (d) the time-related response were the same in both groups of animals. It is concluded that increased vascular permeability, but not gastric emptying, probably has some role in the failure of the development of gastric cytoprotection in surgically vagotomized rats.

Vagus-mediated activation of mucosal mast cells in the stomach: Effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 microg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 microg, i.c.) or vehicle (10 microL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg x kg(-1) 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg x kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 microg, i.c.) or vehicle (0.9% NaCl, 10 microL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 microg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.

Surgical vagotomy enhances the Indomethacin-Induced gastrointestinal mucosal damage in rats

Karádi O, Bódis B, Király Á, Abdel-Salam OME, Sütō G, Vincze Á, Mózsik Gy. Surgical vagotomy enhances the indomethacin-induced gastrointestinal mucosal damage in rats. Inflammopharmacology. 1994;2:389-399.Indomethacin (IND)-induced gastrointestinal mucosal lesions and changes of vascular permeability were studied in rats with and without acute bilateral surgical vagotomy.The aims of study were (a) to compare IND-induced mucosal lesions in the stomach, small intestine and large bowel of rats with intact vagus and acute surgical vagotomy and (b) to evaluate the changes of vascular permeability following these treatments.The gastrointestinal (GI) mucosal damage was produced by IND (20 mg/kg s.c.) at 24 and 48 h after IND administration. Sham operation (laparotomy alone) or surgical vagotomy alone was carried out in control animals. The number and severity of GI mucosal damage was determined. The changes of mucosal vascular permeability were determined by Evans Blue assays in the GI mucosa and in the contents of stomach, small intestine and colon. Evans Blue was given into the tail vein at 15 min before the killing of animals.It was found that (a) no ulceration and change in mucosal vascular permeability was found in any parts of GI tract after sham operation or surgical vagotomy (without IND); (b) IND caused mucosal injury coincidental with vascular permeability in the stomach and small intestine, but not in the large bowel; (c) surgical vagotomy aggravated the IND-induced mucosal damage and increased vascular permeability in the stomach and small intestine, but not in the colon. In conclusion, the intact vagal nerve is required for the prevention of gastric and small intestinal mucosa to protect against IND injury.

Role of the Vagal Nerve in the Development of Gastric Mucosal Injury and its Prevention by Atropine, Cimetidine, β-Carotene and Prostacyclin in Rats

Peptic ulceration including acute erosions is a multifactorial disease involving well-known factors such as trauma, stress, sepsis, hemorrhagic shock, burns, pulmonary and liver diseases1–9 and drugs such as reserpine10, epinephrine11–13, nonsteroidal antiinflammatory drugs7, steroids and other chemicals14.

Cellular mechanisms of β-carotene-induced gastric cytoprotection in indomethacin-treated rats

Indomethacin (IND) is a non-steroidal anti-inflammatory agent which is widely used in the treatment of various inflammatory disorders. The drug causes gastrointestinal injury in humans and experimental animals. The aim of these studies was to examine the time course correlation between the macroscopic appearance of mucosal damage, tissue level of PGE2 and adenosine nucleotide metabolism during the development of indomethacin (IND)-induced mucosal damage and its prevention by β-carotene.The observations were carried out on both sexes of CFY-strain rats, weighing 180–200 g. Gastric mucosal damage was produced by subcutaneous administration of IND (20 mg/kg). β-Carotene (Hoffman-La Roche, Switzerland) was given intragastrically at the time of IND administration at doses of 0.01, 0.1, 1 and 10 mg/kg. The animals were sacrificed at 0, 1, 2, 3 and 4 h after IND administration when the number and severity of mucosal lesions were noted and the tissue levels of ATP, ADP, AMP, cAMP, lactate and PGE2 were measured from the total homogenate of gastric mucosa. The ratio of ADP/ATP, the values of the adenylate pool (ATP+ADP+AMP), and ‘energy charge’ [(ATP+0.5ADP)/(ATP+ADP+AMP)] were calculated.It was found that: (a) gastric mucosal lesions appear macroscopically 2 h after IND administration; (b) the tissue level of ATP decreased, while ADP was increased 1 h after administration; (c) the most significant decrease in cAMP was found 1 h after IND administration, and thereafter its level returned to baseline; (d) β-carotene dose-dependently prevented the IND-induced mucosal damage and elevated the cAMP level, but it did not alter the mucosal PGE2 level 3 or 4 h after IND administration; (e) β-carotene produced an elevation in ATP and a decrease in ADP level; (f) no significant changes were found in ‘energy charge’ of the gastric mucosa in IND-treated animals.The development of gastric mucosal damage due to IND was associated with increased energy liberation, i.e. transformation of ATP into ADP, and decreased ATP-cAMP transformation. The significant decrease in cAMP preceded the macroscopic appearance of mucosal damage. The increase in ATP-cAMP transformation is involved in the development of β-carotene-induced gastric cytoprotection.

Gastric mucosal preventive effects of prostacyclin and β-carotene, and their biochemical effects in rats treated with ethanol and HCl at different doses and time intervals after administration of necrotizing agents

Prostacyclin (PGI2) and β-carotene have a key role in gastric mucosal defence against endogenous or exogenous noxious agents. Prostacyclin has appreciable protective effects on the gastrointestinal (GI) mucosa, while β-carotene (as one of the retinoid compounds) has oxyradical scavenging properties.AimsThe aims of these studies were to evaluate the biochemical mechanisms involving energy metabolism of:1.Gastric mucosal damage affected by oral administration of 0.6 mol/L HCl (representing an acid-dependent model) and 96% ethanol (EtOH) (as a non-acid-dependent model);2.PGI2-induced (ED50=5 μg/kg po) and β-carotene-induced (ED50=1 mg/kg po) gastroprotection on the gastric mucosal damage produced by HCl and EtOH at different times and doses.MethodsSprague-Dawley rats were used. After 24 h starvation (with tap water ad libitum), gastric mucosal damage was induced by oral administration of 1 ml 0.6 mol/L HCl or 96% EtOH. Rats were pretreated with oral saline, PGI2 (5 and 50 μg/kg) and β-carotene (1 and 10 mg/kg) and killed at 0, 1, 5, 15, 30 and 60 min after administration of the necrotizing agents. The number and severity of gastric mucosal lesions, measurement of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), lactate (enzymatically), and cyclic adenosine monophosphate (cAMP) by RIA were carried out at different time intervals, after the necrotizing agents were administered. The ratio of ATP/ADP, adenylate pool (ATP+ADP+AMP) and ‘energy charge’ [(ATP+0.5 ADP)/(ATP+ADP+AMP)] were calculated.ResultsThe results showed that:1.The mucosal damage (number and severity) reached about 50% of that obtained 60 min after administration of the necrotizing agents in both models;2.PGI2 prevented in the early period (0–15 min), while β-carotene inhibited in the later period (15–60 min) the gastric mucosal damage produced by EtOH and HCl;3.The ATP-ADP transformation was decreased in the first (early; 0–15 min) by PGI2 and in the late period (15–60 min) by β-carotene;4.ATP-cAMP transformation was increased in the early period by PGI2 and in the late phase by β-carotene;5.No significant change was obtained in the ‘energy charge’ and lactate by PGI2 or β-carotene administration;6.The changes in adenine nucleotides were the same in the EtOH or HCl models with and without treatment with PGI2 and β-carotene; however, the mucosal protective action of PGI2 and β-carotene, and the energy metabolism, differed significantly dependent on dose and time afteradministration of EtOH and HCl.Conclusions1.The development of gastric mucosal damage and its prevention can be discriminated into early and late phases;2.The early phase of gastric mucosal damage can be prevented by PGI2, and the late phase by β-carotene;3.The β-carotene effect only partly depends on its presumptive scavenging properties; and4.PGI2 prevents the development of gastric mucosal damage, while β-carotene stimulates the repair mechanisms.