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Recent human studies suggest that oesophageal HCO3- secretion, in conjunction with salivary HCO3- secretion and secondary oesophageal peristalsis, is important for the protection of oesophageal mucosa from refluxed gastric contents. This study evaluated simultaneously the responsiveness of oesophageal and salivary HCO3- secretion to oesophageal acidification in eight healthy subjects. A 10 cm segment of oesophagus was perfused at a constant rate of 5 ml/min with a specially designed tube assembly. Saline was used initially, and then 10 mM and 100 mM HCl. The perfusates contained 3H-polyethylene glycol (PEG) as a concentration marker to determine volumes. Corrections were applied for a small degree of contamination by swallowed saliva and refluxed gastric alkali. Oesophageal perfusion with 10 mM HCl did not cause symptoms (nausea and heartburn), but tripled the oesophageal HCO3- output from a baseline of 51 mumol/10 cm/10 min (p = 0.021), while doubling the rate of salivary HCO3- secretion from a median basal value of 140 mumol/10 min (p = 0.021). Oesophageal perfusion with 100 mM HCl was associated with symptoms of nausea and heartburn in all subjects. The median oesophageal HCO3- output increased 32 fold to 1659 mumol/10 cm/10 min (interquartile range 569 to 3373; p = 0.036), and salivary HCO3- secretion approximately tripled from basal values (p = 0.036). In conclusion, oesophageal acidification stimulates both salivary and oesophageal HCO3- secretion, responses which may be protective to the oesophageal epithelium.

The effect of 28 days' continuous administration of oral indomethacin on gastroduodenal morphology, gastric mucosal blood flow, and gastric mucosal prostaglandin E2 (PGE2) metabolism in man was studied to define further the mechanisms of mucosal injury induced by indomethacin. Indomethacin caused acute gastroduodenal damage in all cases, which was maximal at 24 hours of administration. With continued intake, mucosal adaptation occurs resulting in resolution of endoscopic mucosal damage. At the time of maximal mucosal damage, gastric mucosal blood flow was significantly reduced compared with values before treatment (p less than 0.001 in fundus and p less than 0.002 in antrum), with good correlation between the severity of damage and the magnitude of the reduction in blood flow (r = 0.76). Mucosal recovery was associated with a return of the blood flow to normal. PGE2 in mucosal homogenate was significantly reduced by indomethacin in both the fundus (p less than 0.01) and antrum (p less than 0.01) after 24 hours but there was no correlation between the magnitude of this reduction and the severity of mucosal damage (r = -0.34). Despite mucosal recovery by 28 days, PGE2 values remained significantly below those before treatment in both the fundus (p less than 0.01) and antrum (p less than 0.01). The PGE2 degradation capacity was not influenced by indomethacin. In conclusion, mucosal adaptation to acute damage by indomethacin occurs in man and seems independent of local PGE2 metabolism.

Injury of the oesophageal mucosa can result from exposure to refluxed gastric acid and pepsin. Competence of the lower oesophageal sphincter and peristaltic activity serve to reduce contract time between luminal acid and oesophageal mucosa, but intraluminal neutralisation of residual acid by bicarbonate may also be important in preventing oesophageal mucosal injury. Whereas swallowed saliva contains bicarbonate, recent experiments have also demonstrated alkali secretion from the mammalian oesophagus. Bicarbonate secretion from the human oesophagus was therefore examined with an intubation technique and perfusion of the oesophagus with a non-absorbable marker. Saliva, gastric, and oesophageal aspirates were collected and bicarbonate concentrations determined by measurements of pH and pCO2 or by back titration. In 32 normal subjects (17 women, 15 men) median basal oesophageal bicarbonate secretion determined by a pH/pCO2 method was 416 (range 139-1050) mumol/hour/10 cm. In a subgroup of 15 experiments median oesophageal bicarbonate output was 489 (range 157-1033) mumol/hour/10 cm (pH/pCO2 method) compared with a median alkali output of 563 (range 135-799) mumol/hour/10 cm as determined by back titration. The difference was not significant. Salivary contamination of the oesophagus accounted for 25% of all bicarbonate measured within the oesophagus and refluxed gastric bicarbonate accounted for 2.5%. Bicarbonate secretion from the normal human oesophagus may, in combination with swallowed salivary bicarbonate, play a part in preventing oesophageal mucosal damage due to refluxed gastric acid and pepsin.

Acid and alkali secretion have been examined together with prostaglandin E2 production in response to two mucosal protective drugs, colloidal bismuth subcitrate and sucralfate. Doses of colloidal bismuth subcitrate in the therapeutic range (120 and 1200 mg) had no effect on alkali secretion or luminal PGE2 output when perfused into the stomach of human volunteers. Similarly, in the anaesthetised rat, neither gastric acid nor duodenal alkali secretions were influenced by iv (12 mg/kg) or topical (120 mg/ml) administration of colloidal bismuth subcitrate. In contrast, perfusion of the human stomach with 1 g sucralfate stimulated bicarbonate output by 50%, a response which was unaffected by indomethacin (25 mg/h). A rise of 64% in gastric PGE2 output after sucralfate was, however, prevented by indomethacin pretreatment. Alkali secretion by rat duodenum was also increased by sucralfate but the response depended on the basal secretory rate. Low basal secretors (less than 3 mumol) showed a 75% stimulation whereas rats with high basal secretory rates (greater than 3 mumol) showed no significant response. All duodenal preparations regardless of basal secretory rate showed a stimulation of bicarbonate output with topical PGE2. The results suggest that enhancement of gastroduodenal bicarbonate secretion may play a role in the protective action of sucralfate but is unlikely to explain mucosal protection by colloidal bismuth subcitrate.

The effects of non-steroidal anti-inflammatory drugs and prostaglandins E(2) and F(2alpha) on the secretory and electrical activity of isolated rabbit fundic mucosa have been studied. Spontaneous acid secretion was inhibited by serosal side application of sodium thiocyanate (6x10(-2)M) and the resulting alkali secretion measured by pH stat tiration. Serosal side application of indomethacin (10(-5)M) or aspirin (3x10(-3)M) inhibited alkali secretion (0.55+/-0.06 to 0.12+/-0.06 mumol/cm(2)/h, n=6, p0.01 and 0.28+/-0.06 to 0.11+/-0.03 mumol/cm(2)/h, n=7, p0.02 respectively). Mucosal or serosal side prostaglandin E(2) (10(-5) to 10(-10)M) and F(2alpha) (10(-4) to 10(-10)M) failed to alter the rate of alkalinisation but secretion was significantly increased by serosal side 16,16-dimethyl-prostaglandin E(2) (10(-6)M) (0.90+/-0.20 to 1.50+/-0.30 mumol/cm(2)/h, n=6, p0.01). Serosal side application of 10(-6)M prostaglandin E(2) to fundic mucosae pretreated with either aspirin (5x10(-3)M) or indomethacin (10(-5)M), to reduce endogenous E(2) formation, also failed to alter alkali secretion. Pretreatment of the mucosa with 16,16-dimethyl-E(2) (10(-6)M) abolished the inhibitory effect of indomethacin (10(-5)M) on alkali secretion (n=6) but did not modify the secretory response to aspirin (3x10(-3)M) (fall in alkali secretion with aspirin = 81+/-11% and with aspirin plus 16,16-dimethyl-E(2) = 72+/-10%, n=7). In the doses used, none of the prostaglandins or non-steroidal anti-inflammatory drugs altered transmucosal potential difference or electrical resistance. These results show that the damaging agents, aspirin and indomethacin, both inhibit gastric alkali secretion but that modes of action may differ. The observation that prostaglandins, E(2) and F(2alpha) failed to increase alkali production suggests that their protective activity against a variety of damaging agents as shown by others, may be mediated by another mechanism.

The ulcer healing and cytoprotective properties of colloidal bismuth (De-Nol) are well established although its mode of action is unclear. We have examined the action of bismuth subcitrate, the active ingredient of De-Nol, on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Addition of bismuth subcitrate (10(-6) to 10(-4) M) to the luminal solution produced a dose dependent increase in bicarbonate secretion from both gastric and duodenal mucosae without a change in transmucosal potential difference. The magnitude of this stimulation was greater for gastric than duodenal mucosae at all dose ranges. A second bismuth salt, bismuth oxynitrate, produced similar increases in bicarbonate secretion from gastric mucosae. Pretreatment of gastric mucosa with the cyclooxygenase inhibitor, indomethacin (10(-5) and 10(-4) M), did not abolish the secretory response to bismuth subcitrate. Similar treatment with the chloride transport inhibitor, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) (10(-3) M) prevented the secretory response to bismuth subcitrate.

After ingestion of a non-absorbable carbohydrate breath hydrogen excretion increases early at about 10 minutes, and again later when the ingested carbohydrate enters the caecum. The late rise has been used as a marker of mouth to caecum transit time, but the source of the early rise has not been satisfactorily explained. We studied in 60 healthy volunteers the source and frequency of the early rise in breath hydrogen after ingestion of a non-absorbable carbohydrate. After ingestion of either lactulose solution (10 g in 150 ml water), lentil soup (46 g carbohydrate) or solid meal containing baked beans (15 g carbohydrate), breath hydrogen was significantly raised above basal concentrations within 10 minutes (81 +/- 27, 395 +/- 138 and 110 +/- 52% above basal respectively). A significant rise in breath hydrogen (75 +/- 21%) occurred 10 minutes after sham lactulose feeding (lactulose applied to oral cavity but not swallowed), but no early peak occurred after sham saccharin feeding (non-fermentable carbohydrate), intragastric or intraduodenal administration of lactulose. Ten of the 12 subjects given lactulose sham feeding were restudied after oral hygiene with chlorhexidine mouthwash. In these the early hydrogen peak was abolished. Oral hygiene also reduced the occurrence and magnitude of the early hydrogen rise after lactulose ingestion. These findings indicate that the early rise in breath hydrogen observed after ingestion of lactulose is produced by interaction with oral bacteria.

Editorial, discutant differentes hypotheses sur le role de la barriere mucus-bicarbonate dans la protection de la muqueuse gastrique et dans la cicatrisation des ulceres

Carcinoid tumour accounts for one per cent of all gastrointestinal neoplasms and has been reported in 0.5% of appendicectomy specimens. Local gastrointestinal complications occur infrequently and we report a case of repeated and massive gastrointestinal haemorrhage from a non-metabolically active carcinoid tumour of the distal ileum diagnosed by colonoscopy.