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Gastro-oesophageal reflux disease (GORD) is a multifactorial disease. Although it is primarily a motility disorder, several other disturbances can interfere and contribute to determine the severity of symptoms and the degree of lesions. In normal subjects, as in patients with pathological reflux, nearly all the episodes of reflux obey one of the following three mechanisms: (a) a transient complete relaxation of the lower oesophageal sphincter (TLOSR), (b) a transient increase in intra-abdominal pressure which overcomes the resistance of the antireflux barrier ('stress reflux') and, (c) a spontaneous reflux through a permanently hypotonic sphincter. Gastric distension is the major factor that can induce TLOSRs. Whereas, at rest, the diaphragm probably plays little role in cardial competence, diaphragmatic contraction may help prevent reflux in conditions resulting in increased abdominal pressure such as during physical activity and abdominal staining. The presence of a hiatal hernia increases susceptibility to reflux. A delayed gastric emptying may also facilitate reflux and represents a factor of resistance to antireflux therapy. Most studies in humans have shown that motor abnormalities remain unchanged after healing of oesophagitis. Acid and pepsin are the most noxious agents of the upper gastrointestinal secretions that can participate in the pathogenesis of oesophagitis. However, there is no evidence that patients with reflux have greater acid secretion than subjects without reflux. The clearance function is a two-stage phenomenon requiring first a reduction in volume by peristalsis and then chemical neutralization by saliva. Primary peristalsis is mainly responsible for the clearance of acid in both the upright and the supine positions. It takes longer to clear acid in patients with non-reducing hiatal hernia. The layer of mucus which carpets the mucosa comes from the saliva and also from the submucosal glands of the oesophagus. The paracellular pathway is the major route by which mucosal HCl enters and then damages the oesophageal epithelium. Only a minority of acid reflux episodes are accompanied by symptoms. The acid exposure during the time period that precedes a reflux episode (i.e. the acid burden) is a key factor determining whether that reflux episode will be symptomatic or asymptomatic.

Intraduodenal pH, bicarbonate and amylase secretion, and gastric acid and pepsin output were studied in relation to the migrating motor complex in man. The occurrence of a motor complex in the duodenum was preceded by an increase in gastric acid and pepsin output and followed by a peak in bicarbonate and amylase secretion. It is concluded that the interdigestive phase in man is characterized by periodic activity complexes comprising both motor and secretory components. These observations may have important implications for the interpretation of currently used functional tests of gastrointestinal secretion.

Prolonged (24 h) intra-esophageal pH measurements have shown that short-lasting reflux episodes regularly occur in normal subjects, especially in the postprandial period. This phenomenon has been called physiological reflux. When the reflux episodes become more frequent and last longer, symptoms and esophagitis ensue. The mechanism of symptom production (pyrosis and/or chest pain) is incompletely understood. Chemoreceptors are involved but manometric disturbances and irritability of the esophagus may play an important role. The pathogenesis of pathological reflux is multifactorial: 1. An ineffective anti-reflux barrier at the level of the gastroesophageal junction is the most important factor in the pathogenesis of reflux. 2. Once reflux has occurred, an appropriate clearing of the refluxed material is necessary to minimize the contact time of the noxious agent with the esophageal mucosa. This clearing function is a two-step operation. In the refluxed material the concentration of H+ is the most irritant factor although pepsine increases its noxious character. Bile acid reflux decreases the epithelial resistance. The mucosal resistance to noxious agents is determined by the mucous layer, the cytoprotective properties of the epithelium, the regeneration capacity of the cells and by a number of post-epithelial factors.

The effect of rioprostil, a PGE1 analogue, on the interdigestive motility of the upper human small intestine was investigated in 8 normal volunteers in a double-blind, placebo-controlled study. Rioprostil was administered intraduodenally in a dose of 600 μg. The myoelectrical activity was recorded simultaneously at 8 different levels of the jejunum, at 10 cm intervals. Rioprostil, 600 μg, does not disrupt the migrating motor complex (MMC) and does not change the characteristics of phase 3 of the MMC, except for an increased propagation velocity. The main effect of rioprostil, 600 μg, is a marked inhibition of phase 2 contractions without induction of propulsive motility patterns during phase 2. This may explain why rioprostil in a dose of 600 μg is not markedly diarrheogenic in man.

We have tested the hypothesis that the imperfect correlation between the occurrence of plasma motilin peaks and the migrating motor complex (MMC) is related to the site of origin of the MMC. Gastric and small-intestinal motor activity was recorded manometrically in 16 normal subjects after an overnight fast. Blood samples were taken every 10 min and assayed for motilin. Fifty MMCs were recorded: 29 (58%) originated in the antrum and 21 (42%) in the small intestine. For gastric MMCs a motilin peak (45 +/- 5 pM) was found 10 min before the occurrence of the MMC in the duodenum. For intestinal MMCs no peak could be demonstrated. On an individual basis 27 of the 29 gastric activity fronts were associated with a motilin peak, versus 5 out of 21 intestinal MMCs. It is concluded that in man only gastric activity fronts are associated with plasma motilin peaks. Apparently, motilin is only involved in the regulation of the MMCs originating from the stomach.

Basal fluctuations of motilin and their correlation to intestinal motor activity were studied in five hypophysectomized (anterior lobe resection) patients. A cyclic pattern of motor activity identical to the one described in normal volunteers was observed. The mean interval between two activity fronts (AF) was 115 min, which is not significantly different from the normal length. Motilin levels were within the normal range, and fluctuations correlated with the occurrence of an AF. The mean difference between motilin levels 15 min before the AF and at the time of the start of the AF was +15 pM (P less than 0.05). For the levels 15 min after the AF the mean difference was -9 pM (P less than 0.05). These values correlate well with those reported by us in normal volunteers, in whom the mean differences were +11 pM and -14 pM, respectively. It is concluded that the adenohypophysis is not involved in the regulation of motilin levels or in the regulation of interdigestive motility in man.

The effect on the migrating myoelectric complex (MMC) of local nerve blockade in the jejunum was studied in five unanesthetized dogs. A silastic catheter was implanted in a terminal branch of a jejunal artery, perfusing a 5- to 10-cm segment, 45 cm below the ligament of Treitz. Small-bowel motor activity was studied electromyographically with implanted electrodes. Three different doses of tetrodotoxin (166, 333, 500 ng/kg/h) were administered intra-arterially for 5 h. During the 333- and 500-ng but not during the 166-ng/kg/h perfusions ectopic activity fronts started just below the perfused segment. At this time no phase-3 activity was observed in the proximal bowel. In addition to ectopic fronts normal MMCs were observed during the perfusions. These observations show that local nerve blockade induces phase-3 activity, probably by inhibiting an inhibitory nerve action.