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Gastric acid secretion is activated by two distinct pathways: a neuronal pathway via the vagus nerve and release of acetylcholine and an endocrine pathway involving gastrin and histamine. Recently, we demonstrated that activation of H(+)-K(+)-ATPase activity in parietal cells in freshly isolated rat gastric glands is modulated by the calcium-sensing receptor (CaSR). Here, we investigated if the CaSR is functionally expressed in freshly isolated gastric glands from human patients undergoing surgery and if the CaSR is influencing histamine-induced activation of H(+)-K(+)-ATPase activity. In tissue samples obtained from patients, immunohistochemistry demonstrated the expression in parietal cells of both subunits of gastric H(+)-K(+)-ATPase and the CaSR. Functional experiments using the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein and measurement of intracellular pH changes allowed us to estimate the activity of H(+)-K(+)-ATPase in single freshly isolated human gastric glands. Under control conditions, H(+)-K(+)-ATPase activity was stimulated by histamine (100 microM) and inhibited by omeprazole (100 microM). Reduction of the extracellular divalent cation concentration (0 Mg(2+), 100 microM Ca(2+)) inactivated the CaSR and reduced histamine-induced activation of H(+)-K(+)-ATPase activity. In contrast, activation of the CaSR with the trivalent cation Gd(3+) caused activation of omeprazole-sensitive H(+)-K(+)-ATPase activity even in the absence of histamine and under conditions of low extracellular divalent cations. This stimulation was not due to release of histamine from neighbouring enterochromaffin-like cells as the stimulation persisted in the presence of the H(2) receptor antagonist cimetidine (100 microM). Furthermore, intracellular calcium measurements with fura-2 and fluo-4 showed that activation of the CaSR by Gd(3+) led to a sustained increase in intracellular Ca(2+) even under conditions of low extracellular divalent cations. These experiments demonstrate the presence of a functional CaSR in the human stomach and show that this receptor may modulate the activity of acid-secreting H(+)-K(+)-ATPase in parietal cells. Furthermore, our results show the viability of freshly isolated human gastric glands and may allow the use of this preparation for experiments investigating the physiological regulation and properties of human gastric glands in vitro.

To study the role of somatostatin in the regulation of pancreatic and gastric functions, a combined isolated rat stomach and pancreas preparation was developed. This model allowed simultaneous measurements of exocrine and endocrine secretion from the pancreas and gastrin secretion from the stomach. Somatostatin was applied either by a linear gradient or by constant infusion with one concentration in the presence of cerulein, secretin, electric vagal activity, or acetylcholine. Somatostatin did not influence exocrine pancreatic secretion irrespective of what substance was stimulated. In contrast, somatostatin significantly inhibited glucose-dependent insulin and gastrin secretion, either basal or stimulated by vagal activity or acetylcholine. Acetylcholine-induced gastrin secretion was more sensitive to inhibition by somatostatin than insulin. We conclude that in an isolated perfused organ system somatostatin has potent inhibitory effects on endocrine pancreas and stomach but has no effect on exocrine pancreatic volume and enzyme secretion.

Calcitonin given in doses (0.2 and 1 MRC U/kg-1h-1) reproducing the levels observed in medullary carcinoma of the thyroid, induced the appearance of phase III type activity and reduced the duration of the IMC in the small intestine from 123 to 87 min with 0.2 MRC U kg-1h-1 and from 123 to 43 min with 1 MRC U kg-1h-1 but not in the stomach of young volunteers. This increase in phase III-like activity occurred despite a sharp reduction in motilin levels. Only the highest dose of calcitonin reduced significantly acid secretion (by more than 90%) while both doses reduced amylase secretion by respectively 65 and 71% when compared to the control levels. These changes in motility and secretion could partly explain the diarrhea observed in patients with the medullary carcinoma of the thyroid.

Gastrointestinal tissues have a high synthesising capacity for prostaglandins. As exogenous prostaglandins protect the gastrointestinal mucosa against potentially noxious agents, it has been suggested that the generation of prostaglandins plays a crucial role in the maintenance of mucosal integrity. Analgesic and anti-inflammatory drugs with a potent inhibitory action on gastrointestinal cyclo-oxygenase, such as indomethacin, induce gastric and intestinal ulcerations in experimental animals and frequently lead to gastrointestinal side effects in man. However, drugs that do not reduce gastrointestinal prostaglandin formation, such as paracetamol (acetaminophen), are devoid of gastrointestinal toxicity. Various factors, e.g. tissue-specific differences in the sensitivity of cyclo-oxygenase against inhibition and pharmacokinetic properties, modify the inhibitory activity of analgesic and anti-inflammatory drugs on gastrointestinal prostaglandin formation. As leukotriene C4 is a potent gastric vasoconstrictor, increased metabolism of arachidonic acid via the 5-lipoxygenase pathway in the presence of inhibition of cyclo-oxygenase could possibly contribute to drug-induced gastrointestinal damage.