|The gastric acid constitutes a potential threat to the gastroduodenal tissue. The mucosa is therefore supplied with a number of defence mechanisms, including an unstirred layer of mucus into which bicarbonate is secreted by the mucosa. Hydrogen ions approaching the epithelium will react with bicarbonate to form CO2 and water. This mechanism keeps the epithelial surface at pH neutrality in presence of an acidload reaching luminal pH 2. Nevertheless, mucosa-protective functions are activated also in this pH interval. By definition, it cannot be the hydrogen ions themselves that trigger mucosal acid receptors in turn mediating such protective responses. The general aim of the thesis was to investigate how intraluminal acidity influences mucosa-protective functions. The specific aims were to study the regulation of acid-induced duodenal mucosal bicarbonate secretion (DMBS) and the antral feedback inhibition of meal-induced gastrin release. DMBS was measured in-vivo in isolated duodenal segments in anaesthetised rats or pigs. In some experiments, measurements of duodenal blood flow and mucosal output of nitric oxide (NO) were performed. Immunohistochemistry and the Western blot technique were used for detection of isoforms of NO synthase (NOS). Antral regulation of gastrin release was studied in healthy volunteers. In rats, a high intraluminal CO2 tension increased DMBS despite almost pH neutral intraluminal conditions. It was demonstrated that the L-arginine/NO pathway, but not prostaglandins, is involved in acid-induced DMBS. Both functional and pharmacological findings suggested that the NO synthesis is situated within, or close to, the villous epithelium. These data were confirmed in pig experiments, which also showed that the acid-induced DMBS is paralleled by an increased mucosal output of NO. Immunohistochemistry and Western blot analysis of rat duodenal tissue demonstrated that the responsible NOS is of the inducible type (iNOS), and located within the villous epithelial surface cells. In addition, mucosal acid exposure increased the expression of the iNOS, and repeated acid exposure resulted in a further stimulation of DMBS. In humans, CO2 potentiated, whereas luminal NO formation (due to acid-dependent reduction of swallowed nitrite) partly inhibited, meal-induced gastrin release. It is suggested that the neutralisation product CO2 acts as an intermediate messenger between intraluminal acidity and the initiation of DMBS as well as antral gastrin release. In the duodenum, luminal acidity stimulates both the activity and the expression of iNOS located within the villous epithelial cells. The resulting NO formation will initiate an increased DMBS. In the stomach, NO formed luminally inhibits meal-induced gastrin release by so far unknown intramucosal mechanisms.