The aims of this study were to elucidate the distribution of angiotensin receptors (AT₁ and AT₂) in the duodenal wall and to investigate whether AT₂ receptors are involved in the regulation of duodenal mucosal alkaline secretion, which is of importance for the mucosal defense against gastric acid. Immunohistochemistry was used to locate AT₁ and AT₂ receptors in chloralose-anesthetized rats. Duodenal mucosal alkaline output was measured by use of in situ pH-stat titration. Immunohistochemistry demonstrated a distinct staining for both AT₁ and AT₂ receptors in the lamina propria of the villi and also for AT₁ receptors in the muscularis interna. When angiotensin II was infused in the presence of the AT₁ receptor antagonist losartan, mucosal alkaline secretion increased by ~50%. This response was inhibited by the AT₂ receptor antagonist PD-123319. The AT₂ receptor agonist CGP-42112A increased mucosal alkaline secretion by ~50%. This increase was absent in the presence of PD-123319 but not in the presence of losartan or the local anesthetic lidocaine. We conclude that angiotensin II stimulates duodenal mucosal alkaline secretion by activation of AT₂ receptors located in the duodenal mucosa/submucosa.