Peripheral PACAP inhibits gastric acid secretion through somatostatin release in mice

Studies in rats suggest that PACAP modulates gastric acid secretion through the release of both histamine and somatostatin. We characterized the effects of exogenous PACAP on gastric acid secretion in urethane‐anesthetized mice implanted with a gastric cannula and in conscious 2‐h pylorus ligated mice, and determined the involvement of somatostatin and somatostatin receptor type 2 (SSTR2) by using somatostatin immunoneutralization, the SSTR2 antagonist, PRL‐2903, and SSTR2 knockout mice. Urethane‐anesthetized wild‐type mice had low basal acid secretion (0.10±0.01 μ mol (10 min) −1 ) compared with SSTR2 knockout mice (0.93±0.07 μ mol (10 min) −1 ). Somatostatin antibody and PRL‐2903 increased basal secretion in wild‐type mice but not in SSTR2 knockout animals. In wild‐type urethane‐anesthetized mice, PACAP‐38 (3–270 μ g kg −1 h −1 ) did not affect the low basal acid secretion, but inhibited the acid response to pentagastrin, histamine, and bethanechol. In wild‐type urethane‐anesthetized mice pretreated with somatostatin antibody or PRL‐2903 and in SSTR2 knockout mice, peripheral infusion of PACAP‐38 or somatostatin‐14 did not inhibit the increased basal gastric acid secretion. In conscious wild‐type mice, but not in SSTR2 knockout mice, PACAP‐38 inhibited gastric acid secretion induced by 2‐h pylorus ligation. The antisecretory effect of PACAP‐38 was prevented by immunoneutralization of somatostatin. These results indicate that, in mice, peripheral PACAP inhibits gastric acid secretion through the release of somatostatin and the activation of SSTR2 receptors. There is no evidence for stimulatory effects of PACAP on acid secretion in mice.British Journal of Pharmacology (2004) 142 , 67–78. doi: 10.1038/sj.bjp.0705739