El control de la secreción ácida gástrica en el ratóncambios asociados a la gastritis o a la falta del receptor de tipo 2 de la somatostatina.

Résumé

This study characterizes the regulatory mechanisms of gastric acid secretion in mice, in vivo, in different experimental conditions. First, we characterized pathophysiological alterations linked to gastritis of non infectious origin, induced by exposure of the gastric mucosa to the chemical irritant iodoacetamide. Secondly, we studied the role of somatostatin receptors (SSTR1-5), with special emphasis on SSTR2 receptors, on the regulation of gastric acid secretion and the secretory effects of the neuropeptides bombesin and PACAP. In mice, orally administered iodoacetamide induces a mild gastritis characterised by a moderate inflammatory infiltrate, with an increase in the number of mast cells in the submucosa, without any evidence of macro or microscopic damage. However, basal gastric acid secretion and secretory responses to secretagogues were increased during gastritis. Changes in basal secretion might be related to alterations in the feedback control mechanisms between gastrin and somatostatin, as suggested for other inflammatory models. Enhanced secretory responses to secretagogues (pentagastrin and histamine) were blocked by the mast cells stabilizer, sodium cromoglycate, suggesting a mast cells contribution in these hipersecretory responses. On the other hand, pretreatment with indomethacin further enhanced the secretory responses to pentagastrin and histamine suggesting a prostaglandin-dependent counteracting mechanism that might act reducing hypersecretory responses to minimize acid production and exposure of the gastric mucosa. The use of genetically modified mice (knockout for the gene encoding for SSTR2 receptors) together with the immunoneutralization of endogenous somatostatin and the pharmacological manipulation of somatostatin receptors, using selective agonists and antagonists, clearly demonstrates that the antisecretory effects of somatostatin are mediated through SSTR2 receptors. Moreover, similar experimental approach served to demonstrate that the antisecretory effects of the neuropeptides bombesin and PACAP depend upon the release of somatostatin and the activation of SSTR2 receptors. These observations, together with previous studies characterizing the mechanism of action of several inhibitory mediators, suggests that gastric D cells may function as a common target for a variety of inhibitory peptides, which input will be translated into the release of somatostatin and the activation of SSTR2 receptors, leading to an inhibition of acid output.