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Control of Gastric Acid Secretion in Somatostatin Receptor 2 Deficient Mice: Shift from Endocrine/Paracrine to Neurocrine Pathways

Department of Cancer Research and Molecular Medicine (C.-M.Z., D.C.), Norwegian University of Science and Technology, NO-7006 Trondheim, Norway; Safety Assessment-Safety Pharmacology (V.M.), AstraZeneca R&D, Alderley Park, Cheshire SK10 4TF, United Kingdom; Center for Ulcer Research and Education (V.M., L.W., Y.T.), Digestive Disease Research Center, Department of Medicine, University of California at Los Angeles, and Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California 90073; and Research Foundation University Clinic Hospital (L.P.), University of Valencia, 46022 Valencia, Spain

Address all correspondence and requests for reprints to: Dr. Chun-Mei Zhao, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NO-7006 Trondheim, Norway. E-mail: chun-mei.zhao{at}ntnu.no.

The gastrin-enterochromaffin-like (ECL) cell-parietal cell axis is known to play an important role in the regulation of gastric acid secretion. Somatostatin, acting on somatostatin receptor type 2 (SSTR₂), interferes with this axis by suppressing the activity of the gastrin cells, ECL cells, and parietal cells. Surprisingly, however, freely fed SSTR₂ knockout mice seem to display normal circulating gastrin concentration and unchanged acid output. In the present study, we compared the control of acid secretion in these mutant mice with that in wild-type mice. In SSTR₂ knockout mice, the number of gastrin cells was unchanged; whereas the numbers of somatostatin cells were reduced in the antrum (–55%) and increased in the oxyntic mucosa (35%). The ECL cells displayed a reduced expression of histidine decarboxylase and vesicle monoamine transport type 2 (determined by immunohistochemistry), and an impaired transformation of the granules to secretory vesicles (determined by electron microscopic analysis), suggesting low activity of the ECL cells. These changes were accompanied by an increased expression of galanin receptor type 1 in the oxyntic mucosa. The parietal cells were found to respond to pentagastrin or to vagal stimulation (evoked by pylorus ligation) with increased acid production. In conclusion, the inhibitory galanin-galanin receptor type 1 pathway is up-regulated in the ECL cells, and the direct stimulatory action of gastrin and vagal excitation is enhanced on the parietal cells in SSTR₂ knockout mice. We suggest that there is a remodeling of the neuroendocrine mechanisms that regulate acid secretion in these mutant mice.