Abstract
Background/Aim: Muscarinic acetylcholine receptors exist in five subtypes (M1∼M5), and they are widely expressed in various tissues to mediate diverse autonomic functions, including gastric secretion. In the present study, we demonstrated, using M1∼M5 KO mice, the importance of M4 receptors in carbachol (CCh) stimulation of acid secretion and investigated how the secretion is modulated by the activation of M4 receptors.Methods: C57BL/6J mice of wild-type (WT) and M1–M5 KO were used. Under urethane anesthesia, acid secretion was measured in the stomach equipped with an acute fistula. CCh (30 μg/kg) was given subcutaneously (s.c.) to stimulate acid secretion. Atropine or octreotide (a somatostatin analog) was given s.c. 20 min before the administration of CCh. CYN154806 (a somatostatin SST2 receptor antagonist) was given i.p. 20 min before the administration of octreotide or CCh.Results: CCh caused an increase of acid secretion in WT mice, and the effect was totally inhibited by prior administration of atropine. The effect of CCh was similarly observed in the animals lacking M1, M2 or M5 receptors but significantly decreased in M3 or M4 KO mice. CYN154806, the SST2 receptor antagonist, dose-dependently and significantly reversed the decreased acid response to CCh in M4 but not M3 KO mice. Octreotide, the somatostatin analog, inhibited the secretion of acid under CCh-stimulated conditions in WT mice. The immunohistochemical study showed the localization of M4 receptors on D cells in the stomach. Serum somatostatin levels in M4 KO mice were higher than WT mice under basal conditions, while those in WT mice were significantly decreased in response to CCh.Conclusions: These results suggest that under cholinergic stimulation the acid secretion is directly mediated by M3 receptors and indirectly modified by M4 receptors. It is assumed that the activation of M4 receptors inhibits the release of somatostatin from D cells and minimizes the acid inhibitory effect of somatostatin through SST2 receptors, resulting in enhancement of the acid response mediated by M3 receptors on parietal cells.
Highlights
The mechanisms that govern gastric acid secretion involve neurohumoral factors, including histamine, gastrin, and acetylcholine (ACh; Soll, 1994; Hersey and Sachs, 1995; Chen et al, 2004)
We demonstrated the importance of M4 receptors in the cholinergic stimulation of gastric acid secretion and showed how this secretion can be modulated by the activation of M4 receptors, focusing on the relation to D cell/somatostatin
Since the acid stimulatory action of CCh was almost completely inhibited by atropine, the non-selective antagonist of muscarinic acetylcholine receptors (mAChRs), these results confirmed that CCh stimulated gastric acid secretion via the activation of mAChRs
Summary
The mechanisms that govern gastric acid secretion involve neurohumoral factors, including histamine, gastrin, and acetylcholine (ACh; Soll, 1994; Hersey and Sachs, 1995; Chen et al, 2004). The mAChRs consist of five subtypes (M1–M5) and are widely expressed in many peripheral organs as well as central nervous system to mediate diverse autonomic functions, including acid, pepsin and mucus as well as HCO−3 secretions (Kajimura et al, 1992; Helander et al, 1996; Caulfield and Birdsall, 1998; Matsui et al, 2000, 2004; Tobin et al, 2009). No information is currently available on the role of M4 receptors in the cholinergic regulation of gastric acid secretion
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
