Muscarinic acetylcholine receptor subtype 4 is esssential for cholinergic stimulation of duodenal bicarbonate secretion in mice - Relationship to d cell/somatostatin

We investigated the roles of muscarinic (m) acetylcholine receptor subtype in the cholinergic stimulation of duodenal hco3– secretion using knockout (ko) mice. wild-type and m1-m5 ko c57bl/6j mice were used. the duodenal mucosa was mounted on an ussing chamber,and hco3– secretion was measured at ph 7.0 using a ph-stat method in vitro. carbachol (cch) or other agents were added to the serosal side. cch dose-dependently stimulated hco3– secretion in wild-type mice,and this effect was completely inhibited in the presence of atropine. the hco3– response to cch in wild-type mice was also inhibited by pirenzepine (m1 antagonist),4damp (m3 antagonist),and tropicamide (m4 antagonist),but not by methoctramine (m2 antagonist). cch stimulated hco3– secretion in m2 and m5 ko animals as effectively as in wt mice; however,this stimulatory effect was significantly attenuated in m1,m3,and m4 ko mice. the decrease observed in the cch-stimulated hco3– response in m4 ko mice was reversed by the co-application of cyn154806,a somatostatin receptor type 2 (sst2) antagonist. octreotide (a somatostatin analogue) decreased the basal and cch-stimulated secretion of hco3–in wild-type mice. the co-localized expression of somatostatin and m4 receptors was confirmed immunohistologically in the duodenum. we concluded that the duodenal hco3–response to cch was directly mediated by m1/m3 receptors and indirectly modified by m4 receptors. the activation of m4 receptors was assumed to inhibit the release of somatostatin from d cells and potentiate the hco3– response by removing the negative influence of somatostatin via the activation of sst2 receptors. © 2015 polish physiological society. all rights reserved.