Altered contractile responses to angiotensin II and cholinergic stimulation in colonic circular smooth muscle from patients with diverticular disease

Background Abnormal circular smooth muscle contractility is considered a key factor in the pathogenesis of diverticular disease (DD), contributing to increased intraluminal pressure and diverticulum formation. Altered cholinergic responsiveness of colonic smooth muscle has previously been reported in DD. Although angiotensin II (Ang II) regulates gastrointestinal smooth muscle contraction through angiotensin type 1 (AT1R) and type 2 (AT2R) receptors, its role in DD remains poorly understood. The aim of the present study was to investigate alterations in contractile responses to Ang II and cholinergic stimulation in the circular muscle of the colon in DD. Methods Colonic tissue was obtained from 16 patients with DD and 16 control patients undergoing colorectal surgery. Immunofluorescence was performed to determine the localization of AT1R and AT2R. Ang II levels in colonic muscular tissue were quantified by enzyme-linked immunosorbent assay (ELISA), AT1R and AT2R protein expression were evaluated by Western blotting, and their mRNA expression was assessed by RT-qPCR. Circular smooth muscle strips were subsequently studied using in vitro organ bath recordings to assess Ang II-induced contractile responses under basal conditions and following pharmacological blockade with losartan, tetrodotoxin (TTX), or the AT2R antagonist PD123319. Results AT1R was predominantly localized in colonic smooth muscle cells, whereas AT2R was mainly detected in the myenteric plexus and nerve fibers. Compared with controls, DD tissues exhibited increased local Ang II levels and higher AT2R protein expression, accompanied by increased AT2R mRNA expression. Bethanechol-induced contractility was reduced in DD, whereas both peak and mean 5-min Ang II-induced contractile responses were enhanced. Losartan significantly reduced the mean 5-min Ang II-induced contractile response in both groups. However, both peak and mean responses remained significantly greater in DD than in controls following AT1R blockade. Neither TTX nor PD123319 significantly affected Ang II-induced contractions. Conclusions The present study demonstrates altered colonic circular smooth muscle contractility in diverticular disease, characterized by enhanced responses to Ang II and reduced responses to cholinergic stimulation. The distinct muscular and neural distribution of AT1R and AT2R, respectively, suggests that altered local Ang II signaling, together with altered cholinergic regulation, may contribute to the pathogenesis of DD.