Losartan attenuates acetic acid enema-induced visceral hypersensitivity by inhibiting the ACE1/Ang II/AT1 receptor axis in enteric glial cells

• Published in: European journal of pharmacology Vol. 946; p. 175650
• Main Authors: Sun, Yating, Liu, Xiaohui, Wang, Lianli, Li, Laifu, Quan, Xiaojing, Shi, Haitao, Wang, Ting, Mei, Lin, Chen, Yindi, Zhang, Yue, Li, Jingyao, Meng, Ruiting, Wang, Jinhai, Dai, Fei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05-05-2023
• Subjects: Acetic Acid - toxicity; Animals; AT1 receptor; Enema; Enteric glial cell; Inflammation; Irritable bowel syndrome; Irritable Bowel Syndrome - drug therapy; Irritable Bowel Syndrome - metabolism; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; Losartan; Losartan - pharmacology; Losartan - therapeutic use; Neuroglia; Pain - metabolism; Peptidyl-Dipeptidase A - metabolism; Rats; Receptor, Angiotensin, Type 1 - metabolism; Visceral hypersensitivity; Enteric glial cell; Inflammation; Visceral hypersensitivity; Losartan; Irritable bowel syndrome; AT1 receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175650

Enteric glial cells (EGCs) play an important role in visceral hypersensitivity associated with irritable bowel syndrome (IBS). Losartan (Los) is known to reduce pain; however, its function in IBS is unclear. The present study aimed to investigate Los's therapeutic effect on visceral hypersensitivity in IBS rats. Thirty rats were randomly divided into control, acetic acid enema (AA), AA + Los low, medium and high dose groups in vivo. EGCs were treated with lipopolysaccharide (LPS) and Los in vitro. The molecular mechanisms were explored by assessing the expression of EGC activation markers, pain mediators, inflammatory factors and angiotensin-converting enzyme 1(ACE1)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis molecules in colon tissue and EGCs. The results showed that the rats in the AA group showed significantly higher visceral hypersensitivity than the control rats, which was alleviated by different doses of Los. The expression of GFAP, S100β, substance P (SP), calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid 1 (TRPV1), tumor necrosis factor (TNF), interleukin-1β (IL-1β) and interleukin-6 (IL-6) was considerably increased in colonic tissues of AA group rats and LPS-treated EGCs compared with control rats and EGCs, and reduced by Los. In addition, Los reversed ACE1/Ang II/AT1 receptor axis upregulation in AA colon tissues and LPS-treated EGCs. These results show that Los inhibits ACE1/Ang II/AT1 receptor axis upregulation by suppressing EGC activation, resulting in reduced expression of pain mediators and inflammatory factors, thereby alleviating visceral hypersensitivity.
The role of EGC in visceral hypersensitivity in IBS and the mechanism of losartan in reducing visceral hypersensitivity in IBS. [Display omitted]