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Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome
Author(s) -
Nozu Tsukasa,
Miyagishi Saori,
Nozu Rintaro,
Takakusaki Kaoru,
Okumura Toshikatsu
Publication year - 2020
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13819
Subject(s) - irritable bowel syndrome , losartan , sensation , medicine , gastroenterology , psychology , angiotensin ii , neuroscience , receptor
Background Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via corticotropin‐releasing factor (CRF) and proinflammatory cytokines, which is considered to be a rat irritable bowel syndrome (IBS) model. As losartan is known to inhibit proinflammatory cytokine release, we hypothesized that it improves these visceral changes. Methods The threshold of visceromotor response (VMR), that is, abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 minutes spectrophotometrically. Key Results Lipopolysaccharide (1 mg kg −1 ) subcutaneously (s.c.) reduced the threshold of VMR and increased colonic permeability. Losartan (5‐25 mg kg −1 s.c.) for 3 days inhibited these changes in a dose‐dependent manner. Moreover, repeated WAS (1 hour daily for 3 days) or intraperitoneal injection of CRF (50 µg kg −1 ) induced the similar visceral changes as LPS, which were also eliminated by losartan. These effects by losartan in LPS model were reversed by GW9662 (a peroxisome proliferator‐activated receptor‐γ [PPAR‐γ] antagonist), N G ‐nitro‐L‐arginine methyl ester (a nitric oxide [NO] synthesis inhibitor), or naloxone (an opioid receptor antagonist). Moreover, it also inhibited by sulpiride (a dopamine D 2 receptor antagonist) or domperidone (a peripheral dopamine D 2 antagonist). Conclusion & Inferences Losartan prevented visceral allodynia and colonic hyperpermeability in rat IBS models. These actions may be PPAR‐γ–dependent and also mediated by the NO, opioid, and dopamine D 2 pathways. Losartan may be useful for IBS treatment.