Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome
Corresponding Author
Tsukasa Nozu
Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
Center for Medical Education, Asahikawa Medical University, Asahikawa, Japan
Correspondence
Tsukasa Nozu, Department of Regional Medicine and Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
Email: [email protected]
Search for more papers by this authorSaori Miyagishi
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorRintaro Nozu
Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorKaoru Takakusaki
Research Center for Brain Function and Medical Engineering, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorToshikatsu Okumura
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorCorresponding Author
Tsukasa Nozu
Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
Center for Medical Education, Asahikawa Medical University, Asahikawa, Japan
Correspondence
Tsukasa Nozu, Department of Regional Medicine and Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
Email: [email protected]
Search for more papers by this authorSaori Miyagishi
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorRintaro Nozu
Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorKaoru Takakusaki
Research Center for Brain Function and Medical Engineering, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorToshikatsu Okumura
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
Search for more papers by this authorAbstract
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), NG-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 D2 receptor antagonist) or domperidone (a peripheral dopamine D2 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 D2 pathways. Losartan may be useful for IBS treatment.
CONFLICTS OF INTEREST
The authors declare no conflicts of interests.
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