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Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome.

氯沙坦改善肠易激综合征大鼠模型的内脏感觉和肠屏障。

  • 影响因子:3.85
  • DOI:10.1111/nmo.13819
  • 作者列表:"Nozu T","Miyagishi S","Nozu R","Takakusaki K","Okumura T
  • 发表时间:2020-02-14
Abstract

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.

摘要

背景: 脂多糖 (LPS) 或反复回避水应激 (WAS) 通过促肾上腺皮质激素释放因子 (CRF) 和促炎细胞因子诱导内脏异常性疼痛和结肠高通透性, 被认为是大鼠肠易激综合征 (IBS) 模型。由于已知氯沙坦能抑制促炎细胞因子的释放,我们假设它能改善这些内脏变化。 方法: 测定大鼠内脏运动反应 (VMR) 的阈值,即结肠球囊扩张引起的腹部肌肉收缩。通过分光光度法定量结肠组织中吸收的伊文思蓝 15 min,在体内测定结肠通透性。 关键结果: 脂多糖 (1 mg · kg-1) 皮下 (s.c.) 降低 VMR 阈值,增加结肠通透性。氯沙坦 (5-25 mg kg-1 s.c.) 3 天,以剂量依赖性方式抑制这些变化。此外,重复给药 (每日 1 小时,共 3 天) 或腹腔注射 CRF (50 µ g · kg-1) 诱导的内脏变化与 LPS 相似,氯沙坦也消除了这些变化。在 LPS 模型中氯沙坦的这些作用被 GW9662 (一种过氧化物酶体增殖物激活受体-γ [PPAR-γ] 拮抗剂) 逆转, NG-硝基-L-精氨酸甲酯 (一氧化氮 [NO] 合成抑制剂),或纳洛酮 (阿片受体拮抗剂)。此外,舒必利 (多巴胺 D2 受体拮抗剂) 或多潘立酮 (外周多巴胺 D2 拮抗剂) 也可抑制它。 结论: 氯沙坦可预防 IBS 大鼠模型内脏痛觉异常和结肠高通透性。这些作用可能是 PPAR-γ 依赖性的,也由 NO 、阿片类和多巴胺 D2 通路介导。氯沙坦可能对 IBS 治疗有用。

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影响因子:3.72
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影响因子:3.72
发表时间:2020-01-21
DOI:10.1093/ibd/izz331
作者列表:["Ronchetti S","Gentili M","Ricci E","Migliorati G","Riccardi C"]

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关键词: GILZ IBD 自身免疫 炎症
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