Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Japan.
Center for Medical Education, Asahikawa Medical University, Asahikawa, Japan.
Neurogastroenterol Motil. 2020 Jun;32(6):e13819. doi: 10.1111/nmo.13819. Epub 2020 Feb 14.
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.
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.
Lipopolysaccharide (1 mg kg ) subcutaneously (s.c.) reduced the threshold of VMR and increased colonic permeability. Losartan (5-25 mg kg 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 ) 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 -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 receptor antagonist) or domperidone (a peripheral dopamine D 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 pathways. Losartan may be useful for IBS treatment.
脂多糖（LPS）或反复水回避应激（WAS）通过促肾上腺皮质释放因子（CRF）和促炎细胞因子诱导内脏痛觉过敏和结肠高通透性，这被认为是大鼠肠易激综合征（IBS）模型。由于氯沙坦已知抑制促炎细胞因子的释放，我们假设它可以改善这些内脏变化。
通过电生理测量大鼠的内脏运动反应（VMR）阈值，即结肠球囊扩张引起的腹肌收缩。通过定量测量 15 分钟内吸收到结肠组织中的 Evans 蓝来体内测定结肠通透性。
皮下注射 LPS（1mg/kg）降低了 VMR 的阈值并增加了结肠通透性。氯沙坦（5-25mg/kg 皮下注射）连续 3 天以剂量依赖性方式抑制这些变化。此外，反复 WAS（每天 1 小时，连续 3 天）或腹腔内注射 CRF（50µg/kg）引起类似于 LPS 的内脏变化，这些变化也被氯沙坦消除。氯沙坦在 LPS 模型中的这些作用被 GW9662（过氧化物酶体增殖物激活受体-γ[PPAR-γ]拮抗剂）、N-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）逆转。此外，它还被舒必利（多巴胺 D 受体拮抗剂）或多潘立酮（外周多巴胺 D 拮抗剂）抑制。
氯沙坦预防了大鼠 IBS 模型中的内脏痛觉过敏和结肠高通透性。这些作用可能依赖于 PPAR-γ，并通过 NO、阿片和多巴胺 D 途径介导。氯沙坦可能对 IBS 治疗有用。
