INRA, UMR Neuro-Gastroentérologie et Nutrition, Toulouse, France.
Am J Physiol Gastrointest Liver Physiol. 2010 Dec;299(6):G1298-307. doi: 10.1152/ajpgi.00022.2010. Epub 2010 Sep 23.
Vasopressin and its receptors modulate several gut functions, but their role in intestinal inflammation is unknown. Our aims were to determine 1) the localization of V1b receptors in human and rodent colon, 2) the role of vasopressin and V1b receptors in experimental colitis using two approaches: V1b⁻(/)⁻ mice and a selective V1b receptor antagonist, SSR149415, and 3) the mechanisms involved. V1b receptors were localized in normal and inflamed colon from humans and rats. Experimental colitis was induced in rats and mice and some groups were treated before or after colitis induction with oral SSR149415 (3-30 mg/kg). Other groups of mice were submitted to dehydration to increase vasopressin plasma levels, prior to colitis induction. Body weight, damage scores, MPO, and TNF-α tissue levels were determined. Finally, colonic segments of wild-type (WT) and V1b⁻(/)⁻ mice were mounted in Ussing chambers and paracellular permeability in response to vasopressin was studied. V1b receptors were expressed in enterocytes and ganglia cells of the enteric nervous system of human and rat intestine. Expression levels were independent from inflammatory status. Colitis was less severe in rodents treated by either preventive or curative SSR149415 and in V1b⁻(/)⁻ mice. 2,4,6-Trinitrobenzene sulfonic acid induced a strong mortality in dehydrated animals that was reversed by preventive SSR149415 or mast cell stabilizer. Vasopressin significantly increased paracellular permeability in WT, but not in V1b⁻(/)⁻ mice. Preincubation of colon tissues with SSR149415 abolished the vasopressin effect. Similarly, vasopressin had no effect in colonic preparations from WT mice pretreated with mast cell stabilizers. Vasopressin, through V1b receptor interaction, has proinflammatory properties linked to mast cell activation and downstream alterations of the colonic epithelial barrier. These findings underline the potential interest of V1b receptor blockers in gut inflammatory diseases.
加压素及其受体调节多种肠道功能，但它们在肠道炎症中的作用尚不清楚。我们的目的是确定 1）V1b 受体在人类和啮齿动物结肠中的定位，2）使用两种方法研究加压素和 V1b 受体在实验性结肠炎中的作用：V1b⁻（/）⁻小鼠和选择性 V1b 受体拮抗剂 SSR149415，以及 3）涉及的机制。V1b 受体定位于人类和大鼠的正常和炎症结肠。在大鼠和小鼠中诱导实验性结肠炎，并用口服 SSR149415（3-30mg/kg）在结肠炎诱导前或后对一些组进行治疗。将其他组小鼠进行脱水处理，以增加加压素的血浆水平，然后再诱导结肠炎。测定体重、损伤评分、MPO 和 TNF-α组织水平。最后，将野生型（WT）和 V1b⁻（/）⁻小鼠的结肠段置于 Ussing 室中，并研究加压素对其旁细胞通透性的影响。V1b 受体在人类和大鼠肠的肠上皮细胞和肠神经系统的神经节细胞中表达。表达水平与炎症状态无关。用预防性或治疗性 SSR149415 处理的啮齿动物或 V1b⁻（/）⁻小鼠的结肠炎程度较轻。在脱水动物中，2,4,6-三硝基苯磺酸（2,4,6-trinitrobenzenesulfonic acid）引起强烈的死亡率，该死亡率可被预防性 SSR149415 或肥大细胞稳定剂逆转。加压素显著增加 WT 小鼠的旁细胞通透性，但不增加 V1b⁻（/）⁻小鼠的旁细胞通透性。用 SSR149415 预孵育结肠组织可消除加压素的作用。同样，用肥大细胞稳定剂预处理 WT 小鼠的结肠制剂后，加压素也没有作用。加压素通过与 V1b 受体相互作用，具有促炎特性，与肥大细胞激活和结肠上皮屏障的下游改变有关。这些发现强调了 V1b 受体阻滞剂在肠道炎症性疾病中的潜在应用价值。
