Faculty of Medicine, Pharmacology, University of Helsinki, Helsinki, Finland.
Faculty of Veterinary Medicine, Department of Veterinary Biosciences and Finnish Centre for Laboratory Animal Pathology (FCLAP), HiLIFE, University of Helsinki, Helsinki, Finland.
Basic Clin Pharmacol Toxicol. 2023 Sep;133(3):211-225. doi: 10.1111/bcpt.13918. Epub 2023 Jul 18.
Recently, we described local aldosterone production in the murine large intestine. Upregulated local aldosterone synthesis in different tissues has been linked with inflammatory conditions, which have been attenuated by the aldosterone synthase (CYP11B2) inhibitor, fadrozole (FAD286). Therefore, we investigated the effect of inhibition of intestinal aldosterone synthesis on the development of intestinal inflammation. Sprague-Dawley rats were administered 5% (v/w) dextran sodium sulphate (DSS) for 7 days with or without daily FAD286 (30 mg/kg/d) subcutaneous injections on 3 days before, during and one day after DSS. Tissue aldosterone concentrations were evaluated by ELISA, CYP11B2 by Western blot and RT-qPCR. FAD286 halved adrenal aldosterone production but, intriguingly, increased the colonic aldosterone concentration. The lack of inhibitory effect of FAD286 in the colon might have been affected by the smaller size of colonic vs. adrenal CYP11B2, as seen in Western blot. When combined with DSS, FAD286 aggravated the macroscopic and histological signs of intestinal inflammation, lowered the animals' body weight gain and increased the incidence of gastrointestinal bleeding and the permeability to iohexol in comparison to DSS-animals. To conclude, FAD286 exerted harmful effects during intestinal inflammation. Local intestinal aldosterone did not seem to play any role in the inflammatory pathogenesis occurring in the intestine.
最近，我们描述了鼠类大肠中的局部醛固酮产生。不同组织中上调的局部醛固酮合成与炎症状态有关，醛固酮合酶（CYP11B2）抑制剂法地唑（FAD286）可减轻这种情况。因此，我们研究了抑制肠道醛固酮合成对肠道炎症发展的影响。给予 Sprague-Dawley 大鼠 5%（v/w）葡聚糖硫酸钠（DSS），连续 7 天，在 DSS 之前、期间和之后一天每天给予 FAD286（30mg/kg/d）皮下注射。通过 ELISA 评估组织醛固酮浓度，通过 Western blot 和 RT-qPCR 评估 CYP11B2。FAD286 将肾上腺醛固酮的产生减少了一半，但有趣的是，它增加了结肠中的醛固酮浓度。FAD286 在结肠中没有抑制作用可能是由于结肠与肾上腺 CYP11B2 的大小不同所致，Western blot 中可见。当与 DSS 联合使用时，与 DSS 动物相比，FAD286 加重了肠道炎症的宏观和组织学迹象，降低了动物的体重增加，并增加了胃肠道出血的发生率和 iohexol 的通透性。总之，FAD286 在肠道炎症期间产生了有害影响。局部肠道醛固酮似乎在肠道中发生的炎症发病机制中没有发挥任何作用。
