Adverse effects of an aldosterone synthase (CYP11B2) inhibitor, fadrozole (FAD286), on inflamed rat colon.

Recently, we described local aldosterone production in 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 sulfate (DSS) for 7 days with or without daily FAD286 (30mg/kg/d) subcutaneous injections on three 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; it 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.