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

Hanna Launonen, Lotta Luiskari, Jere Linden, Aino Siltari, Hanne Salmenkari, Riitta Korpela, Heikki Vapaatalo

    Tutkimustuotos: ArtikkeliTieteellinenvertaisarvioitu

    1 Sitaatiot (Scopus)
    10 Lataukset (Pure)

    Abstrakti

    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.

    AlkuperäiskieliEnglanti
    Sivut211-225
    Sivumäärä15
    JulkaisuBasic and Clinical Pharmacology and Toxicology
    Vuosikerta133
    Numero3
    DOI - pysyväislinkit
    TilaJulkaistu - syysk. 2023
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

    Julkaisufoorumi-taso

    • Jufo-taso 2

    !!ASJC Scopus subject areas

    • Toxicology
    • Pharmacology

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