Potent inhibition of the inducible isoform of nitric oxide synthase by aminoethylisoselenourea and related compounds

Garry J. Southan, Andrew L. Salzman, Csaba Szabó

    Research output: Contribution to journalArticle

    28 Scopus citations

    Abstract

    The generation of nitric oxide (NO) by nitric oxide synthase (NOS) can be inhibited by certain guanidines and S-alkylisothioureas. In particular, aminoethylisothiourea (AE-TU) shows selectivity towards the inducible isoform (iNOS) over the endothelial isoform (ecNOS). Here we report on the effects of the selenium analog of AE-TU, aminoethylisoselenourea (AE-SeU), and its homologue, aminopropylisoselenourea (AP-SeU), on the activities of iNOS and ecNOS. AE-SeU and AP-SeU inhibited the conversion of L-arginine to L-citrulline in homogenates of lung taken from endotoxin-treated rats (a model of iNOS activity) with potencies (EC50 = 1.1, and 0.1 μM, respectively) greater than that of N(G)-methyl-L-arginine (L-NMA) (22 μM). In contrast, AE-SeU and AP-SeU were weaker than or similar to L-NMA at inhibiting ecNOS activity in homogenized bovine endothelial cells (EC50 values = 104, 15, and 16 μM, respectively). AE-SeU and AP-SeU potently inhibited nitrite formation by immunostimulated J774 macrophages (a model of iNOS activity) with EC50 values of 10 and 4 μM respectively. The corresponding EC50 value for L-NMA was 160 μM. The inhibition was dose-dependently reduced by increasing concentrations of L-arginine in the medium. In vivo, AE-SeU had only modest effects on blood pressure when given as a bolus to anesthetized rats, suggesting only a small effect on ecNOS in vivo, whereas AP-SeU had potent presser effects similar to those of L-NMA. We found that both AE-SeU and AP-SeU were unstable in aqueous solution at pH values above 6. Their disappearance from solution was accompanied by the appearance of a reductive species, probably free selenol. These findings suggest that AE-SeU and AP-SeU exert their inhibitory effects through intramolecular rearrangement to yield selenoethylguanidine and seleno-propylguanidine. Thus, selenoalkylguanidines are novel inhibitors of iNOS.

    Original languageEnglish (US)
    Pages (from-to)1139-1148
    Number of pages10
    JournalLife Sciences
    Volume58
    Issue number14
    DOIs
    StatePublished - Mar 1 1996

    Keywords

    • Aminoalkylselenoureas
    • Blood pressure
    • Nitric oxide synthase inhibitor
    • Selenoalkylguanidines

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Pharmacology, Toxicology and Pharmaceutics(all)

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