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, amlnoethylisoselenourea (AE-SeU), and its homologue, amino-propylisoselenourea (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 (EC5o = 1.1, and 0.1 uM, respectively) greater than that of NG-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 (EC60 values = 104, 15, and 16 uM, 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 ECso value for L-NMA was 160 uM. 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 mo, 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. Thus, AE-SeU and AP-SeU exert their inhibitory effects through intramolecular rearrangement to yield selenoethylguanidlne and seleno-propylguanidine.
|Original language||English (US)|
|State||Published - Dec 1 1996|
ASJC Scopus subject areas
- Molecular Biology