TY - JOUR
T1 - Aminoethylisoselenourea and related compounds are potent inhibition of the inducible isoform of nitric oxide synthase in vitro and in vivo
AU - Southan, G. J.
AU - Salzman, A. L.
AU - Szabó, C.
PY - 1996
Y1 - 1996
N2 - 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.
AB - 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.
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M3 - Article
AN - SCOPUS:33749120487
SN - 0892-6638
VL - 10
SP - A438
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -