Aminoethylisoselenourea and related compounds are potent inhibition of the inducible isoform of nitric oxide synthase in vitro and in vivo

G. J. Southan, A. L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

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, 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 languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number3
StatePublished - 1996
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type II
nitric oxide synthase
Nitric Oxide Synthase
arginine
Arginine
Protein Isoforms
Rats
Guanidines
citrulline
guanidines
Citrulline
Macrophages
Endothelial cells
Blood pressure
endotoxins
Selenium
Nitrites
Endotoxins
nitrites
endothelial cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Aminoethylisoselenourea and related compounds are potent inhibition of the inducible isoform of nitric oxide synthase in vitro and in vivo. / Southan, G. J.; Salzman, A. L.; Szabo, Csaba.

In: FASEB Journal, Vol. 10, No. 3, 1996.

Research output: Contribution to journalArticle

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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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