The mechanism of the inhibitory effect of polyamines on the induction of nitric oxide synthase role of aldehyde metabolites

Csaba Szabo, G. J. Southan, C. Thiemermann, J. R. Vane

Research output: Contribution to journalArticle

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Abstract

1. We have recently found that in the presence, but not in the absence, of foetal calf serum, spermine inhibits the production of nitric oxide (NO) in cultured J774.2 macrophages stimulated with bacterial endotoxin (lipopolysaccharide, LPS) or with γ-interferon (IFN), showing that polyamines may act as suppressants of NO-mediated immune functions. Here, we have studied the mechanisms and the specificity of this inhibitory action. 2. Other polyamines, as well as spermine, inhibit the formation of NO in cultured J774.2 macrophages, with the order of potency being spermine > spermidine >> putrescine = cadaverine. This inhibition of NO formation is not due to any cytotoxic effect of these agents for they neither reduced mitochondrial respiration nor increased the release of lactate dehydrogenase into the supernatant. 3. Spermine is not a direct inhibitor of the activity of iNOS in induced J774.2 cells as measured by its lack of effect on the conversion of L-arginine to L-Citrulline in homogenates. Neither spermine, nor its metabolites, interfere with the production of nitrite from NO or act as scavengers of NO. Thus, spermine is an inhibitor of the induction of iNOS. 4. Spermine inhibits nitrite formation in the presence of foetal, newborn or adult bovine serum, but not rat or human serum. 5. The effect of spermine on nitrite production can be prevented by isoniazid, hydrazine or hydroxylamine, inhibitors of spermine oxidase, as well as by phenylhydrazine, an aldehyde inhibitor. We have, therefore, tested the effects of spermine dialdehyde on malon dialdehyde on the induction of iNOS. Spermine dialdehyde (SDA, 10-5 M) inhibits nitrite formation by IFN-activated J774.2 cells in the absence of serum when given as a pretreatment but not when given 6 h after stimulation. In contrast malon dialdehyde was ineffective. Thus, aldehyde metabolites of spermine, such as SDA, account for the inhibitory effect of polyamines on the induction of NOS in vitro. 6. The inhibitory effect of polyamines on iNOS induction appears to be fairly specific to iNOS, for spermine does not inhibit LPS-induced production of prostaglandin F(2α) or tumour necrosis factor.

Original languageEnglish (US)
Pages (from-to)757-766
Number of pages10
JournalBritish Journal of Pharmacology
Volume113
Issue number3
StatePublished - 1994
Externally publishedYes

Fingerprint

Spermine
Polyamines
Aldehydes
Nitric Oxide Synthase
Nitric Oxide
Nitrites
hydrazine
Serum
Interferons
Lipopolysaccharides
Macrophages
Cadaverine
Citrulline
Hydroxylamine
Putrescine
Spermidine
Isoniazid
Cytotoxins
Prostaglandins F
L-Lactate Dehydrogenase

Keywords

  • Cadaverine
  • Cancer
  • Cyclo-oxygenase
  • Immunosuppression
  • Interferon
  • Lipopolysaccharide
  • Nitric oxide
  • Pregnancy
  • Putrescine
  • Spermidine
  • Spermine
  • Spermine dialdehyde
  • Tumour necrosis factor

ASJC Scopus subject areas

  • Pharmacology

Cite this

The mechanism of the inhibitory effect of polyamines on the induction of nitric oxide synthase role of aldehyde metabolites. / Szabo, Csaba; Southan, G. J.; Thiemermann, C.; Vane, J. R.

In: British Journal of Pharmacology, Vol. 113, No. 3, 1994, p. 757-766.

Research output: Contribution to journalArticle

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