Suppression of inducible nitric oxide generation by agmatine aldehyde: Beneficial effects in sepsis

Joseph Satriano*, Doron Schwartz, Shunji Ishizuka, Mark J. Lortie, Scott C. Thomson, Francis Gabbai, Carolyn J. Kelly, Roland C. Blantz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

The induction of inducible nitric oxide synthase (iNOS) serves an important immuno-protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences. Delineation of the mechanisms that can downregulate iNOS-generated NO in inflammation could have therapeutic relevance. Here we show that agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations. This effect was not cell type specific. Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AIdDH) activities are also representative of inflammatory settings. Increasing the conversion of agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AIdDH activity increases the inhibitory effects of agmatine in an additive fashion. Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of agmatine, as did the addition of AIdDH or reacting aldehydes with phenylhydrazine. We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of agmatine in vivo. Endotoxic rats administered agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis. Agmatine treatment also increased the survival of LPS treated mice. Our data demonstrate the capacity of agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of agmatine in a model of endotoxic shock. How agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed.

Original languageEnglish
Pages (from-to)313-320
Number of pages8
JournalJournal of Cellular Physiology
Volume188
Issue number3
DOIs
StatePublished - 2001
Externally publishedYes

Funding

FundersFunder number
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK045346

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