Non-enzymatic production of nitric oxide (NO) from NO synthase inhibitors

Leonid L. Moroz, Shong Wan Norby, Lou Ann Cruz, Jonathan V. Sweedler, Rhanor Gillette, Robert B. Clarkson

Research output: Contribution to journalArticlepeer-review


The gaseous signal molecule, nitric oxide (NO(·)), is generated enzymatically by NO synthase (NOS) from L-arginine. Overproduction of NO contributes to cell and tissue damage as sequelae of infection and stroke. Strategies to suppress NO synthesis rely heavily on guanidino-substituted L-arginine analogs (L-NAME, L-NA, L-NMMA, L-NIO) as competitive inhibitors of NOS, which are often used in high doses to compete with millimolar concentrations of intracellular arginine. We show that these analogs are also a source for non-enzymatically produced NO. Enzyme-independent NO release occurs in the presence of NADPH, glutathione, L-cysteine, dithiothreitol and ascorbate. This non-enzymatic synthesis of NO can produce potentially toxic, micromolar concentrations of NO and can oppose the effects of NOS inhibition. NO production driven by NOS inhibitors was demonstrated ex vivo in the central nervous and peripheral tissues of gastropod molluscs Aplysia and Pleurobranchaea using electron paramagnetic resonance and spin-trapping techniques. These results have important implications for therapeutic regulation of NO homeostasis.

Original languageEnglish (US)
Pages (from-to)571-576
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number3
StatePublished - Dec 30 1998

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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