Mycophenolic Acid, an Inhibitor of IMP Dehydrogenase That Is Also an Immunosuppressive Agent, Suppresses the Cytokine-Induced Nitric Oxide Production in Mouse and Rat Vascular Endothelial Cells

Transplantation. 1995 Nov 27;60(10):1143-8. doi: 10.1097/00007890-199511270-00015.

Abstract

Mycophenolic acid (MPA), an inhibitor of IMP dehydrogenase and de novo GTP biosynthesis, also has immunosuppressive activity. The effect of MPA on nitric oxide (NO) production by rodent brain vascular endothelial cells in culture was investigated. MPA inhibited NO production by mouse and rat brain endothelial cells that had been stimulated with a combination of interferon-gamma and tumor necrosis factor-alpha. The 50% inhibitory concentration (EC50) was in the range of 0.5-1.0 microM. However, MPA had no effect on basal NO production in mouse brain vascular endothelial cells. Brequinar, an inhibitor of de novo pyrimidine synthesis, had no effect on NO production in cytokine stimulated endothelial cells. Guanosine, which can act as a salvage pathway precursor for GTP biosynthesis, reversed the inhibitory effect of MPA in a dose-dependent fashion. We suggest that inducible NO synthase activity is dependent on GTP level and can be blocked by curtailing IMP dehydrogenase activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / pharmacology*
  • Endothelium, Vascular / metabolism*
  • Guanosine / pharmacology
  • IMP Dehydrogenase / antagonists & inhibitors*
  • Immunosuppressive Agents / pharmacology*
  • Mice
  • Mycophenolic Acid / pharmacology*
  • Nitric Oxide / biosynthesis*
  • Pteridines / pharmacology
  • Pterins*
  • Rats

Substances

  • Cytokines
  • Immunosuppressive Agents
  • Pteridines
  • Pterins
  • Guanosine
  • Nitric Oxide
  • sepiapterin
  • IMP Dehydrogenase
  • Mycophenolic Acid