Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells.

  • Marumo T
  • Nakaki T
  • Hishikawa K
 et al. 
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The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.

Author-supplied keywords

  • Amino Acid Oxidoreductases
  • Animals
  • Blotting, Northern
  • Cells, Cultured
  • Cyclosporine
  • Drug Combinations
  • Drug Stability
  • Enzyme Induction
  • Interleukin-1
  • Lipopolysaccharides
  • Muscle, Smooth, Vascular
  • Nitric Oxide Synthase
  • RNA, Messenger
  • Rats
  • Tacrolimus
  • Tumor Necrosis Factor-alpha
  • antagonists & inhibitors
  • cytology
  • drug effects
  • enzymology
  • genetics
  • metabolism
  • pharmacology

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  • T Marumo

  • T Nakaki

  • K Hishikawa

  • H Suzuki

  • R Kato

  • T Saruta

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