Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells.
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.
Marumo
T
T
Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan.
Nakaki
T
T
Hishikawa
K
K
Suzuki
H
H
Kato
R
R
Saruta
T
T
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004338:Drug Combinations; D004355:Drug Stability; D004790:Enzyme Induction / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D019001:Nitric Oxide Synthase; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004338:Drug Combinations; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D016559:Tacrolimus