FK506 promotes adenosine release from endothelial cells via inhibition of adenosine kinase

The immunosuppressants, cyclosporin A and tacrolimus (FK506) induce an increase in plasma levels of adenosine and mimic ischemic preconditioning. However, the mechanism of action of the two drugs on adenosine metabolism is not clear. Since inhibition of adenosine kinase promotes an increase in endog...

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Bibliographic Details
Published in:European journal of pharmacology 2001-08, Vol.425 (2), p.85-93
Main Authors: Hwang, Kwan-Ki, Hall, Carolyn S, Spielman, William S, Sparks, Harvey V
Format: Article
Language:English
Subjects:
Adenosine
Adenosine - metabolism
Adenosine kinase
Adenosine Kinase - antagonists & inhibitors
Adenosine Kinase - metabolism
Animals
Biological and medical sciences
Biological Transport - drug effects
Cardiovascular system
Cells, Cultured
Endothelial cell
Endothelium - drug effects
Endothelium - metabolism
Enzyme Inhibitors - pharmacology
FK506
Immunomodulators
Medical sciences
Miscellaneous
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - metabolism
Pharmacology. Drug treatments
Rats
Sirolimus - pharmacology
Tacrolimus - pharmacology
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Summary:The immunosuppressants, cyclosporin A and tacrolimus (FK506) induce an increase in plasma levels of adenosine and mimic ischemic preconditioning. However, the mechanism of action of the two drugs on adenosine metabolism is not clear. Since inhibition of adenosine kinase promotes an increase in endogenous adenosine release, we tested a hypothesis that FK506 induces adenosine release via inhibition of adenosine kinase activity. In cultured endothelial cells, FK506 enhanced release of tracer adenosine and inhibited uptake of tracer adenosine. It also reduced adenosine kinase activity of the cell membrane fraction. In addition, FK506 does not inhibit membrane transport of tracer adenosine. These observations indicate that FK506 inhibits in situ adenosine kinase activity in endothelial cells. Other cell signaling inhibitors were found to inhibit adenosine uptake via inhibition of adenosine transport. In conclusion, FK506 promotes adenosine release from endothelial cells by a novel mechanism involving inhibition of adenosine kinase activity associated with the membrane.
ISSN:0014-2999
1879-0712
DOI:10.1016/S0014-2999(01)01179-7