Immunosuppressants enhance superoxide radical/nitric oxide-dependent dexamethasone suppression of ischemic paw edema in mice.
A possible new common action of immunosuppressants, besides suppression of the genes for cytokines like interleukin-2, was investigated in in vivo models. Dexamethasone (0.1 mg/kg, s.c.) failed to suppress ischemic paw edema in mice 1 h after its injection, but maximal suppression was achieved at 3 h (20%) whereafter the suppression decreased at 6 and 18 h (11% and 10%). Pretreatment with oral FK506 (chemical name is recently donated as tacrolimus, 0.1 mg/kg) resulted in 38%, 52%, 23% and 17% suppression at 1, 3, 6 and 18 h, respectively. Cyclosporin A (1 mg/kg), rapamycin (0.1 mg/kg) and deoxyspergualin (1 mg/kg) showed a similar pattern of suppressions after dexamethasone. Transforming growth factor-beta1 (TGF-beta1, 0.3 microg/kg, i.p.) maintained the suppression elicited by an immunosuppressant (42-58%) at 6 h after dexamethasone, whereas transforming growth factor-beta1 and/or an immunosuppressant were not suppressive. Suppression, irrespective of the agent that elicited it, was blocked by nitric oxide (NO) synthase inhibitor, anti-oxidant enzymes and cycloheximide. Endogenous nitric oxide or oxyradicals are essential for the action of dexamethasone in vivo. The four immunosuppressants bound to specific heat-hock proteins (hsp) in the glucocorticoid receptor complex and might enhance the synthesis of anti-inflammatory protein(s).
Oyanagui
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2nd Pharmacology, Drug Development Laboratories I, Fujisawa Pharmaceutical Co., Kashima, Osaka, Japan.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use*; D004347:Drug Interactions; D004487:Edema / Q000188:drug therapy / Q000503:physiopathology; D006614:Hindlimb; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000494:pharmacology; D013481:Superoxides / Q000494:pharmacology; D016559:Tacrolimus / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D013481:Superoxides; D009569:Nitric Oxide; D003907:Dexamethasone; D016572:Cyclosporine; D016559:Tacrolimus