Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling.
Cyclosporine A (CsA)-induced hypertension appears to be caused in part by neurogenic vasoconstriction, but the mechanism by which CsA activates the sympathetic nervous system is unknown. In T lymphocytes, the cellular target of CsA and the macrolide immunosuppressant FK506 (as complexes with their endogenous cytoplasmic receptors, or immunophilins) is the Ca(2+)-calmodulin-dependent phosphatase calcineurin. The presence of calcineurin and its colocalization with immunophilin in the brain led us to hypothesize that the phosphatase also mediates CsA-induced sympathetic activation. We now report that sympathetic activity and arterial pressure in rats are increased not only by CsA but also by FK506, which is structurally unrelated to CsA but inhibits the same calcineurin-sensitive T-cell signaling pathway. In contrast, sympathetic activity and blood pressure are not increased by rapamycin, which forms an immunophilin complex that does not bind calcineurin. Furthermore, CsA- and FK506-induced sympathetic activation is attenuated for drug analogues possessing modest changes in molecular structure in a way that closely parallels the ability of each analogue to inhibit calcineurin-mediated T-cell signaling. These results implicate an important role for extralymphoid (ie, neuronal) calcineurin in mediating immunosuppressive drug toxicity.
Lyson
T
T
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9034.
Ermel
L D
LD
Belshaw
P J
PJ
Alberg
D G
DG
Schreiber
S L
SL
Victor
R G
RG
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors
D002148:Calmodulin-Binding Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D016559:Tacrolimus