CYCLOSPORINE-INDUCED 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 activa tes the sympathetic nervous system is unknown. In T lymphocytes, the c ellular target of CsA and the macrolide immunosuppressant FK506 (as co mplexes with their endogenous cytoplasmic receptors, or immunophilins) is the Ca2+-calmodulin-dependent phosphatase calcineurin. The presenc e 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 ar terial pressure in rats are increased not only by CsA but also by FK50 6, which is structurally unrelated to CsA but inhibits the same calcin eurin-sensitive T-cell signaling pathway. In contrast, sympathetic act ivity and blood pressure are not increased by rapamycin, which forms a n immunophilin complex that does not bind calcineurin. Furthermore, Cs A- and FK506-induced sympathetic activation is attenuated for drug ana logues 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 f or extralymphoid (ie, neuronal) calcineurin in mediating immunosuppres sive drug toxicity.