Lyson T, Ermel L D, Belshaw P J, Alberg D G, Schreiber S L, Victor R G
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9034.
Circ Res. 1993 Sep;73(3):596-602. doi: 10.1161/01.res.73.3.596.
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.
环孢素A（CsA）诱导的高血压似乎部分是由神经源性血管收缩引起的，但CsA激活交感神经系统的机制尚不清楚。在T淋巴细胞中，CsA和大环内酯类免疫抑制剂FK506（与其内源性胞质受体或亲免素形成复合物）的细胞靶点是钙调神经磷酸酶，一种依赖于钙调蛋白的磷酸酶。大脑中存在钙调神经磷酸酶及其与亲免素的共定位使我们推测该磷酸酶也介导CsA诱导的交感神经激活。我们现在报告，大鼠的交感神经活动和动脉血压不仅会因CsA升高，也会因FK506升高，FK506在结构上与CsA无关，但抑制相同的钙调神经磷酸酶敏感的T细胞信号通路。相比之下，雷帕霉素不会升高交感神经活动和血压，雷帕霉素形成的亲免素复合物不结合钙调神经磷酸酶。此外，对于分子结构有适度变化的药物类似物，CsA和FK506诱导的交感神经激活会减弱，其减弱方式与每种类似物抑制钙调神经磷酸酶介导的T细胞信号传导的能力密切平行。这些结果表明，淋巴外（即神经元）钙调神经磷酸酶在介导免疫抑制药物毒性中起重要作用。
