Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
Circ Res. 2022 Aug 5;131(4):345-360. doi: 10.1161/CIRCRESAHA.122.320976. Epub 2022 Jul 15.
Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor-induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone.
We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN.
Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment-induced hypertension in conscious rats.
Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor-induced hypertension.
钙调神经磷酸酶抑制剂（包括环孢素和他克莫司[FK506]）会引起高血压，这是一种常见且严重的不良反应。虽然交感神经放电增加与钙调神经磷酸酶抑制剂诱导的高血压有关，但过量的交感神经输出的来源和潜在机制仍不清楚。钙调神经磷酸酶（蛋白磷酸酶-2B）在大脑中广泛表达，包括下丘脑室旁核（PVN），该核在调节交感血管张力方面起着关键作用。
我们旨在通过确定钙调神经磷酸酶抑制剂在 PVN 中增强突触 N-甲基-D-天冬氨酸（NMDA）受体活性是否会导致延长治疗后交感神经输出增加和持续高血压。
遥测记录显示，14 天内每天给予 FK506（3mg/kg）系统给药可使大鼠的动脉血压逐渐且明显升高，在停止 FK506 治疗后至少持续 7 天。相应地，FK506 的全身治疗显著降低了 PVN 和室周器官中的钙调神经磷酸酶活性，但不降低延髓头端腹外侧区（rostral ventrolateral medulla）中的钙调神经磷酸酶活性，并增加了 PVN 中的 NMDA 受体磷酸化水平和突触易位。免疫细胞化学标记显示钙调神经磷酸酶存在于 PVN 的交感前神经元中。脑片全细胞膜片钳记录显示，FK506 处理增加了 PVN 交感前神经元的基础放电活动；该增加被 NMDA 或α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂阻断。此外，FK506 处理还显著增加了 PVN 交感前神经元的突触前和突触后 NMDA 受体活性。此外，在麻醉大鼠的 PVN 内微注射 NMDA 或α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂可优先减轻 FK506 治疗引起的肾交感神经放电和血压升高。此外，在清醒大鼠中，全身性给予临床使用的 NMDA 受体拮抗剂美金刚可有效减轻 FK506 治疗引起的高血压。
我们的发现表明，PVN 中的正常钙调神经磷酸酶活性通过抑制 NMDA 受体活性来调节自主血管张力，这可能是治疗钙调神经磷酸酶抑制剂诱导的高血压的靶点。
