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Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow
Circulation Research ( IF 16.5 ) Pub Date : 2022-07-15 , DOI: 10.1161/circresaha.122.320976
Jing-Jing Zhou 1 , Jian-Ying Shao 1 , Shao-Rui Chen 1 , Hui-Lin Pan 1
Affiliation  

Rationale: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.Objective: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.Methods and Results: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.Conclusions: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.

中文翻译:

钙调神经磷酸酶控制下丘脑 NMDA 受体活性和交感神经流出

理由:高血压是钙调神经磷酸酶抑制剂(包括环孢素和他克莫司 (FK506))的常见且严重的不良反应。尽管交感神经放电增加与钙调神经磷酸酶抑制剂引起的高血压有关,但交感神经流出过多的来源和潜在机制仍然难以捉摸。钙调神经磷酸酶(蛋白磷酸酶-2B)在大脑中广泛表达,包括下丘脑的室旁核 (PVN),它在调节交感血管舒缩张力方面发挥着重要作用。 目的:我们确定长期使用钙调神经磷酸酶抑制剂治疗是否会导致交感神经输出升高通过增强 PVN 中的突触 N-甲基-D-天冬氨酸 (NMDA) 受体活性来抑制和持续性高血压。方法和结果:遥测记录显示,全身给予 FK506(每天 3 mg/kg)14 天会引起逐渐而深刻的血压升高。大鼠动脉血压升高,在停止 FK506 治疗后持续至少 7 天。相应地,FK506全身治疗显着降低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的活性,并增加PVN中NMDA受体的磷酸化水平和突触运输。免疫细胞化学标记显示钙调神经磷酸酶在 PVN 的交感前神经元中表达。脑切片中的全细胞膜片钳记录显示,FK506 治疗增加了 PVN 前交感神经元的基线放电活动;这种增加被 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 治疗显着增加了 PVN 交感前神经元的突触前和突触后 NMDA 受体活性。此外,将 NMDA 或 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体拮抗剂显微注射到麻醉大鼠的 PVN 中,优先减弱 FK506 治疗引起的肾交感神经放电和血压升高。此外,全身给药美金刚(一种临床使用的 NMDA 受体拮抗剂)可有效减弱 FK506 治疗引起的清醒大鼠高血压。结论:我们的研究结果表明,PVN 中正常的钙调神经磷酸酶活性通过抑制 NMDA 受体活性来组成性地限制交感血管舒缩张力,从而抑制交感血管舒缩张力。可能是治疗钙调神经磷酸酶抑制剂引起的高血压的目标。
更新日期:2022-07-15
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