Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension

钙调神经磷酸酶抑制剂致高血压的神经机制 项目摘要 我们项目的主要目标是确定中枢交感神经系统是如何参与 钙调神经磷酸酶抑制剂引起的高血压(CIH)。钙调神经磷酸酶抑制剂，包括环孢素和他克莫司 (FK506)，使移植医学发生了革命性的变化，大大延长了移植物的存活时间。然而，坚持不懈 高血压仍然是长期使用钙调神经磷酸酶抑制剂的主要不良反应。虽然 钙调神经磷酸酶抑制剂可以增加交感神经的活性，起到中枢交感神经的作用 制度在CIH的发展中被很大程度上忽视了。此外，之前关于神经机制的工作 CIH的研究重点是单次注射钙调神经磷酸酶抑制剂的急性效应。目前尚不清楚地点和地点 CIH中增加的交感神经流出是如何在大脑中产生的。下丘脑室旁核 核团(PVN)在高血压的发病机制中起重要作用，钙调神经磷酸酶(CaN)含量丰富 在室旁核中表达。最近的研究表明，α-2δ-1可以直接调节谷氨酸受体 中枢神经系统(NMDAR)活动。我们的初步研究表明，长期治疗 FK506诱导的动脉血压逐渐持续升高，甚至持续了很多天 在FK506停产后。此外，阻断NMDAR或抑制α2δ-1-NMDAR复合体在 经FK506治疗后，PVN可显著降低血压和增加交感神经放电。 根据我们强大的初步数据，我们建议检验延长治疗的总体假设 钙调神经磷酸酶抑制剂通过增强NMDAR增加对PVN前交感神经元的谷氨酸能输入 磷酸化和α2δ-1介导的突触NMDAR活性，导致交感神经持续增加 外流和高血压。我们将使用几种创新的体外和体内方法来定义持久性 神经可塑性涉及分子、细胞和系统水平的脑出血。我们建议的研究可望 解开交感血管运动持续增加的细胞和分子底物 在CIH的活动。这一新信息将极大地增加我们对脑出血神经机制的理解。 并使设计治疗这种情况的新策略成为可能。

Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension Project Summary The major goal of our project is to determine how the central sympathetic nervous system is involved in calcineurin inhibitor–induced hypertension (CIH). Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), have revolutionized transplant medicine and substantially prolonged graft survival. However, persistent hypertension remains a major adverse effect associated with long-term use of calcineurin inhibitors. Although calcineurin inhibitors can increase the sympathetic nerve activity, the role of the central sympathetic nervous system in the development of CIH has been largely overlooked. Also, previous work on the neural mechanisms of CIH has focused on the acute effect of a single injection of calcineurin inhibitors. It remains unclear where and how the augmented sympathetic outflow in CIH is generated in the brain. The hypothalamic paraventricular nucleus (PVN) plays an important role in the pathogenesis of hypertension, and calcineurin is abundantly expressed in the PVN. Recent studies indicate that α2δ-1 can directly regulate glutamate NMDA receptor (NMDAR) activity in the central nervous system. Our preliminary studies showed that long-term treatment with FK506 induced a gradual and sustained increase in arterial blood pressure, which persisted for many days even after FK506 was discontinued. Furthermore, blocking NMDARs or inhibiting the α2δ-1–NMDAR complex in the PVN profoundly reduced blood pressure and the sympathetic nerve discharges augmented by FK506 treatment. On the basis of our strong preliminary data, we propose to test the overall hypothesis that prolonged treatment with calcineurin inhibitors increases glutamatergic input to PVN presympathetic neurons by potentiating NMDAR phosphorylation and α2δ-1–mediated synaptic NMDAR activity, leading to a sustained increase in sympathetic outflow and hypertension. We will use several innovative in vitro and in vivo approaches to define the persistent neural plasticity involved in CIH at molecular, cellular, and system levels. Our proposed studies are expected to unravel the cellular and molecular substrates responsible for the sustained increase in sympathetic vasomotor activity in CIH. This new information will greatly increase our understanding of the neural mechanisms of CIH and enable the design of new strategies for treating this condition.