Neural Mechanisms of Calcineurin Inhibitor-Induced Hypertension

钙调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 钙调神经磷酸酶诱导的高血压（CIH）。钙调磷酸酶抑制剂，包括环孢素和他克莫司 （FK 506），彻底改变了移植医学，并大大延长了移植物存活。然而，执着 高血压仍然是与长期使用钙调磷酸酶抑制剂相关的主要副作用。虽然 钙调神经磷酸酶抑制剂可增加交感神经活动，作用于中枢交感神经 在CIH的发展中，系统在很大程度上被忽视了。同时，以前对神经机制的研究 CIH的研究集中在单次注射钙调磷酸酶抑制剂的急性效应上。目前还不清楚在哪里， CIH中增强的交感神经流出如何在大脑中产生。下丘脑室旁 室旁核（PVN）在高血压的发病机制中起重要作用， 在PVN中表达。最近的研究表明α2δ-1可直接调节谷氨酸NMDA受体 （NMDAR）在中枢神经系统中的活性。我们的初步研究表明， FK 506诱导动脉血压逐渐持续升高，甚至持续多日。 在FK 506停药后。此外，阻断NMDAR或抑制α2δ-1-NMDAR复合物可使NMDAR的活性降低。 PVN显著降低血压，FK 506处理增强了交感神经放电。 在我们强有力的初步数据的基础上，我们建议检验长期治疗 钙调磷酸酶抑制剂通过增强NMDAR增加对PVN前交感神经元的神经递质输入 磷酸化和α2δ-1介导的突触NMDAR活性，导致交感神经系统的持续增加。 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的 神经可塑性在分子、细胞和系统水平上参与CIH。预计我们的研究将 解开交感神经血管扩张持续增加的细胞和分子底物 在CIH的活动。这些新的信息将大大增加我们对CIH神经机制的理解 并能设计出治疗这种疾病的新策略。

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.