Mechanisms of action of angiotensin-II on C1 neurons.

描述（由申请人提供）：肾素-血管紧张素系统（RAS）存在于脑干的心血管调节中心，是高血压和心力衰竭的重要促成因素。RAS过度活跃被认为是这些疾病中常见的不适当的交感神经兴奋驱动的基础，尽管其机制仍不清楚。延髓头端腹外侧区（RVLM）的前交感神经元，特别是C1肾上腺素能细胞群，在交感血管紧张度的动态控制中起着重要作用，并且可能是这种过度活跃的RAS的靶点。RVLM神经元的活性受到许多因素的调节，包括血管紧张素-II（AngII），其通常是刺激性的，尽管这种调节的分子基础也没有被定义。在病理条件下，RAS（包括AT 1受体和血管紧张素转换酶（ACE））的上调产生交感前神经元的紧张性激活，可通过受体拮抗剂或靶向基因破坏消除。尽管研究试图阐明AngII受体在调节脑干神经元和促进高血压中的作用，但C1神经元表达的AngII受体对高血压的贡献程度仍有待确定。鉴定在C1神经元中由AngII调节的重要离子电导（通过体外记录）和确定这些细胞上AngII受体对促进高血压状态的贡献（通过慢病毒介导的AT 1的C1选择性过表达）是该提议的主要目标。这些研究的结果可以作为开发治疗这些病理的新治疗策略的基础。公共卫生相关性：高血压是最常见的心血管疾病之一，约占人口的33.6%。本文提出的研究将有助于促进我们对这种疾病的发展和维持所涉及的特定机制的理解。

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is present within the cardiovascular regulatory centers of the brainstem and is an important contributing factor to both hypertension and heart failure. RAS hyperactivity is thought to underlie much of the inappropriate sympathoexcitatory drive that is common to these diseases, though the mechanism is still unclear. The presympathetic neurons of the rostral ventrolateral medulla (RVLM), particularly the C1-adrenergic cell group, play an important role in the dynamic control of sympathetic vasomotor tone and are probable targets of this hyperactive RAS. Activity of the RVLM neurons is modulated by many factors including angidtensin-ll (Angll) which is generally stimulatory, though the molecular basis of this modulation is also not defined. Under pathological conditions, upregulation of the RAS, including AT1 receptors and angiotensin converting enzyme (ACE), produces a tonic activation of presympathetic neurons that can be abrogated by receptor antagonists or targeted gene disruption. Although studies have attempted to address the role of Angll receptors in regulating brainstem neurons and in promoting hypertension, the extent to which the Angll receptors expressed by the C1 neurons contribute to hypertension remains to be determined. Identifying the important ionic conductances that are modulated by Angll in C1 neurons (via in vitro recording) and determining the contribution of Angll receptors on these cells to promote the hypertensive state (via lentiviral-mediated, C1-selective overexpression of AT1) are the primary goals of this proposal. Results from these studies could serve as a foundation for the development of novel therapeutic strategies to treat these pathologies. PUBLIC HEALTH RELEVANCE: Hypertension (high blood pressure) is one of the most prevalent cardiovascular disorders, afflicting approximately 33.6% of the population. The research proposed herein will serve to advance our understanding of the specific mechanisms involved in the development and maintenance of this disease.