Mechanisms of action of angiotensin-II on C1 neurons.

血管紧张素-II 对 C1 神经元的作用机制。

• 批准号: 7901594
• 负责人: Seth D DePuy
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901594
• 关键词: Address; Adrenergic Agents; Anesthesia procedures; Angiotensin II; Angiotensins; Blood Pressure; Brain; Brain Stem; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cells; Complement component C1s; Development; Disease; Foundations; Gene Targeting; Goals; Heart failure; Hyperactive behavior; Hypertension; In Vitro; Ion Channel; Label; Maintenance; Molecular; Mus; Neurons; Pathology; Pattern; Peptidyl-Dipeptidase A; Play; Population; Reflex action; Renin-Angiotensin System; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Slice; Subfamily lentivirinae; Up-Regulation; Vasomotor; adrenergic; base; in vivo; lentiviral-mediated; novel therapeutics; overexpression; public health relevance; receptor

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.

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，尽管其机制尚不清楚。延髓吻侧腹外侧（RVLM）的前交感神经元，特别是c1 -肾上腺素能细胞群，在交感血管运动张力的动态控制中起重要作用，可能是这种过度活跃的RAS的靶点。RVLM神经元的活动受到许多因素的调节，包括通常具有刺激作用的血管紧张素- 2 (Angll)，尽管这种调节的分子基础也尚未确定。在病理条件下，RAS（包括AT1受体和血管紧张素转换酶（ACE））的上调会产生前交感神经元的强直性激活，这种激活可以被受体拮抗剂或靶向基因破坏所消除。虽然有研究试图探讨Angll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Angll受体在多大程度上促进高血压仍有待确定。确定Angll在C1神经元中调节的重要离子电导（通过体外记录），并确定Angll受体在这些细胞上促进高血压状态的作用（通过慢病毒介导的，C1选择性的AT1过表达）是本提案的主要目标。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（高血压）是最普遍的心血管疾病之一，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发展和维持的具体机制的理解。