Sympathetic control and hypertension via brainstem cannabinoid signaling

通过脑干大麻素信号传导的交感神经控制和高血压

• 批准号: 9124931
• 负责人: Andrei Derbenev
• 金额: $ 37.51万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124931
• 关键词: Address; Agonist; Animals; Area; Blood Pressure; Brain; Brain Stem; CNR1 gene; Cannabinoids; Cardiovascular Physiology; Cardiovascular system; Cells; Clinical; Coupled; Data; Development; Disinhibition; Endocannabinoids; GTP-Binding Proteins; Glutamates; Goals; Heart Rate; Hypertension; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Kidney; Lateral; Ligands; Light; Link; Measurement; Mediating; Medical; Microinjections; Mus; Nerve; Neural Pathways; Neuraxis; Neurons; Physiological; Play; Presynaptic Terminals; Rattus; Receptor Activation; Reflex action; Regulation; Renal function; Research Proposals; Role; Signal Transduction; Site; Spinal Cord; Structure; Suid Herpesvirus 1; Sympathetic Nervous System; Synapses; Telemetry; Testing; Tracer; Transgenic Mice; Vanilloid; Vasomotor; Viral; awake; base; blood pressure regulation; clinically significant; gamma-Aminobutyric Acid; hypertension control; hypertension treatment; in vivo; light effects; neural circuit; neurotransmission; novel therapeutics; optogenetics; patch clamp; receptor; response; treatment strategy

The overall goal of this research proposal is to assess the physiological significance of the endocannabinoids (eCBs) in the rostral ventrolateral medulla (RVLM) circuits which regulate cardiovascular function. The central nervous system is directly involved in the regulation of arterial blood pressure (ABP), largely through actions of the sympathetic nervous system on renal function and vasculature. The RVLM is a critical component in the central neural pathway since presympathetic RVLM neurons receive inputs from multiple brain areas and from the spinal cord, and thus mediate many cardiovascular reflexes. Hypertension may result from an imbalance between sympathetic vasomotor neuron activity and those cells that inhibit it. An increase in sympathetic nervous system activity is often associated with disinhibition of RVLM neurons; however, the underlying mechanisms remain unidentified. eCBs are endogenous ligands with a broad range of cardiovascular effects which activate: (1) G protein-coupled cannabinoid type-1 receptor (CB1R), (2) transient receptor potential vanilloid type 1 (TRPV1), or (3) both, indicating a duality of function. Our preliminary data demonstrate that activation of TRPV1 decreases both the excitability of presympathetic RVLM neurons as well as ABP and renal sympathetic nerve activity (RSNA). In addition, TRPV1 expressing neurons were identified in the lateral hypothalamus (LH) and these neurons project to the RVLM. Our multi-disciplinary approaches will use in vivo renal nerve and ABP recordings in rats following eCBs administration into RVLM, optogenetics in combination with telemetry measurements of ABP, fluorescent immunostaining, and in vitro patch-clamp recordings of synaptic currents in identified presympathetic RVLM neurons of transgenic mice. We will test the hypothesis that presympathetic RVLM neurons receive TRPV1 and CB1R expressing inhibitory inputs which determine the excitability of RVLM neurons and thus control ABP. Delineating these mechanisms of brainstem eCBs is essential to predict their impact on the central control of cardiovascular function caused by the activation of TRPV1 and/or CB1R. We believe our results will have clinical significance by providing direct evidence about the regulation of ABP by cannabinoids and will allow the development of novel therapeutic strategies for the treatment of hypertension.

该研究建议的总体目标是评估 内源性大麻素（ECB）的腹侧外侧髓质（RVLM）电路，调节心血管 功能。中枢神经系统直接参与了动脉血压（ABP）的调节， 在很大程度上，通过交感神经系统对肾功能和脉管系统的作用。 RVLM是 中央神经途径中的关键成分，因为可交响的RVLM神经元从 多个大脑区域和脊髓，因此介导了许多心血管反射。高血压 可能是由于交感神经X肌神经元活性与抑制它的细胞之间的不平衡引起的。一个 交感神经系统活动的增加通常与RVLM神经元的抑制有关； 但是，基本机制仍然不明。 ECB是内源配体，范围很大 激活的心血管效应：（1）G蛋白偶联的大麻素类型1受体（CB1R），（2）瞬时 受体电位香草素1型（TRPV1）或（3）都表明功能双重性。我们的初步数据 证明TRPV1的激活也降低了相同性RVLM神经元的兴奋性 作为ABP和肾交感神经活动（RSNA）。另外，在 下丘脑（LH）和这些神经元向RVLM投射。我们的多学科方法将 在ECBS施用后，在ECBS施用后，在大鼠中使用体内肾神经和ABP记录 与ABP，荧光免疫染色和体外斑块钳的遥测测量结合 在已鉴定出的转基因小鼠的鉴定出交感神经RVLM神经元中的突触电流记录。我们将测试 假设持续性RVLM神经元接受TRPV1和CB1R表达抑制性输入的假设 确定RVLM神经元的兴奋性，从而控制ABP。描述这些脑干的这些机制 ECB对于预测其对由此对心血管功能的中心控制的影响至关重要 TRPV1和/或CB1R的激活。我们认为我们的结果将通过直接提供临床意义 关于大麻素对ABP调节的证据，并将允许开发新的治疗性 治疗高血压的策略。