Sympathetic control and hypertension via brainstem cannabinoid signaling

这项研究提案的总体目标是评估 延髓头端腹外侧（RVLM）回路中的内源性大麻素（eCB）调节心血管 功能中枢神经系统直接参与动脉血压（ABP）的调节， 主要通过交感神经系统对肾功能和脉管系统的作用。RVLM是一个 中枢神经通路中的关键成分，因为前交感RVLM神经元接收来自 多个脑区和脊髓，从而介导许多心血管反射。高血压 这可能是由于交感血管神经元活动和抑制它的细胞之间的不平衡造成的。 交感神经系统活性增加通常与RVLM神经元的去抑制有关; 然而，其根本机制仍未查明。eCB是内源性配体，具有广泛的 心血管作用，激活：（1）G蛋白偶联大麻素1型受体（CB 1 R），（2）短暂 受体电位香草酸1型（TRPV 1），或（3）两者，表明功能的双重性。我们的初步数据 证明TRPV 1的激活也降低了前交感RVLM神经元的兴奋性 如ABP和肾交感神经活动（RSNA）。此外，TRPV 1表达神经元被鉴定为 外侧下丘脑（LH）和这些神经元投射到RVLM。我们的多学科方法将 在将eCB施用至RVLM后，在大鼠中使用体内肾神经和ABP记录， 结合ABP遥测、荧光免疫染色和体外膜片钳 在转基因小鼠的经鉴定的前交感RVLM神经元中记录突触电流。我们将测试 假设前交感RVLM神经元接受TRPV 1和CB 1 R表达抑制性输入， 确定RVLM神经元的兴奋性，从而控制ABP。描述脑干的这些机制 eCBs对于预测其对心血管功能中枢控制的影响至关重要， TRPV 1和/或CB 1 R的激活。我们相信我们的研究结果将具有临床意义， 关于大麻素调节ABP的证据，将允许开发新的治疗药物。 治疗高血压的策略。

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.