Aging, the Baroreflex and Ang-(1-7) Receptors

衰老的典型特征是心血管调节的进行性损害，可能包括交感神经流出增加，迷走神经活动减少和血管扩张性降低。这些心血管变化还与肾素-血管紧张素系统(RAS)活性降低和胰岛素抵抗有关。项目4的总体目标是确定胰岛素和RAS的特定成分如何共同作用，作为心血管调节改变的主要贡献者，最终导致收缩压升高，并在衰老过程中加剧高胰岛素和高血糖。我们把重点放在对手身上 孤束核AngⅡ和Ang-(1-7)对交感和副交感神经流出的压力感受性反射控制的调节作用。这些研究将确定胰岛素如何通过延髓和下丘脑的心血管相关区域的作用，在自主神经流出的神经调节中与这两个肽协同或相反发挥作用。我们的实验战略将利用项目成员的综合专业知识来定义神经系统、肽受体途径和代谢成分，这些因素相互作用，以解释心血管调节的改变 在衰老过程中。具体目的1研究内源性Ang-(1-7)促进压力感受器反射功能的作用随着年龄的增长而减弱的假说，因此Ang II和胰岛素的作用是不相对立的，从而有助于减少心脏迷走神经流出、增加交感神经流出和高血压。实验将集中在NTS、下丘脑室旁核和延髓头端腹外侧作为大脑中ANG多肽和胰岛素在衰老过程中活动变化的关键部位。作为导致Ang多肽和胰岛素在衰老过程中作用改变的机制之一，特定目标2将检验脑组织中Ang-(1-7)随年龄增长而减少的假说，导致Ang II和胰岛素的功能或表达发生变化。由于受体构成了细胞中的关键功能成分 上述衰老过程中心血管功能的中枢调节，特定目标3将评估Ang II和Ang-(1-7)受体经历动态调节的假设，部分由这两种多肽组织水平的变化决定。特别是，拟议的实验将建立AT1b受体和MAS孤儿受体之间作为响应Ang-(1-7)的关键元件的功能相互作用。拟议的实验利用了脑血管紧张素原(ASrAogen)产生缺陷的转基因大鼠模型，我们发现在相同的时间范围内，Spraogue-Dawley大鼠没有表现出典型的与衰老相关的心血管损害。

Aging is typified by progressive impairments in cardiovascular regulation that may include increased sympathetic outflow, reduced vagal activity and reduced vascular distensibility. These cardiovascular changes are also associated with decreased activity of the renin-angiotensin (Ang) system (RAS) and insulin resistance. The over-arching goal of Project 4 is to define how insulin and specific components of the RAS act together as major contributors to altered cardiovascular regulation that ultimately lead to elevated systolic pressure and exacerbation of hyperinsulinemia and hyperglycemia during the course of aging. We focus on the opposing actions of Ang II and Ang-(1-7) in the nucleus of the solitary tract (nTS) to modulate the baroreceptor reflex control of sympathetic and parasympathetic outflow. The investigations will define how insulin may act in concert with or opposition to these two peptides in neural regulation of autonomic outflow via actions at cardiovascular relevant regions of the medulla oblongata and hypothalamus. Our experimental strategy will draw upon the combined expertise of members of the Project to define the neural systems, peptide receptor pathways, and metabolic components that interact to account for modification of cardiovascular regulation during aging. Specific Aim 1 investigates the hypothesis that the role of endogenous Ang-(1-7) to facilitate baroreceptor reflex function diminishes with aging, such that the effects of Ang II and insulin are unopposed, thereby contributing to reduced cardiac vagal outflow, enhanced sympathetic outflow, and hypertension. Experiments will focus on the nTS, paraventricular nucleus of the hypothalamus, and rostral ventrolateral medulla as key sites in the brain where actions of Ang peptides and insulin change during the aging process. As one mechanism contributing to the altered roles of Ang peptides and insulin during aging Specific Aim 2 will test the hypothesis that Ang-(1-7) in brain tissue diminishes with age, leading to a shift in the function or expression of Ang II and insulin. Since receptors constitute a key functional component in the aforementioned central regulation of cardiovascular function during aging, Specific Aim 3 will assess the hypothesis that Ang II and Ang-(1-7) receptors undergo a dynamic regulation, in part, determined by alterations in the tissue levels of these two peptides. In particular, the proposed experiments will establish the functional interactions that develop between the AT1b receptor and the mas orphan receptor as key elements responsive to Ang-(1-7). The proposed experiments utilize a transgenic rat model deficient in the production of brain angiotensinogen (ASrAogen), which we show does NOT exhibit cardiovascular impairments over the same time frame typically associated with aging in Sprague-Dawley rats.