SYMPATHETIC NERVOUS SYSTEM ACTIVITY AND AGING IN THE RAT

有一种普遍的观点认为，随着年龄的增长，传出的同情 神经系统(SNS)活动在休息时会升高， 在急性“应激”期间，SNS反应的幅度会增加。然而， 这一概念的实验基础相当薄弱，因为 人类和动物都主要起源于外周 血浆去甲肾上腺素(NE)的测定--一种不精确和潜在的 误导性的SNS活跃度指数。拟议研究的目的是 将研究SNS在急性物理和环境中的调节 成人(即成人)和衰老(即老年人)的压力源344 老鼠。与人类相比，这些动物有几个重要的优势 研究衰老对社交网络活动的真正生物学影响：L) Fischer 344大鼠可以接受侵入性外科手术和 人类无法安全承受的各种应激源；2) 随着年龄的增长，Fischer 344大鼠不会患上慢性心血管疾病 疾病或体重增加；3)因为这些动物被关在笼子里- 有限的、显著的、与年龄相关的体力活动水平差异 不会发生；以及4)通过比较不同年龄段的动物 都是相同的菌株和性别，就有可能分离出影响 SNS功能上的年龄本身。来检验一个假设 “高交感状态”随年龄增长而发展，这是一项综合实验 将在这些动物身上采用这种方法。传出的SNS活动将 最初根据NE消耗的测量来估计(即， “周转”)在选定的交感神经支配的器官和 区域血液流动。后续研究将直接评估SNS活动 通过测量交感神经流出。区域SNS多样性将是 根据心脏、肾脏、肾上腺的去甲肾上腺素耗竭率， 肝脏和选定的骨骼肌以及来自 内脏神经、肾神经和肾上腺神经。因为与年龄相关的变化 SNS的行为可能是应激源特有的，SNS的活跃度将被确定 在休息和应对不同类型的急性压力时都是如此，包括 运动、非体力性发热和缺氧(即身体应激源) 以及噪音和空气喷射刺激(即环境应激源)。自.以来 SNS对这些应激源的反应与年龄相关的差异可能是 取决于刺激的强度，几个级别的特定 将施加压力。除了生理上的问题 提出，这些研究应该具有重要的临床意义。为 例如，心脏和肾脏疾病以及高血压的发展 被认为与休息时社交网络活动增加和社交网络夸张有关 对急性压力源的反应能力。此外，这些疾病的流行 病理情况随着年龄的增长而增加。这些信息 从这些拟议的研究中获得的对老鼠的研究可能不直接适用 然而，这些研究的设计和能力 消除人类中普遍存在的许多令人困惑的变量 调查为评估年龄的影响提供了另一种机制 在SNS功能上，在一只容易衰老但不容易衰老的动物身上 容易患上各种与衰老有关的疾病。

There is a widely held view that with advancing age efferent sympathetic nervous system (SNS) activity becomes elevated at rest and that the magnitude of the SNS response is increased during acute "stress". However, the experimental basis for this concept is rather weak because the data in both humans and animals have been derived primarily from peripheral measurements of plasma norepinephrine (NE), an imprecise and potentially misleading index of SNS activity. The purpose of the proposed studies will be to investigate SNS regulation during acute physical and environmental stressors in mature (i.e., adult) and senescent (i.e., older) Fischer 344 rats. These animals have several important advantages over the human for studying the true biological effects of aging on SNS activity: l) The Fischer 344 rat can be subjected to invasive surgical procedures and a variety of stressors that cannot be safely undertaken in humans; 2) With advancing age, Fischer 344 rats do not develop chronic cardiovascular diseases or increased body weight; 3) Because these animals are cage- confined, marked, age-associated differences in physical activity levels do not occur; and 4) By comparing animals within different age groups that are of the same strain and sex, it will be possible to isolate the effects of age per se on SNS function. To test the hypothesis that a "hypersympathetic state" develops with aging, a comprehensive experimental approach will be employed in these animals. Efferent SNS activity will initially be estimated from measurements of NE depletion (i.e., "turnover") rates in selected sympathetically-innervated organs and regional blood flows. Subsequent studies will assess SNS activity directly by measuring sympathetic neural outflow. Regional SNS diversity will be determined from rates if NE depletion in the heart, kidney, adrenal gland, liver and selected skeletal muscles and from direct neural recordings from the splanchnic, renal, and adrenal nerves. Because age-related changes in SNS behavior may be stressor-specific, SNS activity will be determined both at rest and in response to different types of acute stress including exercise, nonexertional heating, and hypoxia (i.e., physical stressors) and noise and air jet stimulation (i.e., environmental stressors). Since age-related differences in the SNS responses to these stressors may be dependent on the intensity of the stimulus, several levels of a particular stress will be applied. In addition to the physiological questions being posed, these studies should have important clinical relevance. For example, the development of heart and kidney disease and hypertension are thought to be linked to elevated SNS activity at rest and exaggerated SNS responsiveness to acute stressors. In addition, the prevalence of these pathological conditions increases with advancing age. The information gained from these proposed studies in rats may not be directly applicable to human aging; however, the design of these studies and the ability to eliminate many of the confounding variables prevalent in human investigations provides another mechanism to evaluate the effects of age on SNS function, in an animal that is susceptible to aging, but not susceptible to a variety of diseases associated with aging.