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， 神经系统（SNS）活动在休息时升高， SNS响应的幅度在急性“应激”期间增加。然而，在这方面， 这一概念的实验基础相当薄弱，因为 人类和动物都主要来自外周血 血浆去甲肾上腺素（NE）的测量，一个不精确的和潜在的 SNS活动的误导指数。拟议研究的目的将 研究急性物理和环境条件下SNS的调节作用， 成熟期的应激源（即，成年）和衰老（即，老）Fischer 344 大鼠这些动物比人类有几个重要的优势， 研究衰老对SNS活动的真实生物学影响：l） Fischer 344大鼠可以进行侵入性外科手术， 各种压力，不能安全地承担在人类; 2）与 随着年龄的增长，Fischer 344大鼠不会发生慢性心血管疾病， 疾病或体重增加; 3）由于这些动物是笼- 身体活动水平的局限性、显著性、年龄相关性差异 4）通过比较不同年龄组的动物， 是相同的菌株和性别，将有可能隔离的影响， 年龄本身对SNS功能的影响。为了验证假设， “交感神经亢进状态”随着年龄的增长而发展，一项综合性的实验研究表明， 将在这些动物中使用该方法。传出的SNS活动将 最初根据NE消耗的测量来估计（即， “周转”）率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量区域SNS多样性将成为 根据心脏、肾脏、肾上腺中NE消耗的速率确定， 肝脏和选定的骨骼肌，并从直接神经记录， 内脏、肾和肾上腺神经。因为年龄相关的变化 SNS行为可能是压力特定的，SNS活动将被确定 无论是在休息时还是在应对不同类型的急性应激时， 运动、非劳力性加热和缺氧（即，物理压力） 以及噪声和空气喷射刺激（即，环境压力）。以来 SNS对这些压力源的反应中与年龄相关的差异可能是 取决于刺激的强度，特定刺激的几个水平 将施加压力。除了生理问题 因此，这些研究应该具有重要的临床意义。为 例如，心脏病、肾病和高血压的发展是 被认为与静息时SNS活动升高和过度SNS有关 对急性应激源的反应。此外，这些疾病的患病率 病理状况随着年龄的增长而增加。的信息 从这些拟定的大鼠研究中获得的结果可能不直接适用 人类衰老;然而，这些研究的设计和 消除了许多在人类中普遍存在的混杂变量， 调查提供了另一种机制来评估年龄的影响， 对SNS功能的影响，在易衰老的动物中，但 易患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.