SYMPATHETIC NERVOUS SYSTEM ACTIVITY AND AGING IN THE RAT

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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.