This program, which began more than 34 years ago, brings together investigators from multiple disciplines with an interest in the integrative aspects of circulatory function. Our major long-term goal has been to develop a quantitative analysis of circulatory dynamics and related control systems, including the kidneys, sympathetic nervous system, and endocrine systems. Two unique features of this program are: 1) it utilizes an integrative approach to understand complex interactions between multiple components of cardiovascular control systems, and 2) it focuses mainly on long-term control of the circulation because many cardiovascular diseases, such as hypertension, are manifestations of abnormal control mechanisms that develop slowly over long periods of time. The research proposed in this application is described by the titles of the specific projects as follows: I. Neurohumoral and Renal Mechanisms of Hypertension; this project will elucidate the neurohumoral and intrarenal mechanisms that contribute to the pathogenesis of obesity hypertension, which is of special relevance to human essential hypertension. II. Renal Control of Body Fluid Volumes and Circulatory Dynamics; this project will define the interaction between endothelin, oxidative stress and tumor necrosis factor in mediating altered renal-pressure natriuresis and hypertension in response to chronic reductions in uterine perfusion pressure in pregnant rats. III. Mechanisms of Salt-Sensitive Hypertension; this project will test the hypothesis that an increase in reactive oxygen species and a decrease in antioxidant mechanisms in the kidney play a major role in the development of salt-sensitive hypertension and associated renal injury. IV. Neural Mechanisms in Cardiorenal Regulation; this project will test the hypothesis that sustained activation of the baroreflex attenuates hypertension by suppressing renal sympathetic activity and promoting sodium excretion, and that these effects are mediated, in part, via suppression of the renin-angiotensin system. V. Role of Humoral Factors in Postmenopausal Hypertension; this project will test the hypothesis that post-menopausal hypertension in rats is caused by impaired renal-pressure-natriuresis mediated by activation of the renin-angiotensin system, and subsequent increases in endothelin and oxidative stress that are due, in part, to increases in serum testosterone. The total program, including core support services, provides a unique interdisciplinary approach toward developing an integrative analysis of long-term regulation of blood pressure and circulatory dynamics in several forms of experimental hypertension that have great relevance to human hypertension.
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