The role of the sympathetic nervous system in the pathogenesis of salt- dependent hypertension remains poorly understood. Animal and clinical studies suggest that sympathetic nerve activity (SNA) is chronically suppressed when dietary sodium chloride (NaCl) is increased. The overall objective of this proposal is to gain a better understanding of the mechanisms responsible for chronic, NaCl-induced, sympathoinhibition. I propose that increased NaCl intake activates splanchnic osmoreceptors which stimulates the release of arginine vasopressin (AVP). Circulating AVP then decreases SNA by a direct affect on the area postrema, a hindbrain structure deficient of a blood/brain barrier. It is proposed that this sympathoinhibitory response to AVP is """"""""gated"""""""" by arterial and cardiopulmonary baroreceptors such that a decrease in tonic baroreceptor activity inhibits the reflex. It is predicted that impairment of the NaCl-hormonal-sympathetic reflex will result in salt-dependent hypertension in experimental animals. There are three Specific Aims to this proposal. The first Specific Aim is to investigate the role of the hormonal-sympathetic reflex in the acute response of SNA to intragastric hypertonic NaCl. Both renal and lumbar SNA will be measured directly in chloralose anesthetized rats before and during intragastric saline infusion. Experiments will be conducted in rats with various surgical and pharmacological interventions of the reflex pathway. The second Specific Aim will be to determine the role of the hormonal-sympathetic-reflex in the chronic regulation of body fluid balance and arterial pressure during increased dietary NaCl. Rats will be chronically instrumented for measurements of arterial pressure and heart rate. The cardiovascular, autonomic and fluid balance responses to increased dietary NaCl will be determined in normal rats and rats with surgical or pharmacological impairment of the reflex. Finally, the third Specific Aim will be to establish whether the reflex regulates arterial pressure by controlling renal or vascular function. Plasma volume and systemic hemodynamics will be measured before and during increased dietary salt in rats with surgical and pharmacological impairment of the reflex. The results from these studies will further our understanding of mechanisms of cardiovascular and body fluid homeostasis during increases in NaCl intake. In addition, these studies will provide essential new data which will be useful in understanding the pathogenesis of salt- dependent hypertension.
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