The revised application will test the hypothesis that angiotensin II (Ang II) mediates sustained increase in efferent renal sympathetic nerve activity (ERSNA) observed in rat models of congestive heart (CHF), cirrhosis due to common bile duct ligation (CBDL) and nephrotic syndrome (NS) by affecting specific central nervous system (CNS) regions involved in arterial/cardiac baroreflex regulation of ERSNA. Increased ERSNA, which mediates renal sodium retention in these edema forming models (wherein Ang II is increased), is dependent on abnormal arterial/cardiac baroreflex regulation of ERSNA. In normal rats, Ang II causes pressure independent resetting and decreased gain of arterial baroreflex control of heart rate. In CHF patients, treatment with ANG converting enzyme inhibitors causes resetting of arterial baroreflex control of heart rate. Major CNS areas and interconnecting pathways involved in arterial/cardiac baroreflex control of ERSNA contain Ang II (AT1 greater than AT2) receptors.
In Specific Aim 1 the applicant will determine the effect of administration of Ang II and Ang II receptor antagonists on ERSNA and its arterial/cardiac baroreflex control in normal rats. The information obtained in these experiments will be utilized in Specific Aim 2 to answer the question of: what is the effect of administration of Ang II antagonists on ERSNA and its arterial/cardiac baroreflex control in rats with CHF, CBDL and NS. Ang II and Ang II AT1 and AT2 receptor antagonists will be administered intravenously (iv), intracerebroventricularly (icv) and microinjected into candidate CNS areas. Endogenous Ang II will be chronically increased or decreased by low or high sodium diet. Validated edema forming rat models of CHF, CBDL and NS and normal rats will be studied. Arterial/cardiac baroreflex control of ERSNA will be examined in conscious rats using pharmacological agents to alter arterial pressure (arterial baroreflex) and iv volume administration/withdrawal to alter left heart filling pressures (cardiac baroreflex) while recording ERSNA. These studies will identify CNS areas where Ang II modulates arterial/cardiac baroreflex control of ERSNA and identify new mechanisms whereby Ang II antagonists exert beneficial effects on arterial and cardiac baroreflex control of ERSNA and, thereby, on renal sodium retention in renal sodium retaining edematous states.
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