CENTRAL CONTROL OF SODIUM AND CARDIOVASCULAR HEMOSTASIS

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The long term objectives of this research project are to define the CNS sites and neurotransmitter systems regulating cardiovascular hemodynamics. The baroreflex is an important central system controlling blood pressure and is modulated by a number of sites in the brain. Sensitivity of the baroreflex is labile and altered in a number of experimental and/or pathological conditions. For example, baroreflex resetting is evident in hypertension, congestive heart failure, and during CNS hyperosmolality. The precise brain sites and neurotransmitter systems controlling baroreflex function have not been characterized. These studies will define the role of two CNS sites, the anteroventral third ventricle (AV3V) and the diagonal band of Broca (DBB), and two neurotransmitters, norepinephrine (NE) and angiotensin II (ang II) in control of baroreflex sensitivity. The proposed research will test the hypothesis that the AV3V and/or DBB contain nerve cell bodies which decrease baroreflex sensitivity during CNS hyperosmolality by stimulation of noradrenergic and/or angiotensinergic mechanisms. The Specific Aims will determine; 1) if cell bodies mediating baroreflex sensitivity are located in the AV3V and/or the DBB, 2) if NE in the AV3V and DBB mediate decreased baroreflex sensitivity to CNS hyperosmolality, 3) if ang II in the AV3V and DBB mediate decreased baroreflex sensitivity to CNS hyperosmolality, and 4) if ang II and NE interact in the AV3V and DBB to decreased baroreflex sensitivity. These specific aims will be achieved by measuring changes in blood pressure, heart rate, and nerve activity in lumbar, renal, adrenal, and splanchnic sympathetic nerves during stimulation of baroreceptor afferent fibers (aortic depressor nerve) and CNS microinjection of neural excitatory agents, neurotoxins, and/or specific pharmacological agonists and antagonists into the AV3V and DBB. In addition, in vivo microdialysis and radioenzymatic assay will be used to evaluate NE release, and c-Fos immunoreactivity used to determine the distribution of activated nerve cell is during baroreceptor afferent stimulation. Results from these studies will contribute to the long term objectives of this research project by characterizing CNS sites and neurotransmitters involved in cardiovascular regulation and baroreflex control of blood pressure, heart rate, and sympathetic nervous system activity. These studies will increase our understanding of central mechanisms which modulate baroreflex sensitivity and the contribution of the CNS to baroreflex resetting.