NEUROHORMONAL MECHANISMS IN HYPERTENSION

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The multidisciplinary research efforts of this Program Project continue to focus on the elucidation of the cellular, biochemical, and functional mechanisms by which the renin-angiotensin- aldosterone system participates in the control of cardiovascular function and the pathogenesis of arterial hypertension. The broad objective of the proposed studies is to explore the biochemical, neuroanatomical, and physiological substrate for the central actions of angiotensin II (Ang II), its congener peptides, and aldosterone on the neuronal circuits of the medulla oblongata and hypothalamus involved in tonic and reflex regulation of cardiovascular function, and integration of neural and humoral factors that maintain extracellular fluid volume and composition. Specifically, we seek to determine the mechanism(s) by which angiotensin peptides (Angs) influence neuronal pathways in the medulla involved in cardiovascular regulation by establishing: 1) the capacity of Angs to alter the electrophysiological characteristics of neurons in an in vitro slice of the dorsomedial medulla (DMM); 2) the ability of Angs to alter the release of substance P, norepinephrine, and serotonin from DMM slices and nodose ganglion explants; 3) the transport mechanisms and functional significance of Ang binding sites in the DMM and cervical vagus; and 4) the anatomical, electrophysiological, and neurohormonal mechanisms involved in the pressor actions of Ang II in the ventrolateral medulla. In addition, we will investigate whether the differing central actions of Ang II are explained by: 1) the location of Ang receptors within vs. outside the blood-brain or cerebrospinal fluid (CSF)-brain barriers, 2) the presence of molecular variants of Angs that act on a common receptor or subpopulations, or 3) a combination of both possibilities. These alternatives will be investigated by determining: 1) the expression and regulation of Ang II and its fragments, and those processing enzymes that may contribute to the generation of multiple biologically active Angs; 2) structure-activity relationships between Ang II and its heptapeptide fragments (Ang- (1-7), Ang-(2-8) that determine receptor binding and impart different roles in neuronal or neurosecretory events: and 3) the physiological mechanisms by which Ang II, Ang-(1-7), and Ang-(2-8) participate in the relate of vasopressin from the neurohypophysis and modulation of the reflex control of arterial pressure by the DMM. Finally, we will examine the hemodynamic and neurohumoral effects of aldosterone given into the CSF in sub-pressor amounts to establish the role of this steroid in central cardiovascular regulation. The proposed studies will take advantage of the multidisciplinary expertise of our group to uncover new information about the neurohormonal mechanisms that regulate homeostasis and can produce hypertension.