(Verbatim from the application): The sympathetic nervous system and the renin-angiotensin system regulate arterial blood pressure and fluid balance in a highly interdependent way. Angiotensin II (AngII) stimulates the sympathetic nervous system both within the central nervous system and at the interface between sympathetic nerve terminals and the effectors. Chronic exposure of animals to AngII yields a dose-and time-dependent increase in blood pressure, which mimics aspects of human hypertension. The basic premise of this application is that the emerging hypertension in response to chronic AngII exposure is accompanied by progressive changes in the relative contribution of the central and peripheral interaction between the sympathetic nervous system and blood pressure. We will test this premise by using novel experimental and mathematical techniques for quantifying the relationship between sympathetic nerve activity (SNA) and blood pressure in the conscious rat at rest, and in response to an acute behavioral challenge. We will couple these sensitive in vivo indicators with in vitro peripheral preparations, which are sensitive to the cellular effects of AngII. Our working hypothesis is that dynamic changes in the relationship between arterial blood pressure and sympathetic nervous system function result from dose-dependent, progressive exposure to AngII.
In Specific Aim 1, we will determine the distribution of power within the arterial blood pressure and renal sympathetic nerve activity power spectra, and the coherence between these two variables following dose-dependent progressive exposure to AngII. Additional studies will determine the dose-dependent effect of progressive exposure to AngII on sympathetic neurotransmission at peripheral sympathetic terminals innervating the kidney and mesenteric artery. Novel studies will determine the role of AngII stimulation of adipose-derived leptin in elevations in SNA and the evolving hypertension.
In Specific Aim 2, we will assess the dose-dependent effect of progressive exposure to AngII upon the pattern and magnitude of changes in SNA and blood pressure evoked by an acute behavioral challenge. Changes in the amplitude, onset latency and/or duration of the sudden burst of sympathetic activity in response to behavioral challenge will be used to assess the effects of exposure to AngII upon the central nervous system. Changes in the relationship between the sudden burst in sympathetic activity and the pressor response to behavioral challenge will be used to assess the effects of exposure to AngII upon the gain of the relationship between sympathetic nervous system activity and vascular smooth muscle contraction. The significance of this research relates to delineation of specific sites for mechanistic interaction between the renin-angiotensin system and the sympathetic nervous system in blood pressure control. Moreover, novel interactions between AngII and leptin in the control of blood pressure may relate to hypertension in the obese population.
