We hypothesize that a central nervous system (CNS) """"""""set point"""""""" exists for the long-term control of mean arterial pressure (MAP), and many forms of hypertension are due to primary resetting of the """"""""CNS-MAP set point"""""""" by sodium retaining hormones such as aldosterone. We propose that this resetting occurs in response to hormonal activation of circumventricular organs (CVOs), which stimulate downstream sympathetic pathways by activation of amiloride-sensitive sodium channels. To test this hypothesis, we will use continuous 24hr/day recordings of MAP and either cardiac output or renal blood flow to characterize the temporal profile of systemic and renal hemodynamics, respectively in the DOCA-salt hypertensive rats.
In Specific Aim 1, we will compare the effects of lesions of the CVOs, the area postrema (AP) and subfornical organ (SFO), and the chronic intracerebroventricular administration of a mineralocorticoid receptor (MR) antagonist and an antagonist of amiloride-sensitive sodium channels (benzamil) on these hemodynamic profiles and Fos immunoreactivity of key central regulatory sites.
In Specific Aim 2, we will establish the effect of interruption of peripheral sympathetic pathways on the systemic and renal hemodynamic profiles using surgical and pharmacological methods, to determine the contribution of renal and """"""""non-renal"""""""" sympathetic targets to the long-term regulation of MAP and the development of DOCA-salt hypertension.
In Specific Aim 3, we will use a combination of frequency domain (i.e., power spectra and coherence analyses) and transfer function analyses on data collected in Specific Aims 1 and 2 to quantitatively determine the dynamic relative contributions of neurogenic and autoregulatory control of vascular tone in DOCA-salt hypertension. Taken together, this integrative physiological approach will advance our understanding of the neural mechanisms for long-term control of arterial pressure and pathogenesis of neurogenic hypertension. ? ?
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