One of the striking features of salt-sensitive hypertension is the blunted response of the reninangiotensin system (RAS) in patients when they switch from low to high salt intake compared with salt-resistant subjects. We recently develop a novel salt sensitive hypertensive animal model that mimics the response observed in salt-sensitive hypertensive patients. Our data show that degeneration of sensory nerves induced by neonatal capsaicin-treatment impairs natriuretic response to high salt intake, and renders the rats responsive to a salt load with a significant and sustained rise in blood pressure. Of key importance to this proposal, plasma renin activity and type 1 angiotensin II (Ang II) receptor (AT1) expression in the renal cortex and medulla are significantly higher in sensory denervated rats fed a high salt diet when compared with sensory nerve intact-rats fed a high salt diet. Moreover, increased superoxide production is evident in sensory denervated-rats fed a high salt diet, and blockade of the AT1 receptor prevents the development of hypertension in these rats. These observations have led to the working hypothesis of the present proposal which states that sensory neurotransmitters counteract the prohypertensive effect of the RAS via inhibition of expression of RAS components and suppression of Ang II-induced oxidative stress in the kidney. Four specific aims will test the hypotheses: 1) that specific receptors for sensory neurotransmitters colocalize with RAS components in the renal nephron; 2) that sensory neurotransmitters inhibit expression of RAS components in a segment-specific manner; 3) that sensory neurotransmitters reduce Ang II -induced oxidative stress in a segment-specific manner via suppression of NADH oxidase, and 4) that sensory neurotransmitters released from renal sensory nerves counteract the prohypertensive effect of Ang II via improvement of the pressure-natriuretic relationship. These studies represent a novel effort to define the dynamic interactions between these two powerful systems and to understand how they may synergistically modulate blood pressure homeostasis. The result of these studies may have important implications both for the designing of future epidemiological and genomic/genetic studies targeting on various components of the sensory nervous system and for the development of novel therapeutic agents that act selectively on the sensory nervous system for treatment of hypertension and end organ damage.