Despite clear clinical relevance in disease states such as hypertension and congestive heart failure, the mechanisms by which activity of the sympathetic nervous system can be chronically elevated are incompletely understood. A current hypothesis invokes an important role for humoral factors, such as angiotensin II (ANGII) and osmolality (OSM) in the generation of sympathetic tone. However, the mechanisms and sites at which ANG II and OSM act and interact to increase sympathetic tone have not been identified. The rostral ventrolateral medulla (RVLM) is a brain region that contains cells that tonically drive sympathetic preganglionic neurons, and the activity of these cells may be influenced by ANGII and OSM. Moreover, water deprivation is a state characterized by increases in both ANGII and OSM. Therefore, this proposal tests the hypothesis that in water deprived rats, increased ANGII and OSM interact to enhance the tonic level of sympathetic activity by a mechanism that includes actions in the RVLM. This hypothesis will be tested in part by determining the effects of ANGII AT1 blockade and decreases in OSM on efferent sympathetic nerve activity in conscious water deprived rats. Additional experiments will specifically examine the role of the RVLM by utilizing urethane-anesthetized rats for microinjections of ANGII and ANGII antagonists, as well as other major neurotransmitter agonists and antagonists.