The long term objectives of this proposal are to gain a greater understanding of the mechanism(s) whereby the brainstem influences the control of renal and other sympathetic function. Our initial studies of the influence of the rostral ventrolateral medulla (RVLM) have demonstrated that both spontaneous (SNA) and stimulus (SNCS) related nerve activity to the kidney are markedly attenuated in hypotensive (WKY) and hypertensive (SHR) rats, which suggests that an increased renal SNA may play a role in the development or maintenance of hypertension in SHR rats. The present studies are designed to evaluate mechanisms by which the RVLM influences SNA and SNCS. Although several studies have demonstrated that GABAergic neurons within the RVLM can modulate sympathetic nerve activity (SNA), relatively little is known about other classes of sympatho-modulatory neurons within the RVLM. Our preliminary observations suggest that an unidentified subpopulation of glutamate-containing neurons within the RVLM exert a powerful inhibitory influence on the tonic and phasic components of renal SNA. This will be examined in the present proposal. We will also examine the influence of the RVLM on sympathetic nerve activity in other cardiovascular control centers as well as on the renal sympatho-inhibition that occurs during water deprivation. To evaluate the mechanism(s) whereby the RVLM modulates SNCS, we will employ several immunohistochemical and pharmacological techniques including whole cell patch clamp recording, RT- PCR and in situ hybridization. These studies are designed to help gain a greater understanding of how the brain exerts an influence on the control of sympathetic outflow and hence the level of blood pressure. This understanding should aid in elucidating the pathophysiological mechanisms responsible for the development and/or maintenance of hypertension and/or may lead to the development of more effective treatment of essential hypertension.