The long-term objectives of this study are to better understand the role of the brain in hypertension. Hypertension is a major contributor to health disparity among minorities and a major cause for both ischemic or hemorrhagic strokes and chronic brain injury. Currently, the causes for most cases of essential hypertension as well as changes in brain signal tranduction pathways during hypertension are not well understood. However, an aberration in neural blood-pressure control mechanisms is known to be necessary for the persistence of raised blood pressure. Melanocortins have been implicated in autonomic control of blood pressure with gamma-2-MSH demonstrating the highest potency in increasing blood pressure and heart rate. Previous studies have also demonstrated an increase in intracellular Ca2+ and protein kinase C (PKC) translocation in rat brain-stem synaptosomes treated with gamma-2-MSH. Modulation of the PKC signaling pathway by gamma-2-MSH was also observed in a brain-stem neuronal cell line transfected with a neural melanocortin receptor, MC3-R. This study will test the hypothesis that melanocortins function in autonomic neurons by modulating signal transduction systems that are coupled to specific neurotransmitter systems. The first aim is to identify changes in neural melanocortin signal transduction in stroke-prone spontaneous hypertensive rat (SHR-SP) brain. Hypothalamus and brain stem slices from SHR-SP and control Wistar Kyoto (WKY) rats will be treated with melanocortins in the presence of agonists for putative melanocortin-sensitive neurotransmitter systems (adrenergic, serotonergic and dopaminergic) and the phosphorylation patterns of total proteins and specific signal transduction components analyzed. Secondly, changes in second messenger molecules will be assayed using ELISA/RIA procedures. The second aim will seek to characterize signaling through the melanocortin 3-receptor (MC3-R) in vitro. Similar studies will be performed in MC3-R trasfected neuronal cells, followed by the analysis of expression and activation of protein kinase A (PKA), protein kinase B (PKB) and PKC SerFFhr kinases, upon treatment with gamma-2- MSH. This study will therefore provide important insights into the role and mechanism of neural melanocortin signaling system in autonomic functions and also identify neural signal transduction cascades that play a potential role in hypertension.