The kidneys participate in integrated volume regulation and circulatory control by providing afferent neurohumoral input regarding their current level of functioning, and by adjusting the rate of sodium excretion in response to the various effector signals which they receive. Although much information exists to define this efferent role of the kidneys, multiple other lines of evidence indicate the existence of additional, imprecisely described neurohumoral mechanisms that could participate in volume homeostasis by regulating Na. Experiments from our laboratory have indicated that one such previously unidentified mechanism involves the secretion of a peptide identical with or closely related to gamma- melanocyte stimulating hormone (gamma-MSH). The plasma concentration of immunoreactive (IR) gamma-MSH increases in association with the natriuresis that results from acute unilateral nephrectomy, and the peptide itself has a direct renal action to increase UNaV. The trigger for gamma-MSH release includes activation of carotid sinus baroreceptors, which provide input to the central nervous system; secretion of the peptide is also dependent on input from renal afferent nerves. Plasma IR-gamma-MSH concentration is also higher in rats ingesting high salt diet compared to rats on a low salt intake, suggesting physiologic regulation of the peptide. The projects described in this application will characterize in detail the factors regulating the secretion and metabolism of gamma-MSH-like peptides by (1) determining if stimulation of renal afferent nerves increases plasma IR- gamma-MSH activity; (2) characterizing the interaction between carotid sinus and renal afferents in the regulation of gamma-MSH secretion; (3) identifying the pituitary lobe responsible for gamma-MSH secretion and the factor(s) mediating its release in vitro; (4) quantitating the pituitary content of the precursor protein proopiomelanocortin (POMC) messenger RNA in rats ingesting diets high or low in sodium content, and relating this to simultaneous plasma and pituitary contents of gamma-MSH; (5) determining the metabolic clearance rate of gamma-MSH, before and after acute unilateral nephrectomy. These studies should in aggregate extend greatly our understanding of the biology of this peptide and its importance in volume homeostasis and circulatory control.