Humans, experiencing chronic intermittent hypoxia (CIH), are prone to develop hypertension. Previous studies showed that rats and mice exposed to CIH have increased blood pressure, elevated circulating catecholamines (CA) and increased levels of vasoactive substances including norepinephrine and neuropeptide Y (NPY) in the adrenal medulla. To begin to define the mechanism(s) by which CIH evokes cardiovascular changes, we propose to test the following interlinked hypotheses: i) CIH facilitates the synthesis and stimulus-evoked release of NPY;ii) Exogenously released NPY, in turn, via activation of NPY receptor subtypes and the downstream G-protein mediated signaling cascade contributes to CIH-induced increases in CA release, and iii) CIH-evoked functional interaction between NPY and CA in the sympathetic nervous system contributes to cardiovascular changes elicited by CIH. These hypotheses will be tested in the adrenal medulla of rats exposed to CIH. In Aim 1, the effects of CIH on the synthesis of bioactive NPY both at the mRNA (preproNPY) and at the peptide levels and the potential contribution of peptidylglycine a-amidating monooxygenase (PAM) in CIH-induced alterations in NPY levels will be assessed. In Aim 2, the effects of CIH on stimulus-evoked NPY release and the role of cytosolic calcium in eliciting this response will be determined. Studies in Aim 3 will examine the critical role(s) of NPY Y receptors (Y1 and Y2) and G-protein mediated cell signaling in CIH-induced facilitation of CA release by hypoxia. To delineate the potential contribution of NPY receptor subtypes, the effects of NPY receptor subtype specific antagonists and targeted deletion of NPY receptor subtypes on CIH-evoked changes in CA release will be assessed. Studies in Aim 4 are designed to assess the direct and/or indirect contributions of NPY and its receptor subtypes and PAM to CIH-evoked cardiovascular changes in unanesthetized, awake animals. It is anticipated that the proposed studies will provide new mechanistic insights into CIH-evoked functional alterations in the peripheral sympathetic nervous system and aid in the identification of novel therapeutic targets for effective intervention of cardiovascular abnormalities associated with recurrent apneas. PUBLIC HEALTH RELEVANCE. Sleep-disordered breathing with recurrent apneas is a major cause of morbidity and mortality in the United States population, affecting an estimated 18 million people. Patients with chronic intermittent hypoxia (CIH) caused by sleep apnea have a greatly increased risk for the development of systemic hypertension. The mechanism(s) by which CIH associated with recurrent apneas are initiated leading to cardio-respiratory morbidity, however, are not fully understood. The proposal aims to elucidate the role of functional interactions between two potent vasoactive substances such as neuropeptide Y and catecholamines in the peripheral sympathetic nervous system in CIH-evoked elevation in blood pressure. These studies are expected to provide new therapeutic targets for alleviating the cardiovascular morbidity associated with recurrent apneas.