Intermittent Hypoxia Enhances Neuropeptide Y Synthesis in Adrenal Medulla via Reactive Oxygen Species‐dependent Alterations in Precursor Peptide Processing

Obstructive sleep apnea which entails recurrent episodes of intermittent hypoxia (IH) often leads to cardiovascular abnormalities. Neuropeptide Y (NPY), a sympathetic neurotransmitter which co‐localizes with norepinephrine in the adrenal medulla (AM), has been implicated in blood pressure regulation during persistent stress. Here, we investigated whether IH alters NPY synthesis in the rat AM and examined the role of ROS signaling in NPY synthesis during IH. IH increased NPY‐like immunoreactivity in many dopamine‐β‐hydroxylase expressing chromaffin cells with a concomitant increase in preproNPY mRNA and protein. The activity of proNPY processing enzymes was higher in IH treated rats compared to normoxic controls. This increase was due, in part, to elevated protein expression and increased proteolytic processing. IH is associated with increased oxidative stress in AM and antioxidant treatment reversed IH‐induced increases in ROS, preproNPY and proNPY processing. IH treatment increased blood pressure and antioxidants as well as inhibition of NPY amidation prevented this response. These findings suggest that IH‐induced elevation in NPY expression in the rat AM is mediated by ROS dependent augmentation of preproNPY mRNA expression and proNPY processing and contributes to IH‐induced elevation of blood pressure (Supported by HL‐89616 and HL‐90554).