neuropeptide-y and Sleep-Apnea-Syndromes

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the alpha-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O(2)-sensitive peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O(2) for 15 s followed by 21% O(2) for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of alpha-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM ( approximately 1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases V(max) but has no effect on K(m). IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem.

Topics: Amidine-Lyases; Animals; Antioxidants; Brain Stem; Disease Models, Animal; Enzyme Activation; Hypoxia; Kinetics; Male; Metalloporphyrins; Mixed Function Oxygenases; Multienzyme Complexes; Neuropeptide Y; Peptide Hydrolases; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Sleep Apnea Syndromes; Substance P

Topics: Amidine-Lyases; Animals; Brain Stem; Enzyme Activation; Humans; Hypoxia; Mixed Function Oxygenases; Multienzyme Complexes; Neuropeptide Y; Protein Processing, Post-Translational; Reactive Oxygen Species; Signal Transduction; Sleep Apnea Syndromes; Substance P

Muscle nerve sympathetic activity (MSA) was recorded during wakefulness in 11 patients with obstructive sleep apnea (OSA) and in 9 sex- and age-matched healthy control subjects. Plasma levels of norepinephrine (NE) and neuropeptide Y were analyzed. Five patients had established hypertension (resting supine systolic BP/diastolic BP > or = 160/95 mm Hg). The investigation was performed after a minimum of 3 weeks' washout period of antihypertensive medication. Muscle sympathetic activity during supine rest was higher in patients compared with controls (p < 0.01) with no difference between normotensive and hypertensive patients. However, systolic, but not diastolic, BP was positively related to resting MSA (n = 20, p < 0.01). There was no significant correlation between body mass index and MSA. Resting MSA was unrelated to disease severity expressed as apnea frequency or minimum SaO2 during the overnight recording. Both the arterial and venous plasma norepinephrine was higher in patients compared with controls (p < 0.05). Plasma levels of NE correlated to resting MSA (p < 0.01) in the whole study group (patients and controls) but not within the respective subgroups. No significant correlation, however, was found between plasma NE (arterial and venous) and BP. Plasma neuropeptide Y-like immunoreactivity was similar in patients and controls. However, one patient with hypertension had approximately twice this level in repeated samples. It is concluded that neurogenic sympathetic activity as well as circulating plasma NE is increased in patients with OSA. This increased sympathetic activity during awake supine rest may reflect a pathophysiologic adaptation to hypoxia and hemodynamic changes occurring at repetitive apneas during sleep. The correlation between MSA and systolic BP implies that this mechanism may be directly or indirectly involved in the development of cardiovascular complications in OSA.

Topics: Adult; Blood Pressure; Humans; Hypertension; Leg; Male; Middle Aged; Muscles; Neuropeptide Y; Norepinephrine; Prospective Studies; Sleep Apnea Syndromes; Sympathetic Fibers, Postganglionic; Sympathetic Nervous System; Wakefulness