Abstract
Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague–Dawley rats were exposed to air (normoxic control) or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg) or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD)-1 and SOD-2) were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) and mediators (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome.
Highlights
Patients with sleep-disordered breathing suffer from recurrent episodes of apnea/hypopnea caused by obstruction of the upper airway and/or lowered central ventilatory activities
The NTR level in melatonin-treated hypoxic group was significantly lower than that of the vehicle-treated group (Figure 2). These results suggest an increased level of reactive nitrogen species (RNS) caused by chronic intermittent hypoxia (CIH)-induced oxidative stress in the adrenal medulla under CIH condition, which could be mitigated by melatonin treatment
We demonstrated that the CIH exposure mimicking a severe obstructive sleep apnea (OSA) condition in rats induces lipid peroxidation, local inflammation and apoptotic cell death in the adrenal medulla with decreased expressions of antioxidant enzymes (Figure 6)
Summary
Patients with sleep-disordered breathing suffer from recurrent episodes of apnea/hypopnea caused by obstruction of the upper airway and/or lowered central ventilatory activities. Studies have shown that recurrent episodes of apnea/hypopnea cause chronic intermittent hypoxia (CIH), which induces lipid peroxidation and subsequently causes the pathophysiological change in the OSA patient [4,5,6]. It has been shown that that cellular injuries caused by lipid peroxidation lead to inflammation, which induces the inflammatory response that could be an important contributing factor in promoting cardiovascular morbidity in OSA patients [9,10]. A growing amount of evidence supports pathophysiological roles of CIH-induced lipid peroxidation and inflammation in cardiovascular morbidities in OSA patients [12,13,14]
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