The role of NMDA glutamate receptors in lung injury caused by chronic long-term intermittent hypobaric hypoxia

Chronic intermittent hypoxia (CIH), a component of sleep apnea-hypopnea syndrome, is suggested to cause damage to lung tissue, and the role of glutamate is not well studied. We used a chronic long-term intermittent hypobaric hypoxia (CLTIHH) model of rats to find out if such procedure causes lung injury and the potential effect of N-methyl-D-aspartate receptors (NMDARs) by using receptor antagonist MK-801 (dizocilpine). Thirty-two rats were placed into four groups; a control and three CLTIHH groups where rats were placed into a low-pressure chamber set to 430 mmHg for 5 h/day, 5 days/week, for 5 weeks. Only one group received MK-801 (0.3 mg/kg, ip) daily. We evaluated tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nuclear factor (NF)-kB for the inflammatory process, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), total antioxidant status (TAS), and total oxidant status (TOS) for oxidative stress, and caspase-9 levels. Blood plasma, bronchoalveolar fluid (BALF), and lung tissue extracts were evaluated. Both oxidant and inflammatory parameters were significantly increased in all the mediums of the CLTIHH groups except the group that received MK-801. Significant evidence was collected on MK-801 alleviating the effect of CLTIHH. Histological evaluations revealed lung damage and fibrotic changes in the CLTIHH groups. It was first shown that the CLTIHH procedure caused chronic lung injury, and that inflammation and oxidant stress were influential in the formation of lung injury. Secondly, NMDAR antagonist MK-801 effectively inhibited the development of lung injury and fibrosis.

The effect of central and peripheral administration of acetylcholine and epinephrine on respiration.

The experiments were conducted in dogs anesthetized with Na-pentobarbital i.v. tidal volume (VT) and respiratory frequency (f min-1) were recorded. The central effects of acetylcholine (Ach) and epinephrine on respiration were investigated after injections of these substances directly into the cerebrospinal fluid by atlanto-occipital punction. The peripheral effects of Ach and epinephrine on respiration were studied after i.v. injections. Both central and peripheral administration of epinephrine caused significant increase in f min-1 and VT. After vagotomy the effects of centrally and peripherally administered epinephrine on f min-1 were abolished. The effect of central injection of epinephrine on VT persisted after vagotomy. The increase in VT in response to peripheral epinephrine administration was abolished by vagotomy. Both central and peripheral injection of Ach increased f min-1. In VT an initial decrease was followed by an increase. The initial decrease in VT was abolished by atropine. After vagotomy the effects of central and peripheral administration of Ach on f min-1 were abolished. The effects of central injection of Ach on VT persisted after vagotomy. Vagotomy abolished the effects of peripheral administration of Ach on VT.