Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: An oxidative stress response (original) (raw)
Related papers
Journal of Cerebral Blood Flow & Metabolism, 2003
Hyperoxia causes a transient decrease in CBF, followed by a later rise. The mediators of these effects are not known. We used mice lacking endothelial or neuronal nitric oxide synthase (NOS) isoforms (eNOS -/and nNOS -/mice) to study the roles of the NOS isoforms in mediating changes in cerebral vascular tone in response to hyperoxia. Resting regional cerebral blood flow (rCBF) did not differ between wild type (WT), eNOS -/mice, and nNOS -/mice. eNOS -/mice showed decreased cerebrovascular reactivities to N G -nitro-Larginine methyl ester (L-NAME), PAPA NONOate, acetylcholine (Ach), and SOD1. In response to hyperbaric oxygen (HBO 2 ) at 5 ATA, WT and nNOS -/mice showed decreases in rCBF over 30 minutes, but eNOS -/mice did not. After 60 minutes HBO 2 , rCBF increased more in WT mice than in eNOS -/or nNOS -/mice. Brain NO-metabolites (NO x ) decreased in WT and eNOS -/mice within 30 minutes of HBO 2 , but after 45 minutes, NO x rose above control levels, whereas they did not change in nNOS -/mice. Brain 3NT increased during HBO 2 in WT and eNOS -/but did not change in nNOS -/mice. These results suggest that modulation of eNOS-derived NO by HBO 2 is responsible for the early vasoconstriction responses, whereas late HBO 2 -induced vasodilation depends upon both eNOS and nNOS.
Nitric oxide and cerebral blood flow responses to hyperbaric oxygen
Journal of Applied Physiology, 2000
We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but...
Activation of nitric oxide synthase gene expression by hypoxia in central and peripheral neurons
Molecular Brain Research, 1996
Ž . Ž . In the present study we examined the effects of hypobaric hypoxia on neuronal n and endothelial e nitric oxide synthase NOS Ž . gene expression in the central and peripheral nervous system. Adult rats were exposed either to normoxia room air or to hypobaric Ž . hypoxia 0.4 atm for 4, 12 or 24 h and cerebellum and nodose ganglion representing the central and peripheral neurons, respectively, were removed. Messenger RNAs encoding n-and eNOS as well as b-actin were analyzed by reverse transcriptase polymerase chain Ž . reaction RT-PCR technique. Hypoxia increased nNOS mRNA expression with maximal changes occurring after 12 h wherein mRNA levels were increased by 10.4 " 1.3 and 2 " 0.4 fold in nodose ganglion and cerebellum, respectively. Hypoxia, on the other hand, had no significant effect on eNOS and b-actin mRNA levels. Analysis of nNOS protein and enzyme activity showed near doubling of these variables in both tissues after 24 h of hypoxia, indicating that nNOS protein levels are increased and that the protein is functionally active. These observations demonstrate that 12-24 h of hypobaric hypoxia selectively activates nNOS gene expression, which is reflected in an increase in nNOS protein in central and peripheral neurons. It is suggested that up-regulation of nNOS leads to increased generation of nitric oxide, which in turn may contribute to the readjustments of cardio-respiratory systems during the early stages of chronic hypoxia.
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2002
Hyperoxia reduces the hemodynamic latency and enhances the response magnitude of the evoked local cerebral blood Ž . Ž . flow LCBF . The objective of this study was to test the hypothesis that a change in the production of nitric oxide NO is involved in a unique change in evoked LCBF during hyperoxia. We measured LCBF in ␣-chloralose-anesthetized rats Ž . by laser-Doppler flowmetry. Systemic administration of the NO synthase inhibitor N -nitro-L-arginine LNA caused a Ž . Ž . decline in the baseline level of LCBF P-0.01 . The LNA intravenous injection during hyperoxia hyperoxia with LNA Ž . reduced the normalized evoked LCBF normalization with respect to the baseline level of LCBF in response to Ž . somatosensory stimulation by approximately 37% when compared under normal conditions normoxia without LNA Ž . Ž . P -0.01 , although that during normoxia normoxia with LNA did not cause a significant difference in the normalized evoked LCBF. The integrated neuronal activity under hyperoxia with LNA was approximately 11% lower than that Ž . under normoxia without LNA P-0.05 , although there was no significant difference in integrated neuronal activity between normoxia with LNA and normoxia without LNA. These results do not support our hypothesis and suggest the existence of another interaction mechanism involving oxygen for the enhancement of evoked LCBF under hyperoxia. ᮊ
Archives of Biochemistry and Biophysics, 2008
Reactive nitrogen species (RNS) and oxygen species (ROS) have been reported to modulate the function of nitric oxide synthase (NOS); however, the precise dose-dependent effects of specific RNS and ROS on NOS function are unknown. Questions remain unanswered regarding whether pathophysiological levels of RNS and ROS alter NOS function, and if this alteration is reversible. We measured the effects of peroxynitrite (ONOO À ), superoxide (O 2 ÁÀ ), hydroxyl radical ( . OH), and H 2 O 2 on nNOS activity. The results showed that NO production was inhibited in a dose-dependent manner by all four oxidants, but only O 2 ÁÀ and ONOO À were inhibitory at pathophysiological concentrations (650 lM). Subsequent addition of tetrahydrobiopterin (BH 4 ) fully restored activity after O 2 ÁÀ exposure, while BH 4 partially rescued the activity decrease induced by the other three oxidants. Furthermore, treatment with either ONOO À or O 2 ÁÀ stimulated nNOS uncoupling with decreased NO and enhanced O 2 ÁÀ generation. Thus, nNOS is reversibly uncoupled by O 2 ÁÀ (650 lM), but irreversibly uncoupled and inactivated by ONOO À . Additionally, we observed that the mechanism by which oxidative stress alters nNOS activity involves not only BH 4 oxidation, but also nNOS monomerization as well as possible degradation of the heme.
Stroke, 2006
Background and Purpose-Neonates that survive very preterm birth have a high prevalence of cognitive impairment in later life. A common factor detected in premature infants is their postnatal exposure to high oxygen tension relative to that in utero. Hyperoxia is known to elicit injury to premature lung and retina. Because data on the exposure of the brain to hyperoxia are limited, we studied the effects of high oxygen on this tissue. Methods-Rat pups were exposed from birth until day 6 to 21% or 80% O 2. Cerebral vascular density was quantified by lectin immunohistochemistry. Immunoblots for several proteins were performed on brain extracts. We assessed cerebral functional deficits by visual evoked potentials. Results-Exposure of pups to hyperoxia leads to cerebral microvascular degeneration, diminished brain mass, and cerebral functional deficits. These effects are preceded by an upregulation of endothelial nitric oxide synthase (eNOS) in cerebral capillaries and a downregulation of Cu/Zn superoxide dismutase (SOD). The imbalance in nitric oxide (NO) production and antioxidant defenses favors the formation of nitrating agents in the microvessels revealed by increased nitrotyrosine (3-nt) immunoreactivity and decreased expression of NF-B and the dependent vascular endothelial growth factor receptor 2. NOS inhibitors and eNOS deletion as well as an SOD mimetic (CuDIPS) restore vascular endothelial growth factor receptor-2 levels and nearly abolish the vasoobliteration. NOS inhibitors and SOD mimetic also prevent O 2-induced diminished brain mass and functional deficit. Conclusions-Data identify NO and nitrating agents as major mediators of cerebral microvascular damage, ensuing impaired brain development and function in immature subjects exposed to hyperoxia.
Hypoxia-induced expression of neuronal nitric oxide synthase in astrocytes of human corpus callosum
Brain Structure and Function, 2021
Nitric oxide (NO) is a gaseous neurotransmitter largely diffused in the brain; among other functions, it regulates the cerebral blood flow in response to hypoxia. NO can be synthetized by three different isoforms of the enzyme NO synthase: neuronal (nNOS), typical of neurons, endothelial and inducible. The aim of this study was to assess nNOS expression in human corpus callosum (CC) astrocytes, and its relationship with the hypoxia duration. Autoptic samples of CC from adult human subjects have been processed with immunohistochemistry and immunofluorescence using antibodies anti-nNOS and anti-glial fibrillary acidic protein (GFAP), the astrocyte marker. Results demonstrated for the first time the presence of nNOS-immunopositive astrocytes in the human CC. In particular, nNOS-positive astrocytes were absent in subjects deceased after a short hypoxia; their number and labeling intensity, however, increased with hypoxia prolongation. Neuronal NOS immunopositivity of CC astrocytes seems...
Journal of Applied Physiology, 2015
The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal ...
Nitric Oxide in Health and Disease of the Nervous System
Antioxidants & Redox Signaling, 2009
Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration. Antioxid. Redox Signal. 11, 541-553.