Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase

Brown, Guy C.; Cooper, Chris E.

doi:10.1016/0014-5793(94)01290-3

Cited by 965 publications

(751 citation statements)

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“…The most direct effect of NO on chondrocytes appears to be the suppression of energy metabolism (4,(11)(12)(13)34,35). Indeed, it is currently hypothesized that one of the main functions of NO is metabolic regulation, which has been determined, in part, by decreased ATP production (11,12), decreased O 2 consumption (11,12), and decreased matrix synthesis (13).…”

Section: Discussionmentioning

confidence: 99%

“…This inhibition can be accomplished by many distinct mechanisms. For example, it has been reported that NO can form stable nitrosyl adducts with reduced iron contained within the heme of the oxygen-binding site of cytochrome c oxidase (complex IV) of the mitochondrial electron transport chain (34,35). This reaction is rapid and highly competitive with oxygen because nanomolar concentrations of NO have been shown to reversibly inhibit synaptosomal Figure 6.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of NO donor compounds have been shown to inhibit mitochondrial respiration, as determined by decreased ATP production and decreased O 2 consumption in other cell types (34,35), and more recently in chondrocytes (11,12). However, studies on cellular NADH and NADPH levels as a function of the inhibitory effect of NO on mitochondrial respiration have not been previously reported.…”

Section: Del Carlo and Loesermentioning

confidence: 99%

“…DEL CARLO AND LOESER respiration by competing with oxygen at cytochrome c oxidase (35). Alternatively, NO can also affect energy metabolism by activating other heme-containing intracellular enzymes including soluble guanylyl cyclase (GTP pyrophosphate-cyclase [sGC]) (39).…”

mentioning

confidence: 99%

“…In addition to its high affinity for transition metals, either contained within heme (34,35) or as part of an iron-sulfur cluster (42), NO also displays a high affinity for other ROS and can therefore act directly as an antioxidant (32). This direct scavenging ability may represent another mechanism by which NO is cytoprotective under conditions of oxidative stress, such as when chondrocytes were cultured in the absence of L-cystine and GSH, and in the presence of H 2 O 2 or tBH.…”

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confidence: 99%

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Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Carlo

Loeser

2002

Arthritis & Rheumatism

227

178

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Objective. Chondrocyte cell death, possibly related to increased production of endogenous nitric oxide (NO), has been observed during the pathogenesis of osteoarthritis and rheumatoid arthritis. The purpose of this study was to investigate the potential role of NO in causing chondrocyte cell death and to determine the contribution of other reactive oxygen species (ROS).Methods. Cell death and cytotoxicity were evaluated in human articular chondrocytes in response to various NO donor compounds with and without agents that stimulate or inhibit the production of additional ROS using both the alginate bead and the monolayer culture systems. Cell death was quantified by a total cell count with fluorescent labels, and cytotoxicity was measured as a function of cellular NADH-and NADPHdependent dehydrogenase activity. To determine if the redox status of the chondrocyte could influence the observed effect of NO, cells were preincubated for 24 hours in L-cystine-and glutathione (GSH)-depleted media to reduce intracellular GSH levels, a major defense mechanism against oxidative stress. Apoptosis was analyzed with the quantification of histoneassociated DNA fragments. Conclusion. These results show that NO by itself is not cytotoxic to cultured chondrocytes and can even be protective under certain conditions of oxidative stress. Chondrocyte cell death from NO occurs under conditions where other ROS are also generated. Results. Treatment of chondrocytes with peroxynitrite (ONOONitric oxide (NO) participates in the normal functioning of a wide array of mammalian processes, including vasodilation, inhibition of platelet aggregation, neurotransmission, and macrophage-mediated immunity (1-4). Paradoxically, however, NO has also been proposed to be the cytotoxic species responsible for an increasing number of pathologic disorders, including rheumatic (5) and neurodegenerative (6) diseases. Expression of inducible nitric oxide synthase (iNOS) has been associated with chondrocytes during the pathogenesis of osteoarthritis (OA) (7) and rheumatoid arthritis (RA) (8); however, the exact role of NO in this regard is not fully understood. While it has been reported that NO causes chondrocyte cell death (9,10), other more recent reports have proposed NO to be a physiologic regulator of mitochondrial respiration in chondrocytes (11,12). Moreover, production of high levels of endogenous NO by overexpression of the iNOS gene in transfected chondrocytes did not cause cell death (13).The direct investigation of the function of exogenous NO production on chondrocytes has been hampered by the lack of uniformity that exists between the different types of NO donor compounds. Knowledge of the precise reactive nitrogen species (RNS) that is

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Del Carlo and Loesermentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Carlo

Loeser

2002

Arthritis & Rheumatism

227

178

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NMDA receptor-dependent nitric oxide and cGMP synthesis in brain hemispheres and cerebellum during reperfusion after transient forebrain ischemia in gerbils: Effect of 7-nitroindazole

Chalimoniuk

Strosznajder

1998

J. Neurosci. Res.

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In this study, the N-Methyl-D-Aspartate (NMDA) receptor-dependent nitric oxide and cyclic GMP (cGMP) synthesis in the course of reperfusion after 5 min of ischemia in gerbil brain hemispheres and cerebellum were investigated. Moreover, the role of the neuronal isoform of nitric oxide (NO) synthase (nNOS) in liberation of NO in postischemic brain and the involvement of NO in membrane lipoperoxidations activated during reperfusion were evaluated. Enhancement of Ca2+/calmodulin-regulated NOS activity and cGMP level in brain hemispheres and in cerebellum during reperfusion was found to be coupled to the activation of the NMDA receptor. cGMP concentration 40% above the control level was observed to persist up to 7 days after ischemia. The amount of conjugated double bounds in membrane lipids and the level of thiobarbituric acid reactive substances were increased exclusively in brain hemispheres, indicating activation of lipid peroxidation. The NMDA receptor antagonist, MK-801, eliminated, and a rather selective nNOS inhibitor, 7-Nitroindazole (7-NI) attenuated, NMDA receptor-evoked enhancement of NOS activity and cGMP level in brain hemispheres and in cerebellum during reperfusion. Moreover, 7-NI decreased significantly membrane lipid peroxidation during the early time of reperfusion. Histological examination demonstrated that 7-NI protects against death a selected population of neuronal cells in CA1 layer of hippocampus. It is suggested that NMDA receptor dependence of NO release during reperfusion is responsible for the degeneration of some populations of neurons and that the effect is mediated by activation of free radical formation and lipid peroxidation. Moreover, in cerebellum, ischemia-evoked activation of glutamatergic system stimulates NO-dependent signal transmission. Our results indicated that 7-NI has a significant ameliorating effect on biochemical alterations evoked by ischemia, suggesting nNOS inhibitors as a potential therapeutic agents in reperfusion injury.

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Stickstoffmonoxid: die rätselhafte Chemie eines biologischen Botenstoffes

Pfeiffer¹,

Mayer²,

Hemmens³

1999

Angewandte Chemie

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Enorm gestiegen ist das Interesse an der Biologie von Stickstoffmonoxid (NO) in den letzten Jahren. NO wirkt als Signalmolekül in Blutgefäßen und im Gehirn, spielt aber auch eine wichtige Rolle bei der zellulären Immunabwehr. Die chemischen und biologischen Eigenschaften dieses vielseitigen kleinen Moleküls werden vorgestellt und diskutiert, um zu einem besseren Verständnis seiner zahlreichen biologischen Funktionen beizutragen.

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Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase

Cited by 965 publications

References 24 publications

Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

Nitric oxide–mediated chondrocyte cell death requires the generation of additional reactive oxygen species

NMDA receptor-dependent nitric oxide and cGMP synthesis in brain hemispheres and cerebellum during reperfusion after transient forebrain ischemia in gerbils: Effect of 7-nitroindazole

Stickstoffmonoxid: die rätselhafte Chemie eines biologischen Botenstoffes

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