Nitric Oxide‐Mediated Inhibition of the Mitochondrial Respiratory Chain in Cultured Astrocytes

Bolaños, Juan P.; Peuchen, S; Heales, Simon; Land, John M.; Clark, John B.

doi:10.1046/j.1471-4159.1994.63030910.x

Cited by 395 publications

(239 citation statements)

References 34 publications

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“…By injecting NO into the solution containing the aorta, we could simultaneously observe both the NO inhibition of aortic O 2 consumption and the effect of O 2 concentrations on aortic NO consumption. Our results show that NO can inhibit the aortic O 2 consumption, which is consistent with previous results from mitochondria (5,9,16,17), cells (1,4,10), and tissues (3,24). In the meantime, the rate of aortic NO consumption also depends on O 2 concentration.…”

Section: Discussionsupporting

confidence: 92%

Biphasic modulation of vascular nitric oxide catabolism by oxygen

Cheng

Zorko

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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derived nitric oxide (NO) plays an important role in the regulation of vascular tone. Lack of NO bioavailability can result in cardiovascular disease. NO bioavailability is determined by its rates of generation and catabolism; however, it is not known how the NO catabolism rate is regulated in the vascular wall under normoxic, hypoxic, and anaerobic conditions. To investigate NO catabolism under different oxygen concentrations, studies of NO and O2 consumption by the isolated rat aorta were performed using electrochemical sensors. Under normoxic conditions, the rate of NO consumption in solution was enhanced in the presence of the rat aorta. Under hypoxic conditions, NO consumption decreased in parallel with the O2 concentration. Like the inhibition of mitochondrial respiration by NO, the inhibitory effects of NO on aortic O2 consumption increased as O2 concentration decreased. Under anaerobic conditions, however, a paradoxical reacceleration of NO consumption occurred. This increased anaerobic NO consumption was inhibited by the cytochrome c oxidase inhibitor NaCN but not by the free iron chelator deferoxamine, the flavoprotein inhibitor diphenylene iodonium (10 M), or superoxide dismutase (200 U/ml). The effect of O2 on the NO consumption could be reproduced by purified cytochrome c oxidase (CcO), implying that CcO is involved in aortic NO catabolism. This reduced NO catabolism at low O2 tensions supports the maintenance of effective NO levels in the vascular wall, reducing the resistance of blood vessels. The increased anaerobic NO catabolism may be important for removing excess NO accumulation in ischemic tissues. aorta; hypoxia; ischemia; cytochrome c oxidase ENDOTHELIUM-DERIVED NITRIC OXIDE (NO) is a potent vasodilator (11, 12). To dilate blood vessels, NO needs to diffuse from the endothelial layer of blood vessels into smooth muscle cells to activate soluble guanylate cyclase (sGC). The physiological role of NO is largely dependent on the bioavailability of NO, which is determined by its generation rate and decay rate. To understand the physiological role of NO in blood vessels, it is very important to study the characteristics of NO catabolism in the vascular wall because the rate of NO catabolism can greatly affect NO bioavailability.It is known that NO can react with O 2 in the water, but the reaction rate is relatively slow at physiological concentrations of NO (22). However, the reaction of NO with O 2 can be accelerated within biological membranes in the body (14, 17). Furthermore, NO and O 2 can interact with each other through heme proteins. This interaction between NO and O 2 has important physiological significance, which makes it possible to efficiently regulate the rate of O 2 consumption by NO or regulate the rate of NO consumption by O 2 . For example, O 2 can be rapidly reduced by cytochrome c oxidase (CcO) in mitochondria, whereas NO can bind to the binuclear center in CcO to efficiently inhibit the reduction of O 2 . On the other hand, NO can be consumed by CcO (15,20), and the consumpti...

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Section: Discussionsupporting

confidence: 92%

Biphasic modulation of vascular nitric oxide catabolism by oxygen

Cheng

Zorko

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…The other mechanism is the inhibition of the mitochondrial complexes, leading to diminished ATP production. NO was reported to inhibit complexes II and III (Bolanos et al 1994), and also complex IV (Cassina and Radi 1996;Lizasoain et al 1996) in neuron-derived mitochondria. It was also reported that NO inhibits neuronal energy production in cultured hippocampal neurons (Brorson et al 1999), leading to rapid ATP depletion.…”

Section: Discussionmentioning

confidence: 99%

Neuronal nitric oxide synthase proteolysis limits the involvement of nitric oxide in kainate‐induced neurotoxicity in hippocampal neurons

Araújo

Ambrósio

Leal

et al. 2003

Journal of Neurochemistry

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In this work, we investigated the role of nitric oxide (NO) in neurotoxicity triggered by a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in cultured hippocampal neurons. In the presence of cyclothiazide (CTZ), short-term exposures to kainate (KA; 5 and 15 min, followed by 24-h recovery) decreased cell viability. Both NBQX and D-AP-5 decreased the neurotoxicity caused by KA plus CTZ. Long-term exposures to KA plus CTZ (24 h) resulted in increased toxicity. In short-, but not in long-term exposures, the presence of NO synthase (NOS) inhibitors (L-NAME and 7-NI) decreased the toxicity induced by KA plus CTZ. We also found that KA plus CTZ (15-min exposure) significantly increased cGMP levels. Furthermore, short-term exposures lead to decreased intracellular ATP levels, which was prevented by NBQX, D-AP-5 and NOS inhibitors. Immunoblot analysis revealed that KA induced neuronal NOS (nNOS) proteolysis, gradually lowering the levels of nNOS according to the time of exposure. Calpain, but not caspase-3 inhibitors, prevented this effect. Overall, these results show that NO is involved in the neurotoxicity caused by activation of nondesensitizing AMPA receptors, although to a limited extent, since AMPA receptor activation triggers mechanisms that lead to nNOS proteolysis by calpains, preventing a further contribution of NO to the neurotoxic process.

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“…Furthermore, astrocytes in the SN are found to express particularly high levels of intercellular adhesion molecule 1 (ICAM-1), which mediates sustained inflammation (193), and overproduction of this molecule has been found in reactive astrocytes in the SNpc in post mortem PD brains (194). In this way, astrocytes may be linked to propagation of the disease, potentially accelerated by generation of nitric oxide (NO) (186,195). NO produced in astrocytes forms reactive intermediates that results in elevated oxidative stress (195), and NO overproduction and radicals in are shown in post mortem PD brains (196).…”

Section: Astrocytesmentioning

confidence: 99%

“…In this way, astrocytes may be linked to propagation of the disease, potentially accelerated by generation of nitric oxide (NO) (186,195). NO produced in astrocytes forms reactive intermediates that results in elevated oxidative stress (195), and NO overproduction and radicals in are shown in post mortem PD brains (196).…”

Section: Astrocytesmentioning

confidence: 99%