Nitric oxide promotes arteriolar dilation during cortical spreading depression in rabbits.

Colonna, David M.; Meng, Wei; Deal, Dwight D.; Busija, David W.

doi:10.1161/01.str.25.12.2463

Cited by 42 publications

(21 citation statements)

References 40 publications

(57 reference statements)

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“…NMDA can cause CSD when directly applied to the hippocampus (C. Ayata, unpublished observations), cerebral cortex, or cerebellum (29,38). CSD was a major contributor to NMDA-induced vasomotor responses in our experiments, because 1) NMDA-induced vascular changes were abrupt, and the peak dilation was transient; 2) there was often a superimposed early and brief decrease in vessel caliber, reminiscent of the hypoperfusion observed in mouse and rat cortex during KCl-induced CSDs (3,14); 3) this vasoconstriction was augmented after L-NNA superfusion as previously reported for CSD-induced CBF changes in mice and other species (3,8,9,13,14); and 4) on washout of NMDA, a delayed and prolonged vasoconstriction was observed, possibly reflecting post-CSD oligemia.…”

Section: Discussionsupporting

confidence: 64%

Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-d-aspartate superfusion

Ayata

Moskowitz²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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Pial arterioles do not express N-methyl-D-aspartate (NMDA) receptors but dilate in response to topical NMDA application. We explored the mechanism underlying NMDA-mediated responses in murine pial arterioles (11-31 microm), using a closed cranial window preparation, and found that arteriolar dilation was not concentration dependent. Pial arteriolar diameter abruptly increased within 3 min of superfusing 50 or 100 microM NMDA. Dilation reached a peak within 1 min (46 +/- 14%) and then declined to a plateau (28 +/- 13%) for the duration of superfusion. Whereas a higher concentration (200 microM) did not produce further dilation, lower concentrations (1-10 microM) did not dilate the arterioles at all. MK-801 (10 microM) abrogated the dilation response, whereas Nomega-nitro-L-arginine (1 mM) attenuated the peak and abolished the sustained dilation during NMDA superfusion. We determined that NMDA-induced pial arteriolar responses were evoked by cortical spreading depression, because abrupt vasodilation during 50 or 100 microM NMDA superfusion was associated with a large negative slow potential shift and electrocorticogram suppression that spread from the superfusion window to distant cortical areas. Our data suggest that the responses of pial arterioles to NMDA are caused in part by neurovascular coupling due to cortical spreading depression.

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Section: Discussionsupporting

confidence: 64%

Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-d-aspartate superfusion

Ayata

Moskowitz²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…As expected, L-NAME increased systemic blood pressure, reduced resting NO levels, and significantly diminished the biphasic NO response to SD (385). Although L-NAME has antimuscarinic effects that may be confounding, N-nitro-L-arginine (L-NA), which is a more specific NOS inhibitor, also reversibly suppressed SD-induced peak hyperemia by up to 40 -70% when applied topically or systemically in rabbits (65,66,314,315). Moreover, 7-nitroindazole (7-NI), a relatively specific inhibitor of neuronal NOS in vivo, also reduced the peak hyperemia to SD by 35%, without a significant change in resting CBF or systemic blood pressure, implicating a neuronal origin for NO (66).…”

Section: Nosupporting

confidence: 52%

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Ayata

Lauritzen

2015

Physiological Reviews

472

600

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Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

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“…For example, increased shear stress has been shown to selectively activate mitochondria in endothelium and secondarily promote relaxation of smooth muscle of human coronary arteries (29,30). In addition, cortical spreading depression depolarizes mitochondria in neurons but not in astroglia and we have shown that NO is an important mediator of vasodilation (7,8,16). Thus we propose that cell specific mitochondrial depolarization in the neurovascular unit during changes in physiological status, such as occurs during neuronal activation, will lead to appropriate blood flow changes due to production of NO.…”

Section: Discussionmentioning

confidence: 70%

“…We also examined the effects of BMS on relaxation of endothelium-denuded cerebral arteries, which contain intact perivascular innervation, to demonstrate that our studies in cultured neurons are supported by results from naturally occurring neurons. nNOS is located in perivascular nerves supplying the cerebral vasculature (39), and NO from both the perivascular (7,8,39) and parenchymal neurons (31) has access via diffusion to the cerebral vasculature. Although several investigators have indicated that nNOS or other NOS isoforms are present in mitochondria as well as in the cytosol, the prevailing evidence does not support a mitochondrial localization of NOS under basal conditions in neurons or cardiac cells (25,44).…”

Section: The Current Study Provides Evidence That Pharmacological Depmentioning

confidence: 99%

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

Katakam

Dutta

Sure

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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-The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial K ATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries. MITOCHONDRIAL MEMBRANE POTENTIAL is a critical regulator of cellular activity and survival and is controlled by a variety of factors including the ATP-sensitive potassium (mitoK ATP ) channels located on the inner mitochondrial membrane (2). Pharmacological activators of mitoK ATP channels, such as BMS-191095 (BMS) and diazoxide, decrease the mitochondrial membrane potential by facilitating the influx of potassium from cytosol into the matrix (2). Signaling events following mitochondrial depolarization appear to be diverse in the various cell types comprising the neurovascular unit (cerebral vascular endothelium and smooth muscle, perivascular neurons, parenchymal neurons, and glia). Both BMS and diazoxide applications result in dilation of isolated cerebral arteries; however, individual effects on vascular smooth muscle and endothelium, which contribute to the overall vascular effect, are completely different (20,22,35,42). Thus BMS and diazoxide relax cerebral vascular smooth muscle cells via generation of localized calcium sparks by sarcoplasmic reticulum linked to mitochondrial depolarization, resulting in decreased global intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (20, 42). Conversely, mitochondrial depolarization in cerebral endothe...

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Nitric oxide promotes arteriolar dilation during cortical spreading depression in rabbits.

Cited by 42 publications

References 40 publications

Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-d-aspartate superfusion

Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-d-aspartate superfusion

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide

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