Glutamate-Induced Cerebral Vasodilation Is Mediated by Nitric Oxide Through
            <i>N</i>
            -Methyl-
            <scp>d</scp>
            -Aspartate Receptors

Meng, Wei; Tobin, Joseph R.; Busija, David W.

doi:10.1161/01.str.26.5.857

Cited by 121 publications

(94 citation statements)

References 41 publications

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“…Glutamate is a dilator in the cerebral circulation in vivo (8,11,39). Release of glutamate from presynaptic neurons increases blood flow to match the increased metabolic demands of stimulated neurons (37).…”

Section: Discussionmentioning

confidence: 99%

“…Release of glutamate from presynaptic neurons increases blood flow to match the increased metabolic demands of stimulated neurons (37). Neuronal activation in response to excitatory neurotransmitters may affect brain vessels via neurally derived vasorelaxant factors, including NO (11,39,51) and CO (2). Glutamate and selective NMDA-and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor agonists increase CO production by piglet cerebral microvessels (29,43) and astrocytes (52).…”

Section: Discussionmentioning

confidence: 99%

“…The inhibitory effect of TTX on NMDAinduced cerebrovascular dilation suggests activation of NMDA receptors on neurons causes release of a substance(s) that promotes dilation (11). Since Meng et al (39) reported blockade of dilation to NMDA by N G -nitro-L-arginine, a potential neuronal derived dilator is NO generated by neuronal NO synthase (nNOS). We recently demonstrated that NO can increase CO production by cerebral microvessels (28), so neuronally derived NO could stimulate CO production in astrocytes, neurons, endothelium, and/or vascular smooth muscle to cause dilation.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs

Leffler

Parfenova²,

Fedinec

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

106

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Astrocytes can act as intermediaries between neurons and cerebral arterioles to regulate vascular tone in response to neuronal activity. Release of glutamate from presynaptic neurons increases blood flow to match metabolic demands. CO is a gasotransmitter that can be related to neural function and blood flow regulation in the brain. The present study addresses the hypothesis that glutamatergic stimulation promotes perivascular astrocyte CO production and pial arteriolar dilation in the newborn brain. Experiments used anesthetized newborn pigs with closed cranial windows, piglet astrocytes, and cerebrovascular endothelial cells in primary culture and immunocytochemical visualization of astrocytic markers. Pial arterioles and arteries of newborn pigs are ensheathed by astrocytes visualized by glial fibrillary acidic protein staining. Treatment (2 h) of astrocytes in culture with L-2-␣-aminoadipic acid (L-AAA), followed by 14 h in toxin free medium, dose-dependently increased cell detachment, suggesting injury. Conversely, 16 h of continuous exposure to L-AAA caused no decrease in endothelial cell attachment. In vivo, topical L-AAA (2 mM, 5 h) disrupted the cortical glia limitans histologically. Such treatment also eliminated pial arteriolar dilation to the astrocytedependent dilator ADP and to glutamate but not to isoproterenol or CO. Glutamate stimulated CO production by the brain surface that also was abolished following L-AAA. In contrast, tetrodotoxin blocked dilation to N-methyl-D-aspartate but not to glutamate, isoproterenol, or CO or the glutamate-induced increase in CO. The concurrent loss of CO production and pial arteriolar dilation to glutamate following astrocyte injury suggests astrocytes may employ CO as a gasotransmitter for glutamatergic cerebrovascular dilation. glia limitans; cerebrovascular circulation; gasotransmitter; glia toxin IN THE CEREBROVASCULAR circulation, signals to vascular smooth muscle can come from endothelium, nerves, astrocytes, or pericytes, which interact to form a neurovascular unit (15). L-Glutamic acid (glutamate) is the principal excitatory neurotransmitter in the central nervous system (38). It is a dilator of cerebral arterioles in vivo (8, 12), although direct effects of glutamate on the vascular smooth muscle are uncertain. Release of glutamate from presynaptic neurons dilates cerebral arterioles, causing blood flow to increase to match metabolic demands (37).Astrocytes are the most abundant cell type in the higher mammalian brain. They function as intermediaries between neurons and cerebral arterioles in regulation of cerebral vascular tone in response to neuronal activity, thereby adjusting cerebral blood flow to metabolism (15,25). Whether astrocytes are involved in dilation in response to glutamate released at excitatory synapses and the nature of astrocyte-derived vasodilator(s) employed remain uncertain.The gas CO is produced physiologically by catabolism of heme to CO, iron, and biliverdin (36). This reaction is catalyzed by heme oxygenase (HO) with oxidation of...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs

Leffler

Parfenova²,

Fedinec

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

106

View full text Add to dashboard Cite

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“…Indeed, the BBB was found to be intact even after 24-h L-glut infusion in rats (20). Third, L-glut and NMDA dilate cerebral arteries in vivo (3,30) but not in vitro (37,44), suggesting that CMVECs do not respond directly to L-glut.…”

mentioning

confidence: 93%

Cerebromicrovascular endothelial cells are resistant to l-glutamate

Domoki

Kis

Gáspár

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Cerebral microvascular endothelial cells (CMVECs) have recently been implicated as targets of excitotoxic injury by L-glutamate (L-glut) or N-methyl-Daspartate (NMDA) in vitro. However, high levels of L-glut do not compromise the function of the blood-brain barrier in vivo. We sought to determine whether primary cultures of rat and piglet CMVECs or cerebral microvascular pericytes (CMVPCs) are indeed sensitive to L-glut or NMDA. Viability was unaffected by 8-h exposure to 1-10 mM L-glut or NMDA in CMVECs or CMVPCs isolated from both species. Furthermore, neither 1 mM L-glut nor NMDA augmented cell death induced by 12-h oxygen-glucose deprivation in rat CMVECs or by 8-h medium withdrawal in CMVPCs. Additionally, transendothelial electrical resistance of rat CMVEC-astrocyte cocultures or piglet CMVEC cultures were not compromised by up to 24-h exposure to 1 mM L-glut or NMDA. The Ca 2ϩ ionophore calcimycin (5 M), but not L-glut (1 mM), increased intracellular Ca 2ϩ levels in rat CMVECs and CMVPCs assessed with fluo-4 AM fluorescence and confocal microscopy. CMVEC-dependent pial arteriolar vasodilation to hypercapnia and bradykinin was unaffected by intracarotid infusion of L-glut in anesthetized piglets by closed cranial window/intravital microscopy. We conclude that cerebral microvascular cells are insensitive and resistant to glutamatergic stimuli in accordance with their in vivo role as regulators of potentially neurotoxic amino acids across the blood-brain barrier.N-methyl-D-aspartate; blood-brain barrier; cerebrovascular reactivity; glutamate excitotoxicity; intracellular calcium L-GLUTAMATE (L-glut) is one of the most important excitatory amino acids in the central nervous system. Apart from its well-known neurotransmitter role, L-glut plays a critical role in ammonia removal from the brain. L-Glut transported from the blood plasma takes up ammonia and leaves as L-glutamine (12). This balanced L-glutamate/L-glutamine countertransport is regulated by cerebral microvascular endothelial cells (CMVECs) forming the blood-brain barrier (BBB). Furthermore, CMVECs can pump L-glut from the brain to the blood, and thus they provide a functional interface for the regulated bidirectional transport of L-glut (18, 39). Human blood plasma L-glut levels range between 20 and 200 M, and they may exceed 700 M after ingestion of high amounts of L-glut under experimental conditions (4, 41). These plasma L-glut concentrations are not neurotoxic in vivo, although these levels are excitotoxic to neurons in vitro, suggesting that CMVECs are resistant to high L-glut levels and prevent the passive transport of L-glut into the brain.Surprisingly, several recent reports have proposed that the L-glut levels that occur during cerebral ischemia can injure or kill CMVECs via excitotoxic mechanisms in vitro. CMVECs have been reported to possess various L-glut receptor subunits or L-glut binding sites in rat, piglet, or human CMVECs (1,5,27,34,36,45). High concentrations of L-glut (1-3 mM), at least in vitro, are claimed to result in N-met...

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“…IN NEWBORN PIGS, CEREBRAL arterioles dilate to glutamate and its receptor subtype-specific analog N-methyl-Daspartate (NMDA) via a multistep process, involving the activation of NMDA receptors, neuronal production, and release of nitric oxide (NO), and subsequent relaxation of smooth muscle (10,16,25). Because glutamate is the predominant excitatory neurotransmitter in the central nervous system, it has been suggested that this sequence of events may represent one important mechanism for coupling neuronal activity with local blood flow (3,11,16).…”

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confidence: 99%

Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets

Perciaccante

Domoki

Puskar

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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We determined whether cerebral arteriolar dilation to N-methyl-d-aspartate (NMDA), a response dependent on stimulation of cortical neurons and inhibited by anoxic stress, would be preserved by hypothermia during and following ischemia. Pial arteriolar diameters in anesthetized piglets were determined via intravital microscopy. Arteriolar responses to NMDA (10, 50, and 100 μmol/l) were measured before and 1 h after 10 min of global ischemia. Piglets were exposed to either total body or selective brain cooling (33–34°C). Arteriolar dilation to lower doses or to 100 μmol/l NMDA was not affected by hypothermia alone (51 ± 3 vs. 46 ± 7%, normothermia vs. hypothermia; n = 7) in nonischemic animals. However, arteriolar responses to 100 μmol/l NMDA were clearly attenuated after ischemia despite body cooling during ischemia (53 ± 3 vs. 32 ± 6%; n = 8), hypothermia during ischemia and early reperfusion (49 ± 10 vs. 20 ± 3%; n = 8), or selective brain cooling (48 ± 5 vs. 20 ± 5%; n = 10). In contrast, pretreatment with indomethacin resulted in complete preservation of NMDA-induced vasodilation after ischemia. Thus, hypothermia fails to protect against neuronal dysfunction during ischemia.

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Glutamate-Induced Cerebral Vasodilation Is Mediated by Nitric Oxide Through N -Methyl- d -Aspartate Receptors

Abstract: Glutamate-induced cerebral arteriolar dilation is mediated by NO through NMDA receptors, and NO does not play a major role in the cerebral arteriolar dilation to hypercapnia (PCO2 = 40 to 68 mm Hg) in newborn pigs.

Cited by 121 publications

References 41 publications

Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs

Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs

Cerebromicrovascular endothelial cells are resistant to l-glutamate

Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets

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