Carbon monoxide mediates vasodilator effects of glutamate  in isolated pressurized cerebral arterioles of newborn pigs

Fiumana, Elisa; Parfenova, Helena; Jaggar, Jonathan H.; Leffler, Charles W.

doi:10.1152/ajpheart.00881.2002

Cited by 67 publications

(65 citation statements)

References 35 publications

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“…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). We found pressurized pial arteries respond to glutamate by endothelium-dependent vasodilation (14), although less strongly than in vivo (48). Of note, others have failed to detect glutamate receptor-mediated responses at all in isolated cerebral arteries (50).…”

Section: Discussioncontrasting

confidence: 46%

“…Of note, others have failed to detect glutamate receptor-mediated responses at all in isolated cerebral arteries (50). The smaller or absent dilatory response to glutamate in vitro compared with the in vivo response, coupled with similar dilator responses to isoproterenol in vitro and in vivo (2,14,53), suggests that cells underrepresented in the isolated arteriole contribute to the dilation in response to glutamate in vivo. The present data suggest that astrocytes, although immunodetectable on our isolated pial arterioles, could be the underrepresented cell type when the arteriole is removed from the intact brain.…”

Section: Discussionmentioning

confidence: 99%

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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

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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: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

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

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106

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“…4,8,18,19 Postictal cerebral vascular responses to glutamate (10 − 4 mol/L) and the AMPA receptor agonist quisqualic acid (10 − 4 mol/L) were reduced by 60% to 70% compared with the intact control group (Figure 2). Heme oxygenase expressed in cerebral vascular endothelium and cortical astrocytes is an important contributor to cerebrovascular dilator function.…”

Section: Acute Effects Of Enteral Corm-a1 In Systemic and Cerebral CImentioning

confidence: 99%

Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

Liu

Fedinec

Leffler

et al. 2014

J Cereb Blood Flow Metab

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Cerebral blood flow dysregulation caused by oxidative stress contributes to adverse neurologic outcome of seizures. A carbon monoxide (CO) donor CORM-A1 has antioxidant and cytoprotective properties. We investigated whether enteral supplements of CORM-A1 can improve cerebrovascular outcome of bicuculline-induced seizures in newborn piglets. CORM-A1 (2 mg/kg) was given to piglets via an oral gastric tube 10 minutes before or 20 minutes after seizure onset. Enteral CORM-A1 elevated CO in periarachnoid cerebrospinal fluid and produced a dilation of pial arterioles. Postictal cerebral vascular responses to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested 48 hours after seizures by intravital microscopy. The postictal responses of pial arterioles to bradykinin, glutamate, the AMPA receptor agonist quisqualic acid, ADP, and heme were greatly reduced, suggesting that seizures cause injury to endothelial and astrocyte components of the neurovascular unit. In contrast, in the two groups of piglets receiving enteral CORM-A1, the postictal cerebral vascular responsiveness to these dilators was improved. Overall, enteral supplements of CORM-A1 before or during seizures offer a novel effective therapeutic option to deliver cytoprotective mediator CO to the brain, reduce injury to endothelial and astrocyte components of cerebral blood flow regulation and to improve the cerebrovascular outcome of neonatal seizures.

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“…Experimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9].…”

Section: A Vasoactive Effects Of Exogenous Co In Cerebral Vesselsmentioning

confidence: 99%

“…In newborn pigs, CO-RM-A1 (2 mg/kg iv or ip) increases the CO level in the brain above the threshold level and elicits dilator effects in pial arterioles [7]. Ex vivo, pressurized cerebral arterioles from newborn pigs dilate in response to DMDC, a light-activated CO-RM, upon illumination [3,4]. In vitro, smooth muscle cells from cerebral arterioles of newborn pigs respond to gaseous CO by activating large conductance Ca 2+ -activated K + channels (BK Ca channels) [2,6,10].…”

Section: A Vasoactive Effects Of Exogenous Co In Cerebral Vesselsmentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

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Carbon monoxide mediates vasodilator effects of glutamate in isolated pressurized cerebral arterioles of newborn pigs

Cited by 67 publications

References 35 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

Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

Cerebroprotective Functions of HO-2

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