The Vasorelaxation of Cerebral Arteries by Carbon Monoxide

Komuro, Taro; Borsody, Mark K.; Ono, Shigeki; Marton, Linda S.; Weir, Bryce; Zhang, Zhen-Du; Paik, Eun Chan; Macdonald, R. Loch

doi:10.1177/153537020122600909

Cited by 29 publications

(26 citation statements)

References 40 publications

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“…However, developmental differences seem plausible considering low sensitivity to CO is found in isolated cerebral arteries from adult rats (1), rabbits (7), and dogs (26). Developmental mechanisms would not be surprising.…”

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

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%

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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“…However, cerebral arteries isolated from mice, rats, and rabbits did not dilate to 10 -6 -10 -4 M CO [12,13]. Conversely, in another study, dog basilar artery segments did dilate to CO [14].…”

Section: A Vasoactive Effects Of Exogenous Co In Cerebral Vesselsmentioning

confidence: 98%

“…Although the measurements of extracellular concentration in CSF reflect the dynamics of overall CO production by the brain, they do not allow direct estimation of the intracellular level of CO. Brain CO production by the brain is rapidly activated (over 3-fold increase in [10][11][12][13][14][15][16][17][18][19][20] Overall, these experiments identify CO as a potent cerebral vasodilator endogenously produced by the brain and cerebral vasculature. Of particular significance is that immediate activation of brain HO is essential in maintaining blood flow to the brain during selected cerebrovascular insults, including epileptic seizures, hypoxia, and hypotension.…”

Section: B Endogenously Produced Co and Cerebral Vascular Reactivitymentioning

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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“…The effect of CO on adult cerebral arteries has been studied sparingly and with conflicting results. In one study, CO caused dilation of canine basilar arteries (23), whereas another study found that CO did not dilate the basilar arteries of rabbits or dogs (4). With the exception of pial arterioles in newborn pigs (28), vasodilation to CO in the aforementioned studies usually occurs at relatively high concentrations (10 Ϫ5 M or greater).…”

Section: M) Dilated Both Rat and Mouse Mcas At 10mentioning

confidence: 99%

“…In adult animals, there are conflicting reports of the effect of CO on cerebral arteries. One study (23) of canine basilar arteries found that exogenous CO (5.7 ϫ 10 Ϫ7 to 5.67 ϫ 10 Ϫ4 M) caused dilation beginning at 5.7 ϫ 10 Ϫ5 M, a concentration that would be considered supraphysiological (6,14,32,51), whereas another study (4) using the same vessels found that CO did not elicit dilation even up to 3 ϫ 10 Ϫ4 M. In yet another study (17), blockade of NO⅐ synthase by endogenously produced CO impaired NO⅐-dependent vasodilation of adult rat pial arterioles. Data from the present study convincingly demonstrate that adult cerebral arteries from rats do not dilate to CO (Fig.…”

Section: Effect Of Co In Cerebral Vesselsmentioning

confidence: 99%

Effects of carbon monoxide and heme oxygenase inhibitors in cerebral vessels of rats and mice

Andresen¹,

Shafi²,

Durante³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Effects of carbon monoxide and heme oxygenase inhibitors in cerebral vessels of rats and mice. Am J Physiol Heart Circ Physiol 291: H223-H230, 2006. First published February 17, 2006 doi:10.1152/ajpheart.00058.2006 has been postulated to be a signaling molecule in many tissues, including the vasculature. We examined vasomotor responses of adult rat and mouse cerebral arteries to both exogenously applied and endogenously produced CO. The diameter of isolated, pressurized, and perfused rat middle cerebral arteries (MCAs) was not altered by authentic CO (10 Ϫ6 to 10 Ϫ4 M). Mouse MCAs, however, dilated by 21 Ϯ 10% at 10 Ϫ4 M CO. Authentic nitric oxide (NO⅐, 10 Ϫ10 to 10 Ϫ7 M) dilated both rat and mouse MCAs. At 10 Ϫ8 M NO⅐, rat vessels dilated by 84 Ϯ 4%, and at 10 Ϫ7 M NO⅐, mouse vessels dilated by 59 Ϯ 9%. Stimulation of endogenous CO production through heme oxygenase (HO) with the heme precursor ␦-aminolevulinic acid (10 Ϫ10 to 10 Ϫ4 M) did not dilate the MCAs of either species. The metalloporphyrin HO inhibitor chromium mesoporphyrin IX (CrMP) caused profound constriction of the rat MCA (44 Ϯ 2% at 3 ϫ 10 Ϫ5 M). Importantly, this constriction was unaltered by exogenous CO (10 Ϫ4 M) or CO plus 10 Ϫ5 M biliverdine (both HO products). In contrast, exogenous CO (10 Ϫ4 M) reversed CrMP-induced constriction in rat gracilis arterioles. Control mouse MCAs constricted by only 3 Ϯ 1% in response to 10 Ϫ5 M CrMP. Magnesium protoporphyrin IX (10 Ϫ5 M), a weak HO inhibitor used to control for nonspecific effects of metalloporphyrins, also constricted the rat MCA to a similar extent as CrMP. We conclude that, at physiological concentrations, CO is not a dilator of adult rodent cerebral arteries and that metalloporphyrin HO inhibitors have nonspecific constrictor effects in rat cerebral arteries. cerebral arteries; chromium mesoporphyrin; endothelium-derived hyperpolarization factor; gracilis arteriole HEME OXYGENASE (HO) is the major enzyme responsible for degrading heme (29). Three isoforms of HO (HO-1, -2, and -3) catalyze the conversion of heme to carbon monoxide (CO), biliverdine IX␣, and iron (29,35,54). CO, in turn, has been postulated to be a signaling molecule in many tissues, including the vasculature (22, 29, 40 -42, 48, 54, 55, 58). HO-1 is not normally expressed in most tissues, although it may be upregulated by a wide variety of stimuli, including subarachnoid hemorrhage (45) and ischemia-reperfusion (38). HO-2 is constitutively expressed and is found in most tissues, including the brain, vascular smooth muscle, and endothelium (8,29,30,38,47,57). HO-3 may be constitutively expressed in the rat, although recent work suggests that it is a splice variant of HO-2 transcripts (16,31,54).CO binds to heme moieties such as those found in soluble guanylyl cyclase, nitric oxide (NO⅐) synthase, and cytochrome P-450 enzymes. Binding of CO to heme moieties can either increase or decrease enzymatic activity (7, 17, 22, 29, 40 -43, 46). Large-conductance calcium-dependent K ϩ channels can also be activated by CO (18,24,28,...

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The Vasorelaxation of Cerebral Arteries by Carbon Monoxide

Cited by 29 publications

References 40 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

Cerebroprotective Functions of HO-2

Effects of carbon monoxide and heme oxygenase inhibitors in cerebral vessels of rats and mice

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