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Laboratory for Research in Neonatal Physiology, Departments of Physiology and Pediatrics, Vascular Biology Center, University of Tennessee Health Science Center, Memphis, Tennessee 38163
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The excitatory neurotransmitter glutamate
causes dilation of newborn pig cerebral arterioles in vivo that is
blocked by inhibition of carbon monoxide (CO) production. CO, a potent
dilator in cerebral circulation in vivo, is produced endogenously in
cerebral microvessels via heme oxygenase (HO). In isolated pressurized
cerebral arterioles (~200 µm) from newborn pigs, we investigated
the involvement of CO and the endothelium in response to glutamate. A
CO-releasing molecule, dimanganese decacarbonyl
(10
8-106 M), dilated cerebral
arterioles. Glutamate (106-104 M) and
1-aminocyclopentane-cis-1,3-dicarboxylic acid
(cis-ACPD; 106-105 M), a
N-methyl-D-aspartate (NMDA) receptor agonist,
caused cerebral vascular dilation. Dilation of cerebral arterioles to
glutamate and cis-ACPD was abolished by chromium
mesoporphyrin (CrMP; 106 M), a HO inhibitor. In contrast,
CrMP did not alter dilation to isoproterenol, a 
-adrenergic receptor
agonist. Endothelium-denuded cerebral arterioles did not dilate to
glutamate or bradykinin (endothelium-dependent dilator), whereas
responses to isoproterenol were preserved. These data indicate that
cerebral arterioles from newborn pigs may directly respond to glutamate
and the NMDA receptor agonists by endothelium-dependent dilation that
involves stimulation of CO production via the HO pathway in the endothelium.
heme oxygenase; endothelial
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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L-GLUTAMIC
ACID (glutamate) is the principal excitatory neurotransmitter in
the central nervous system (20). In the cerebral circulation in vivo, glutamate is a vasodilator (4, 8, 9, 27). Glutamate may exert its effects via different types of receptors, including N-methyl-D-aspartate
(NMDA), 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA),
and kainate-type ionotropic glutamate receptors (10). Our
data in vivo indicate that carbon monoxide (CO) is essential for the
vasodilator effects of glutamate in the newborn pig cerebral circulation (17). CO is a potent vasodilator in the
cerebral circulation of newborn pigs and plays an important role in
maintaining cerebral vascular tone (17, 18). Heme
oxygenase (HO) is the enzyme that produces CO from the catabolism of
heme (19). Three different isoforms of HO have been
identified: the easily inducible HO-1; the constitutively expressed,
poorly inducible HO-2; and an isoform with much lower heme-degrading
activity, HO-3 (19). Both vascular endothelium and smooth
muscle cells express HO-1 and HO-2 (5, 26, 34). HO-2 is
expressed in high concentration in the brain and in cerebral
microvessels (1, 18, 19, 26). Recently, we
(27) demonstrated that glutamate and agonists of NMDA and
AMPA/kainate-type glutamate receptors cause dose-dependent vasodilation
of newborn pig pial arterioles that is blocked by HO inhibitors.
Cerebral microvessels and, specifically, cerebral microvascular endothelial cells express glutamate receptors. Krizbai et al. (16) reported the presence of glutamate receptors in cultured cerebral endothelial cells isolated from the rat brain. We (25, 26) recently detected high-affinity glutamate receptors in cerebral microvascular endothelial cells of newborn pigs in primary culture. Additionally, glutamate stimulates HO activity and increases CO production in freshly isolated cerebral microvessels in vitro (25, 27). These data indicate that, in addition to neuronal-mediated influences, cerebral microvessels may also respond directly to glutamate.
The present study was designed to investigate whether cerebral arterioles, removed from the brain, respond to glutamate by changing vascular tone via an endothelium-dependent and CO-mediated mechanism.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The animal protocols used were reviewed and approved by the Animal Care and Use Committee of the University of Tennessee Health Science Center.
Pressurized cerebral arterioles. Newborn pigs (1-5 days old) of either sex were anesthetized with ketamine hydrochloride (33 mg/kg im) and acepromazine (3.3 mg/kg im). The brain was removed and placed into a physiological saline solution (in mM: 132 NaCl, 3 KCl, 24.6 NaHCO3, 1.8 CaCl2, 1.5 MgCl2, and 10 glucose) at 4°C. Arteriolar branches of the middle cerebral artery (~200 µm in diameter) were dissected from the brain and cleaned of connective tissue. An arteriolar segment was placed in a temperature-controlled perfusion chamber and cannulated with glass pipettes at each end. The bathing chamber was continuously superfused at 3-6 ml/min with physiological solution equilibrated with a mixture of 6% CO2-6% O2-88% N2 to pH 7.4 and maintained at 37°C. Arterioles were observed with a charge-coupled device (CCD) camera coupled to an inverted microscope (Nikon TS 100-F). Arteriolar diameter was continuously monitored using the automatic edge-detection function of IonWizard software (IonOptix; Milton, MA).
Cerebral arterioles were pressurized to 10 mmHg, and, after a 10-min equilibration period, intraluminal pressure was increased to 30 mmHg. Typically, an elevation in intraluminal pressure resulted in an immediate increase in the diameter of the arteriole, followed by myogenic constriction. After 40-50 min of stabilization, tested compounds (glutamate, glutamate receptor agonist, or CO-releasing molecule) were applied in increasing concentrations. The variation of the internal diameter in the single isolated vessel was continuously measured and recorded by videomicroscopy. The maximal steady-state diameter attained over a 10-min period was recorded as the response to each dose. At the end of each tested response, the vessel was superfused with physiological solution to remove the previous stimulus and allow the arteriole to return to the baseline diameter. In a separate set of experiments, arterioles were denuded of endothelium using a pipette introduced into the lumen. The effectiveness of denudation was confirmed by the absence of the dilatory response to bradykinin (105 M), an
endothelium-dependent cerebral vasodilator (33). The response to an endothelium-independent vasodilator, the
-adrenoreceptor agonist isoproterenol (106 M), was
tested to verify that vascular smooth muscle integrity was preserved.
To investigate the involvement of HO in cerebral arteriolar dilations
induced by glutamate and glutamate receptor agonists, the arterioles
were superfused with a HO inhibitor, chromium mesoporphyrin (CrMP;
106 M). Nimodipine (106 M), a
voltage-dependent calcium channel blocker, was applied at the end of
the experiment to determine the passive arteriolar diameter.
HO-2 immunofluorescence in cerebral microvascular endothelial cells. To identify HO-2, the constitutive isoform of HO, in cerebral vascular endothelium, we used primary cultures of endothelial cells from cerebral microvessels (60-300 µm) of newborn pigs. Isolation of cerebral microvessels and endothelial cells has been described previously (26). Endothelial cells from cerebral microvessels were plated on Matrigel-covered glass coverslips and cultured in DMEM with 20% FBS, 30 µg/ml endothelial cell growth supplement, 1 U/ml heparin, and an antibiotic/antimycotic mixture for 5-6 days until confluence. Cells were exposed to a serum-depleted medium (0.1% FBS) for 15-20 h before the immunostaining to achieve quiescence. Cells were fixed with 3.7% paraformaldehyde in PBS (pH 8.4) (15 min, room temperature) and permeabilized by 0.1% Triton X-100 solution in PBS (10 min, room temperature). The nonspecific binding sites were blocked by 5% BSA (1 h at room temperature). Cells were incubated with the anti-HO-2 polyclonal antibody (dilution 1:50, StressGen; Victoria, Canada) for 1 h at 37°C followed by FITC-conjugated anti-rabbit IgG (dilution 1:100, Vector Laboratories; Burlingame, CA) for 1 h at 37°C (26). Coverslips were mounted on glass slides using antifade mounting medium (Vector Laboratories). Slides were viewed by a Nikon Diaphot microscope in conjunction with a cooled CCD camera (Photometric model 250 CH) and processed using an Image Deconvolution system. Three consequent images taken from each slide were deconvolved using Vaytech software for deconvolution and IPLab Spectrum software for image collection. For negative controls, cells were incubated with secondary antibody only and processed further as described above. Negative controls showed no immunofluorescence.
Materials. Glutamate, isoproterenol, bradykinin, and nimodipine were purchased from Sigma (St. Louis, MO). 1-Aminocyclopentane-cis-1,3-dicarboxylic acid (cis-ACPD), a NMDA receptor agonist, was purchased from Tocris (Ellisville, MO). Dimanganese decacarbonyl (DMDC; Sigma) was dissolved in DMSO and then stored under nitrogen at 0°C. The release of CO from the carbonyl metal complex is induced by photodissociation (24). Therefore, the compound was protected from light during storage and delivery to the chamber. Photodissociation was induced in the chamber by the microscope light. CrMP was purchased from Porphyrin Products (Logan, UT). CrMP and nimodipine were protected from light at all times, and the chamber was illuminated only during arteriolar diameter measurements. Cell culture reagents were purchased from Sigma, Life Technologies (Gaithersburg, MD), Becton Dickinson (Bedford, MA), and Hy-Clone (Logan, UT).
Data analysis. Values are presented as means ± SE. Data were analyzed by ANOVA with Fisher's protected least-significant-difference test to compare two individual groups. A level of P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Vasoactive effects of the CO-releasing molecule and HO inhibition.
To investigate whether CO dilates isolated cerebral arterioles, we used
DMDC, a CO-releasing molecule (24). Pressurized cerebral
arterioles of newborn pigs were superfused with DMDC at concentrations
between 108 and 106 M, and CO release by
photodissociation was induced in the perfusion chamber by the
microscope light. DMDC dilated isolated cerebral arterioles in a
concentration-dependent manner (Figs. 1 and
2). To investigate the contribution of CO
produced endogenously by HO to vascular
tone, the arterioles were exposed to a HO inhibitor, CrMP. CrMP
effectively inhibits HO activity in cerebral microvascular endothelial
cells (26) and blocks HO-mediated cerebral vascular responses in newborn pigs in vivo (17). CrMP
(106 M) caused constriction of pressurized arterioles
(percent change compared with the basal diameter: 
13 ± 4, P < 0.05), suggesting a possible contribution of
endogenously produced CO to basal vascular tone.
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Vasoactive effects of glutamate on intact cerebral arterioles.
We investigated whether glutamate regulates tone in isolated cerebral
arterioles. After development of myogenic tone, cerebral arterioles
were superfused with progressively increasing concentrations of
glutamate (106-103 M). Glutamate
induced concentration-dependent dilation of cerebral arterioles, with
the maximum vasodilation at 104 M (Figs. 3 and
4). In arterioles pretreated with CrMP
(106 M), vasodilator
responses to glutamate were blocked (Figs. 4 and
5). Similar to glutamate,
cis-ACPD, a potent NMDA receptor agonist, at concentrations
of 106 and 105 M, caused cerebral
vasodilation that was completely inhibited by CrMP (Fig.
6). In contrast, CrMP did not alter the
dilation to cAMP-dependent isoproterenol (106 M),
suggesting that CrMP does not nonselectivity inhibit CO-independent changes in vascular reactivity (Fig. 7).
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Vasoactive effects of glutamate in endothelium-denuded cerebral
arterioles.
The importance of the endothelium for vasodilation to glutamate was
investigated in endothelium-denuded arterioles. To test the
effectiveness of denudation, vascular responses to bradykinin (105 M), an endothelium-dependent vasodilator
(33), and to isoproterenol (106 M), an
endothelium-independent vasodilator, were examined. Glutamate (106 and 105 M) and bradykinin
(105 M) induced vasodilation in endothelium-intact
cerebral arterioles and caused vasoconstriction in endothelium-denuded
arterioles (Fig. 8). In contrast,
isoproterenol induced vasodilation in both endothelium-intact and
-denuded arterioles (Fig. 8). These data suggest that in isolated
cerebral arterioles, glutamate and bradykinin are endothelium-dependent
vasodilators, and isoproterenol dilates in the absence of intact
endothelium.
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HO-2 immunostaining in cerebral vascular endothelium.
Our data demonstrate the importance of the endothelium and HO activity
in dilation responses of isolated cerebral microvessels to glutamate.
HO-2 is the constitutive isoform of HO, is highly expressed in isolated
cerebral microvessels of newborn pigs, and produces CO from cellular
heme (17, 27). Therefore, we examined cerebral
microvascular endothelial cells to confirm the presence of HO-2. HO-2
was detected in vascular endothelial cells from cerebral microvessels
(60-300 µm) by indirect fluorescent immunostaining using
selective antibodies (Fig. 9). In
endothelial cells, HO-2 is localized in the perinuclear area of the
cytoplasm (the endoplasmic reticulum area) and in the nuclear envelope
(Fig. 9), confirming our previous findings (26).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The novel findings of this study in isolated pressurized cerebral arterioles from newborn pigs are as follows: 1) DMDC, a CO-releasing molecule, dilates isolated cerebral arterioles; 2) glutamate and an NMDA receptor agonist, cis-ACPD, dilate isolated cerebral arterioles; 3) glutamatergic vasodilation is blocked by HO inhibition; and 4) glutamate is an endothelium-dependent vasodilator in isolated cerebral arterioles.
CO is a vasodilator in vivo (15, 17, 30). Endogenous CO
can play an important role in the regulation of vascular tone. HO
inhibition causes hypertension in normotensive rats, and intravenous administration of the HO substrate reduces blood pressure in
hypertensive rats (13, 14). In isolated pressurized rat
gracilis muscle arterioles, superfusion with CrMP, a HO inhibitor,
decreased arteriolar diameter (15). In the present study,
we also found that CrMP at a concentration that blocks HO activity in
cerebral microcirculation in vitro [106 M
(26)], constricted isolated cerebral arterioles form
newborn pigs. In isolated rat tail arterioles, CO caused dose-dependent vasodilation (15, 30). In vivo, cerebral arterioles of
newborn pigs respond to CO with vasodilation that is dose dependent
(17). Initially, the vasodilator effects of CO were
attributed to a direct action on vascular smooth muscle cells by a
cGMP-mediated relaxing mechanism (5, 7, 11, 22, 30).
However, CO can cause vasodilation independently of cGMP by causing
smooth muscle hyperpolarization via activation of calcium-activated
potassium channels (11, 12, 17, 29, 31, 32). In the
isolated rat tail artery, both mechanisms can be involved in CO-induced relaxation (30-32).
A previous attempt to demonstrate dilation of isolated cerebral arterioles in response to CO was not successful (3). Failure to detect dilation of isolated arterioles may be because gaseous CO is difficult to maintain at intended concentrations in solutions exposed to air (30). To circumvent this problem, we superfused isolated pressurized cerebral arterioles with a molecule that releases CO on exposure to light (24). In our experiments, the CO-releasing molecule, DMDC, caused a concentration-dependent vasodilation, which is similar to that observed when pial arterioles were exposed to CO under a closed cranial window in vivo (17).
Glutamate is a major excitatory neurotransmitter in the brain. In the cerebral microcirculation of several animal species in vivo, glutamate is a vasodilator (4, 6, 8, 9, 21, 27, 28). The mechanisms underlying these vasoactive effects are unclear. Glutamate may, by increasing neuronal discharge activity, promote the neuronal production of vasorelaxant factors, including nitric oxide (NO) (6, 8, 9, 21), and CO (1, 34). CO and NO may play complementary roles in cerebral arteriolar diameter regulation. A recent study (18), designed to analyze the interactions between CO and NO, demonstrated that NO was acting in a permissive way to allow CO-induced cerebral vasodilation in newborn pigs. These data, combined with those of Meng et al. (21), suggest the possibility that the ability of NO synthase inhibitors to block dilation to glutamate could result from loss of the necessary permissive enabler for CO-induced dilation.
We investigated whether cerebral arterioles removed from the neuronal influences can directly respond to glutamate. To exclude neuronal influences, we conducted the experiments in isolated cerebral arterioles. In preparations of isolated arterioles, perivascular neurons (even if present in such small precapillary vessels in the brain in vivo) have been cut and severely damaged during arteriole removal from the brain parenchyma. Damaged neurons lose the ability to hold a membrane potential and to respond to stimulation, and, therefore, functional contribution of perivascular innervation to the responses of isolated arterioles is unlikely. Data are available on expression and functioning of glutamate receptors in isolated cerebral microvessels and cerebral endothelial cells of rat and pigs (16, 25, 26), although some investigators did not detect such receptors (2, 23). Recently, we detected NMDA-type glutamate receptors in endothelial cells from cerebral microvessels of newborn pigs by a competitive radioligand binding assay and by immunoblotting (25). It has been shown that rat cerebral microvessels express ionotropic and metabotropic glutamate receptor subunits and that the effects of glutamate agonists in the modulation of blood-brain barrier function are mediated directly through the sites of action on cerebral microvessels (28). Our present study shows that isolated cerebral arterioles respond to amino acid excitatory neurotransmitters, glutamate and a NMDA receptor agonist, cis-ACPD, by vasodilation. The dilator responses of pressurized cerebral arterioles to glutamate receptor stimulation are comparable with the responses to such potent vasodilators as bradykinin and isoproterenol. These data support the hypothesis that cerebral arterioles can be directly targeted by glutamate via a glutamate receptor- mediated mechanism.
Our data show that HO inhibition completely blocked vasodilation of isolated arterioles to glutamate and an NMDA receptor agonist, suggesting involvement of cerebrovascular-derived CO. In cerebral microvessels from newborn pigs, HO is highly expressed (17, 26), and HO-directed CO production is stimulated by glutamate via ionotropic glutamate receptors, including NMDA-type receptor (27). HO-2, the constitutive isoform of HO, is expressed in vascular endothelium of cerebral microvessels. Cultured cerebral microvascular endothelial cells respond to agonists of ionotropic glutamate receptors by increasing CO production (25). Therefore, we hypothesized that an intact endothelium is essential for cerebral arteriolar dilation to excitatory amino acids. To investigate the role of the endothelium in the CO-mediated response to glutamate, we studied intact and endothelium-denuded cerebral arterioles. Functional denudation of arterioles was confirmed by the absence of dilation to bradykinin, an endothelium-dependent vasodilator in the cerebral circulation of newborn pigs in vivo (33). We obtained dilation to glutamate only in isolated pressurized arterioles with an intact endothelium but not in endothelium-denuded arterioles. The loss of these responses was not due to generalized injury to the arteriole because isoproterenol, an endothelium-independent vasodilator, produced similar dilation after endothelial removal. Therefore, endothelial removal abolished the responses to glutamate, suggesting that CO released from the endothelium is important in vasodilation of cerebral arterioles to excitatory neurotransmitters.
In conclusion, our data suggest that cerebral arterioles from newborn pigs may directly respond to glutamatergic stimulation via a glutamate receptor-mediated mechanism. Endothelium-dependent vasodilator effects of glutamate in cerebral circulation involve CO as vascular-derived vasorelaxant factor.
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ACKNOWLEDGEMENTS |
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The authors thank Alex Fedinec for excellent technical support and Danny Morse and Greg Short for helping with preparation of the figures.
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FOOTNOTES |
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This research was supported by the National Heart, Lung, and Blood Institute, the American Heart Association, and the Southeast Affiliate of the American Heart Association.
Address for reprint requests and other correspondence: H. Parfenova, Dept. of Physiology, Univ. of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163 (E-mail: hparf{at}physio1.utmem.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00881.2002
Received 7 October 2002; accepted in final form 26 November 2002.
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ABSTRACT
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METHODS
RESULTS
DISCUSSION
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A. Zimmermann, C. W. Leffler, D. Tcheranova, A. L. Fedinec, and H. Parfenova Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2501 - H2507. [Abstract] [Full Text] [PDF]
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C. W. Leffler, H. Parfenova, A. L. Fedinec, S. Basuroy, and D. Tcheranova Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2897 - H2904. [Abstract] [Full Text] [PDF]
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A. Kanu, J. Whitfield, and C. W. Leffler Carbon monoxide contributes to hypotension-induced cerebrovascular vasodilation in piglets Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2409 - H2414. [Abstract] [Full Text] [PDF]
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 S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]
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 C. W. Leffler, H. Parfenova, J. H. Jaggar, and R. Wang Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation J Appl Physiol, March 1, 2006; 100(3): 1065 - 1076. [Abstract] [Full Text] [PDF]
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 E. M. Sanhueza, R. A. Riquelme, E. A. Herrera, D. A. Giussani, C. E. Blanco, M. A. Hanson, and A. J. Llanos Vasodilator tone in the llama fetus: the role of nitric oxide during normoxemia and hypoxemia Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R776 - R783. [Abstract] [Full Text] [PDF]
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E. Barkoudah, J. H. Jaggar, and C. W. Leffler The permissive role of endothelial NO in CO-induced cerebrovascular dilation Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1459 - H1465. [Abstract] [Full Text] [PDF]
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 S. W. Ryter, D. Morse, and A. M. K. Choi Carbon Monoxide: To Boldly Go Where NO Has Gone Before Sci. Signal., April 27, 2004; 2004(230): re6 - re6. [Abstract] [Full Text] [PDF]
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P. Koneru and C. W. Leffler Role of cGMP in carbon monoxide-induced cerebral vasodilation in piglets Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H304 - H309. [Abstract] [Full Text] [PDF]
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P. Carratu, M. Pourcyrous, A. Fedinec, C. W. Leffler, and H. Parfenova Endogenous heme oxygenase prevents impairment of cerebral vascular functions caused by seizures Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1148 - H1157. [Abstract] [Full Text] [PDF]
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