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1 Laboratory for Research in Neonatal Physiology, Departments of Physiology and Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38163; 2 Department of Pharmacology, New York Medical College, Valhalla, New York 10595; and 3 Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Carbon
monoxide (CO) is an endogenous dilator in the newborn cerebral
microcirculation. Other dilators include prostanoids and nitric oxide
(NO), and interactions among the systems are likely. Experiments on
anesthetized piglets with cranial windows address the hypothesis that
CO-induced dilation of pial arterioles involves interaction with the
prostanoid and NO systems. Topical application of CO or the heme
oxygenase substrate heme-L-lysinate (HLL) produced
dilation. Indomethacin,
N
-nitro-L-arginine
(L-NNA), and either iberiotoxin or tetraethylammonium chloride (TEA) were used to inhibit prostanoids, NO, and
Ca2+-activated K+ (KCa) channels,
respectively. Indomethacin, L-NNA, iberiotoxin, or TEA
blocked cerebral vasodilation to CO and HLL. Vasodilations to both CO
and HLL were returned to indomethacin-treated piglets by topical
application of iloprost. Vasodilations to both CO and HLL were returned
to L-NNA-treated piglets by sodium nitroprusside but not
iloprost. In iberiotoxin- or TEA-treated piglets, dilations to CO and
HLL could not be restored by either iloprost or sodium nitroprusside.
The dilator actions of CO involve prostacyclin and NO as permissive
enablers. The permissive actions of prostacyclin and NO may alter the
KCa channel response to CO because neither iloprost nor
sodium nitroprusside could restore dilation to CO when these channels
were blocked.
heme oxygenase; permissive, potassium channels
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CONSIDERABLE EVIDENCE is accumulating that carbon monoxide (CO) can be an important vascular paracrine factor. CO is produced physiologically via metabolism of heme to CO, biliverdin, and free iron by heme oxygenase (HO) (18). Both HO-1 and HO-2 have been identified in vascular endothelial and smooth muscle cells (4, 31). Endogenously produced CO and exogenous CO can cause endothelium-independent dilation of arteries and arterioles (4, 5, 9, 10), and endogenous CO appears to provide a tonic vasodepressor effect via inhibition of an autonomic pressor mechanism (8). CO has been suggested as an additional endothelially derived relaxing factor important in vascular regulation (31). HO-2 is strongly expressed in the piglet cerebral microvasculature (16). Exogenous CO and topical application of HO substrate dilate piglet cerebral arterioles. The dilation to heme, but not to CO, is blocked by the HO inhibitor chromium mesoporphyrin, suggesting endogeneous HO can produce sufficient CO to dilate the cerebral microvasculature. It has been suggested that the similarity of cellular locations of HO and nitric oxide (NO) synthase (NOS), to which we add prostaglandin cyclooxygenase (COX), may imply coordinated and potentially complementary roles of the paracrine mediators that are the currently identified endothelium-derived relaxing factors (31).
Prostacyclin plays an important role in control of the newborn cerebral circulation (14). Prostacyclin can cause dilation directly via increases in vascular smooth muscle cAMP (21). Endothelial prostacyclin can also provide a permissive signal to cerebral microvascular smooth muscle allowing dilation in response to another stimulus (15), hypothetically communicating confirmation of the functional integrity of the vessel wall (12). Extensive cross-talk occurs between this prostanoid and NO systems in control of vascular tone (25). Recently, it has been shown that CO may join the group because CO produced from endogenous HO can stimulate prostaglandin synthesis in the rat hypothalmus (19). Furthermore, NO can cause upregulation of HO-1 in vascular smooth muscle independently of cGMP (6). Finally, it has been suggested that the effects of CO on cerebral blood flow may be mediated by NO (20).
Therefore, the present experiments were designed to address the hypothesis that CO-induced dilation of newborn cerebral arterioles in vivo involves interaction with the cerebral prostanoid and NO systems.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All procedures that involve animals were reviewed and approved
by the Animal Care and Use Committee of the University of Tennessee Health Science Center. Newborn pigs (1-3 days old; 1-2.5 kg)
were anesthetized with ketamine hydrochloride (33 mg/kg im) and
acepromazine (3.3 mg/kg im) and maintained on 
-chloralose (50 mg/kg
iv). The animals were intubated and ventilated with air. Catheters were inserted into the femoral vein for maintenance of anesthesia and drug
injections and into the femoral artery to record blood pressure and
draw samples for blood gases and pH analysis. Blood gases and pH were
maintained within normal ranges. Body temperature was maintained at
37-38°C. The scalp was retracted, and a hole 2 cm in diameter
was made in the skull over the parietal cortex. The dura was cut
without touching the brain, and all cut edges were retracted over the
bone so that the periarachnoid space was not exposed to bone or damaged
membranes. A stainless steel and glass cranial window was placed in the
hole and cemented into place with dental acrylic. The space under the
window was filled with artificial cerebrospinal fluid (aCSF), which was
equilibrated with 6% CO2-6% O2-88%
N2 and produced gases and pH within the normal
range for CSF (pH = 7.33-7.40,
PCO2 = 42-46 mmHg, and
PO2 = 43-50 mmHg). aCSF could be
injected and samples could be collected from needle ports on the sides
of the window. The volume of the fluid directly beneath the window was
500 µl and was contiguous with the periarachnoid space. Pial vessels
were observed with a dissecting microscope. Diameters were measured
with a video micrometer coupled to a television camera mounted on the
microscope and to a video monitor. Two pial arterioles of different
sizes were measured in each piglet.
Materials.
CO was purchased as compressed gas (99.5%). A saturated solution was
produced in ethanol at 37°C (7 × 10
3 M). The
stock was diluted in aCSF for injection under the cranial window at
concentrations from 1012 to 105 M. The HO
substrate heme-L-lysinate (38 mM) was prepared using methods described by Tenhunen et al. (27). It was
protected from light at all times until placement beneath the cranial
window, and the cranial window was only illuminated during vessel
diameter measurements. Heme-L-lysinate was stored at
30°C. Lysinate vehicle (L-lysine, H2O,
propylene glycol, and ethanol) was used as 0 M heme-L-lysinate at a dilution equal to that with
heme-L-lysinate at 2 × 106 M. Heme-L-lysinate was diluted in aCSF
(108-2 × 106 M) for placement
under the cranial window. The HO inhibitor chromium mesoporphyrin was
purchased from Porphyrin Products (Logan, UT). Water-soluble
indomethacin (indomethacin trihydrate) was a gift from Merck (Rahway,
NJ). Iloprost was a gift from Schering AG (Berlin, Germany). Other
reagents were purchased from Sigma Chemical (St. Louis, MO).
Experiments.
CO and heme-L-lysinate were applied directly to pial
arterioles, and the maximal diameter attained over a 10-min period was recorded as the response to each dose. Repeat ascending dose-response curves to CO or heme-L-lysinate were produced before and
after no treatment or treatment with indomethacin (5 mg/kg iv)
(14) or
N-nitro-L-arginine
(L-NNA; 103 M topically) (2).
Collections of CSF (300 of 500 µl total) were made from beneath the
cranial window at the end of each 10-min period for later measurements
of 6-keto-PGF1
.
6 M topically for 5 min), hypercapnia (10% CO2 ventilation for 5 min), or
sodium nitroprusside (107 M topically for 5 min) were
measured before and after treatments.
Experiments to investigate potential permissive contributions of
prostacyclin and NO (see RESULTS) were conducted by
applying either iloprost (1012 M) or sodium nitroprusside
topically during treatment with either CO or
heme-L-lysinate after inhibition of COX or NOS with
indomethacin or L-NNA, respectively. In experiments in
which responses to CO were determined in the presence of sodium
nitroprusside and L-NNA, the concentration of sodium
nitroprusside used was 107 M. When responses to
heme-L-lysinate were determined with sodium nitroprusside
and L-NNA, the concentration of sodium nitroprusside was 2 × 107 M, because in four preliminary experiments the
results with 107 M were not consistent.
Also, either iloprost or sodium nitroprusside was topically given
during treatment with CO after inhibition of KCa channels with iberiotoxin (106 M) or tetraethlylammonium chloride
(TEA) (103 M) (16).
6-keto-PGF1 was measured in the CSF by radioimmunoassay
as described previously (21).
Statistical analysis. Values for each variable are presented as means ± SE. Comparisons among populations within each experimental group used ANOVA with repeated measures. Fisher's protected least-significant difference test was used to determine differences between populations within each group. P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CO produced dose-dependent dilation of larger and smaller piglet
pial arterioles (Fig. 1). Repeat
dose-response curves were virtually superimposable (data not shown)
(n = 5). Heme-L-lysinate also caused
dose-dependent dilation of pial arterioles (Fig.
2). Repeat dose-response curves were
superimposable and larger and smaller arterioles responses were
similar, so only data from ~60-µm arterioles are shown.
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Indomethacin treatment blocked vasodilations to both CO (Fig. 1) and
heme-L-lysinate (Fig. 2). L-NNA also blocked
vasodilation to both CO (Fig. 3) and
heme-L-lysinate (Fig. 4).
Neither indomethacin nor L-NNA altered dilatory responses
to sodium nitroprusside (107 M) or isoproterenol
(106 M) (data not shown).
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Dilation to CO that had been blocked by indomethacin treatment was
partially restored in the presence of 1012 M iloprost
(which did not cause significant dilation on its own) and was again
absent after removal of the iloprost (Fig.
5). When sodium nitroprusside
(107 M) was given with CO, no dose-dependent restoration
of dilation to CO could be documented (Fig.
6). In contrast, sodium nitroprusside (107 M) totally restored vasodilation to CO after
inhibition of NOS by L-NNA (Fig.
7). Removal of topical sodium
nitroprusside eliminated the dilation to CO, and the dilation was again
restored when sodium nitroprusside was reapplied.
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As with CO responsiveness, cerebral vasodilation to topical
heme-L-lysinate that had been blocked by indomethacin
returned when a prostacyclin (IP) receptor agonist background
was provided in the form of iloprost (1012 M) (Fig.
8). In the case of
heme-L-lysinate-induced dilation, iloprost cotreatment
completely restored dilation to indomethacin-treated piglets. On
removal of iloprost, as with CO, vasodilation to
heme-L-lysinate was absent. Application of sodium
nitroprusside to indomethacin-treated piglets appeared to partially
allow dilation to heme-L-lysinate to occur (Fig.
9).
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As with CO, L-NNA blocked responses to
heme-L-lysinate. Sodium nitroprusside (2 × 107 M) cotreatment restored dilation in response to
heme-L-lysinate (Fig. 10).
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Results for iberiotoxin and TEA were identical and thus were combined.
Inhibition of KCa channels blocked dilation to CO. Neither
iloprost nor SNP restored any dilation to CO in piglets treated with
iberiotoxin or TEA (Fig. 11).
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Neither CO nor heme-L-lysinate had effects on cerebral
prostacyclin production that could be detected by measuring
6-keto-PGF1 in cortical periarachnoid fluid. CO caused
no significant change at any concentration from 1012 to
107 M (n = 13) (data not shown). Although
heme-L-lysinate appeared to increase cortical periarachnoid
6-keto-PGF1 concentration slightly, significance was
reached only at the highest concentration [6-keto-PGF1
concentration: vehicle, 1,050 ±148 pg/ml; and heme-L-lysinate (2 × 106 M), 1,699 ± 539 pg/ml].
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The new findings of the current study are that 1) both prostanoids and NO appear to contribute to CO-induced cerebral vasodilator responses via permissive signals, and 2) KCa channels mediate vasodilations to CO downstream of the actions of prostanoids and NO.
CO is a potential paracrine mediator with multiple similarities to NO. Constitutively expressed enzymes responsible for the generation of both gases are found in the endothelium, vascular smooth muscle, and perivascular neurons (3, 18, 31). Both can produce vasodilation and inhibit platelet activation via activation of soluble guanylyl cyclase (4, 11, 18, 28), although considerable evidence suggests CO can produce dilation independently of cGMP (7, 26). Dilation to CO and NO can involve vascular smooth muscle hyperpolarization via K+ channel activity (23, 24, 28, 29, 30). CO and NO appear to have special roles in the brain where they can function as cotransmitters or as modulators of neuropeptides. The localizations of HO-2 and brain NOS (bNOS) in the brain suggest special roles for CO and NO in cerebral function, including regulation of cerebrovascular circulation.
Prostacyclin provides a predominant dilator influence in the neonatal cerebral vasculature (14). This influence was originally conceived to involve cAMP-dependent modulation of cerebrovascular tone. However, it is becoming increasingly clear that, although prostacyclin may allow specific cAMP-dependent responses to occur, the physiological role of prostacyclin in the newborn circulation can be a permissive one that is independent of direct coupling between the IP receptor and adenylyl cyclase (12). It is proposed that endothelially derived prostacyclin communicates the functional integrity of the arteriolar wall to the vascular smooth muscle, greatly modifying vascular smooth muscle responses to additional imputs. NO signals from bNOS may provide additional confirmation of perivascular neuronal integrity in the older individual (13). Concerning the question of "permissive" versus "conventional" actions of prostacyclin and NO, one must also consider the possibility that elevations of production of mediators in very localized areas could be occurring, allowing conventional function in either an autocrine or a paracrine manner. Such small increases might not be detectable by collections of periarachnoid fluid. Nevertheless, it is clear that both prostacylcin and NO can act in a permissive enabling manner, because with production systems blocked and only a constant exogeneously supplied addition of either iloprost or sodium nitroprusside the full dose-response relationship to CO or heme-L-lysinate can be restored.
We now report that CO appears to interact with both of these other
classical autocrine/paracrine mediators in producing cerebral vasodilator responses. Interactions between the CO and NO systems have
been reported before (18). In fact, it has been reported previously that CO-induced cerebral vasodilation in the adult rat
appears to be mediated by NO (20), although the mechanism is not known. Over a longer period NO can cause upregulation of HO-1
(6), but the time course of the present experiments
obviates any such mechanism being involved in our data. Whereas NO and CO are both capable of activating soluble quanylyl cyclase and thus
potentially summating in producing cGMP-dependent dilation, we could
detect no increase in cerebral cGMP production coincident with CO- or
heme-L-lysinate-induced dilation in contrast to NO-induced (sodium nitroprusside) dilation (16). CO has been shown to
stimulate prostaglandin synthesis (19). However, increased
prostanoid production does not appear to be necessary for CO-induced
cerebral vasodilation, because a background of only 1012
M iloprost is sufficient to promote CO and heme-L-lysinate
dilations in piglets treated with indomethacin and neither
heme-L-lysinate nor CO increased cerebral prostacyclin
production markedly. cAMP does not appear to play a major role in the
dilator responses to CO because increases in cerebral cAMP production
in response to CO or heme-L-lysinate were small and the
dose dependency was poor (16) in contrast to
dose-dependent dilations produced by iloprost or isoproterenol
(22). Therefore, it appears that, while CO-induced
cerebral vasodilation involves interactions with both the prostanoid
and nitric oxide systems, cyclic nucleotides are not the primary second
messengers in CO-induced dilation in this system. Particularly likely
is involvement of hyperpolarization via a KCa channel
(17, 29, 30).
Many unanswered questions remain. Surprisingly, both indomethacin and L-NNA totally abolished dilation to either CO itself or heme-L-lysinate. Iloprost alone restored much of the dilation after indomethacin treatment but not after L-NNA. Similarly, sodium nitroprusside alone restored dilation to CO and heme-L-lysinate after L-NNA, but iloprost was without effect. It appears that obligatory permissive enabler roles are played by both prostacyclin and NO. It has been reported that dilation to prostacyclin can be mediated by NO but that such dilation involved vasodilator levels of prostacyclin and increased cGMP (1). Therefore, although the present experiments strongly suggest a contribution of endogenous NO to CO-induced dilation, the mechanisms remain illusive.
Previous permissive actions of IP receptor activation have involved cAMP-dependent dilators. Iloprost appears to increase the cAMP production in response to, for example, hypercapnia, histamine, and epoxyeicosatrienoic acids by a mechanism involving protein kinase C (12). However, vasodilation to CO is not coincident with a detectable elevation of cAMP. Instead, the dilation to CO appears to be mediated by KCa channels, because the dilation was totally abolished by either TEA or iberiotoxin. The permissive actions of prostacyclin and NO may alter the KCa channel response to CO because neither iloprost nor sodium nitroprusside could restore dilation to CO when KCa channels were blocked.
The dilator actions of CO appear to be intimately involved with the prostanoid and NO systems and subsequent activation of KCa channels by CO.
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ACKNOWLEDGEMENTS |
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We thank Danny Morse and Laura Malinick for preparing the final figures and Barbara Rawls for secretarial assistance.
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FOOTNOTES |
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This research was supported by the National Heart, Lung, and Blood Institute.
Address for reprint requests and other correspondence: C. W. Leffler, Dept. of Physiology, 894 Union Ave., Memphis, TN 38163 (E-mail: cleffler{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.
Received 31 July 2000; accepted in final form 1 November 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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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A. Rebel, S. Cao, H. Kwansa, S. Dore, E. Bucci, and R. C. Koehler Dependence of acetylcholine and ADP dilation of pial arterioles on heme oxygenase after transfusion of cell-free polymeric hemoglobin Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1027 - H1037. [Abstract] [Full Text] [PDF]
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 L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]
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C. W. Leffler, L. Balabanova, A. L. Fedinec, and H. Parfenova Nitric oxide increases carbon monoxide production by piglet cerebral microvessels Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1442 - H1447. [Abstract] [Full Text] [PDF]
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C. W. Leffler, A. L. Fedinec, H. Parfenova, and J. H. Jaggar Permissive contributions of NO and prostacyclin in CO-induced cerebrovascular dilation in piglets Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H432 - H438. [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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Q. Xi, D. Tcheranova, H. Parfenova, B. Horowitz, C. W. Leffler, and J. H. Jaggar Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing apparent Ca2+ sensitivity of {alpha}-subunits Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H610 - H618. [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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E. Fiumana, H. Parfenova, J. H. Jaggar, and C. W. Leffler Carbon monoxide mediates vasodilator effects of glutamate in isolated pressurized cerebral arterioles of newborn pigs Am J Physiol Heart Circ Physiol, April 1, 2003; 284 (4): H1073 - H1079. [Abstract] [Full Text] [PDF]
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J. S. Naik, T. L. O'Donaughy, and B. R. Walker Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H838 - H845. [Abstract] [Full Text] [PDF]
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J. S. Robinson, A. L. Fedinec, and C. W. Leffler Role of carbon monoxide in glutamate receptor-induced dilation of newborn pig pial arterioles Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2371 - H2376. [Abstract] [Full Text] [PDF]
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 H. Parfenova, R. A. Neff III, J. S. Alonso, B. V. Shlopov, C. N. Jamal, S. A. Sarkisova, and C. W. Leffler Cerebral vascular endothelial heme oxygenase: expression, localization, and activation by glutamate Am J Physiol Cell Physiol, December 1, 2001; 281(6): C1954 - C1963. [Abstract] [Full Text] [PDF]
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H. L. Xu, R. A. Santizo, H. M. Koenig, and D. A. Pelligrino Chronic estrogen depletion alters adenosine diphosphate-induced pial arteriolar dilation in female rats Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2105 - H2112. [Abstract] [Full Text] [PDF]
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J. S. Robinson, A. L. Fedinec, and C. W. Leffler Role of carbon monoxide in glutamate receptor-induced dilation of newborn pig pial arterioles Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2371 - H2376. [Abstract] [Full Text] [PDF]
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P < 0.05 compared
with no indomethacin.
