From the Departments of Clinical Neurosciences (R.P.W., H.S.M.) and
Medical Physics and Engineering (C.D.), King's College School of
Medicine and Dentistry and the Institute of Psychiatry; and the Centre for
Clinical Pharmacology, University College (P.V.), London, UK.
Correspondence to Dr Hugh Markus, Department of Neurology, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK. E-mail h.markus{at}iop.bpmf.ac.uk
Methods—L-NMMA was administered as an intravenous
bolus at three doses (1, 3, and 10 mg/kg). CBF was assessed by color
velocity ultrasonic imaging of internal and common carotid artery
volume flow (ICA flow and CCA flow) and transcranial
Doppler ultrasound measurement of middle cerebral artery flow
velocity (MCA
Results—L-NMMA produced a dose-dependent reduction in basal
mean±SD CCA flow from 415.2±51.9 to 294±56.2 mL/min (at 10 mg/kg)
and ICA flow from 268.8±59.4 to 226.2±72.6 mL/min
(P<.005 and P<.05, respectively,
comparing areas under the dose-response curve). This was reversed by
L-arginine. Mean±SD systemic blood pressure rose from
85.2±6.4 to 100.8±9.6 mm Hg (P<.01). There was
no significant reduction in MCA
Conclusions—Basal NO release is important in controlling human
CBF, but intravenously administered L-NMMA does not inhibit
the hypercapnic hyperemic response in humans. The discrepancy
between CBF and MCA
It has been suggested that the vasodilatory response to hypercapnia is
mediated by NO. In a number of studies, this response has been
inhibited by L-arginine
analogues.10 11 12 13 14 However, results have not been
consistent, with differences in sensitivity to NOS
inhibitors described within and between
species.1 14 15
Although in isolated human cerebral arteries NO has been shown to
mediate relaxation,16 17 its relative
contribution to basal CBF control in humans has been inferred but not
previously established. In humans, the contribution of NO to basal
vascular tone in peripheral vascular beds is well
demonstrated.18 However, variation between
different vascular beds may occur. In addition, extrapolating animal
data to the human cerebrovasculature can be potentially misleading.
Studies of previously identified potential mediators such as
prostaglandins have demonstrated different results between
animal models and humans.19 20
In this study we determined the contribution of NO release to basal CBF
and the hyperemic response to hypercapnia in humans using the
NOS inhibitor L-NMMA. To control for the potentially
confounding influence of blood pressure elevation following systemic
L-NMMA administration, we also studied basal and hyperemic
responses after noradrenaline administration at an
equivalent pressor dose.
Therefore, a total of 18 studies were performed in 13 healthy
volunteers (4 women), mean±SD age 27.9±3.3 years and weight
73.7±16.5 kg. In 5 individuals, two studies were performed, but at
least 1 month was allowed between the two studies. All subjects had
abstained from alcohol for the preceding 24 hours and fasted for 2
hours before the studies. Four of the volunteers were current smokers,
but all had abstained for the preceding 24 hours. The project was
approved by the King's College Hospital Ethics Committee. Informed
written consent was obtained from all subjects.
Ultrasonic quantification of right CCA and ICA blood volume flow was
performed using a color velocity imaging system (Philips P700 CVI-Q).
This is a color flow imaging method that combines M-mode imaging with
time-domain processing for simultaneous determination of
flow velocity and functional vessel diameter, from which effective flow
volume is calculated as an integrative function. In vitro validation
with flow phantoms shows good correlation with volume flows within the
physiological range.21 22 We
have previously determined the reproducibility of flow measurements in
18 healthy subjects.22 Mean±SD percent variation
between repeated measurements was 6.3±6.9% for the CCA and 9.7±9.8%
for the ICA. MCA
During all studies, end-tidal CO2 was
continuously recorded (Datex Normocap 200). For the hypercapnia
study, CO2 was administered via a face mask with
both inspiratory and expiratory limbs protected by one-way valves.
During all studies, MAP and pulse rate were monitored using an
automated blood pressure cuff (Omega 1400, In-Vivo Laboratories plc),
and for each reading a mean of three measurements was taken. All
subjects were studied in a supine position with the head elevated on a
pillow, after a 15-minute rest period.
Basal CBF Study
Hypercapnic Hyperemia Study
Noradrenaline Study
Statistical Analysis
There was a dose-dependent increase in MAP and reduction in pulse rate
(Fig 1
Hypercapnic Hyperemia Study
The effect of L-NMMA on the vasodilatory response to both 6% and 8%
CO2 are shown in Table 2
After L-NMMA there was no significant difference in resting MCA
The baseline resting CCA flow was still suppressed at 45 minutes after
10 mg/kg L-NMMA. After L-arginine, baseline and absolute
CCA flow responses to hypercapnia returned to pre–L-NMMA values (Table 3
Noradrenaline Study
The effects on basal CBF are consistent with those found in a
large variety of animal studies.1 3 4 15 L-NMMA
also resulted in an increase in MAP, and this may have reduced the
magnitude of the fall in CBF seen in response to NOS inhibition.
Noradrenaline at an equivalent pressor, and therefore
systemic vasoconstrictor, dose to L-NMMA did not reduce CBF to the same
degree as L-NMMA, indicating that NO inhibition has a specific effect
on the cerebral circulation. In both the L-NMMA and
noradrenaline studies, repeated measurements of CBF were
made. It has been suggested that CBF may fall with repeated
measurements; however, the significantly greater reduction in the
L-NMMA group, despite repeated measurements being made in both groups,
indicates that the reduction seen after L-NMMA is not due to the effect
of repeated measurements but that L-NMMA has a specific effect on basal
CBF. Without an independent measure of NOS activity, or a more
isoform-selective inhibitor, it is impossible to assess the
relative contribution of eNOS and nNOS to our observations. The
systemic hypertensive effects of L-NMMA are due to increasing tone in
resistance vessels that are normally maintained in a partially
vasodilated state by tonic NO release thought to derive from
eNOS,18 and this is supported from studies in
eNOS knockout mice.24 The fall in carotid artery
flow we observed mirrored closely the elevation in MAP, and this
synchrony with the systemic effects would be in keeping with a
predominant effect of eNOS. This is supported by the finding that NOS
inhibition reduces CBF in wild-type mice but not in eNOS knockout
mice.9
In contrast to its effects on basal CBF, L-NMMA had no significant
effect on the hypercapnic vasodilatory response even at a dose that
resulted in significant changes in blood pressure and basal CBF. We
estimated this response both as the absolute rise in CBF and the
percentage of rise. This lack of inhibition occurred both at moderate
concentrations of CO2 (6%) and at higher
concentrations (8%) which cause maximal vasodilation. There was a
nonsignificant fall in the absolute increase in CCA flow during
CO2 administration after L-NMMA, and a
nonsignificant rise in the percent increase in CCA flow, but these
changes probably reflect the lower baseline flow during L-NMMA
administration. Previous animal studies have shown conflicting effects
of NOS inhibitors on this response. Most studies in rats
have shown NO dependence of the hypercapnic response, although
sometimes less so at high CO2
concentrations.11 12 13 However, results in higher
species have been less consistent. Inhibition of 20% in cats
has been reported, whereas results in primates have shown conflicting
results.1 14 The reasons for these differences
within species are unclear, although newborn animals may show quite
different responses from juvenile or adult
animals,25 and there may be differences within
different brain regions in NO dependence.1
Furthermore, in these animal studies, anesthesia may alter
cerebrovascular responses. The failure of our study to demonstrate
attenuation of the hypercapnic hyperemic response may be a
function of the short duration of biological activity of L-NMMA and
poor blood-brain barrier penetration in systemic bolus administration.
However, blood-brain barrier penetration is not necessary for
inhibition of eNOS, and animal studies using a similar route of
administration have shown inhibition of the response. One recent study
in humans, published in abstract form, suggested that 5 minutes after
NOS inhibition with L-NMMA at a dose of 3 mg/kg,
CO2 reactivity was reduced. However, this study
used transcranial Doppler to estimate CBF, with no
absolute measure of CBF. However, because of the effect of L-NMMA on
MCA diameter in this situation, velocity does not correlate well with
CBF, making the results difficult to
interpret.26
Human MCA diameter remains constant during a number of
physiological alterations, such as blood pressure
and CO2 changes. Therefore, MCA
In view of these difficulties in interpreting transcranial
Doppler flow velocity changes, we used a quantitative method of
measuring CBF, color velocity flow imaging. Doppler-based methods
are widely used in measuring carotid volume flow and in assessing the
effects of pharmacological agents on the cerebral
circulation.28 Reproducible measurements can be
obtained, but inaccuracies can occur because of the need for
measurement of the cross-sectional area of the
vessel.28 In color velocity flow imaging, the
velocity profile is investigated by a series of small sample volumes.
If each velocity component is assumed to be
representative of velocities in that semiannulus, the
volume flow can be obtained by summing of the velocity
components.22 This method obviates the need for
an image-based measurement of diameter because the calculation relies
on the effective diameter of flow whose limit is determined by the
minimum velocities detected near the vessel wall. Previous studies
using the same equipment as that used in this study have shown that the
flow values obtained correlate well with absolute flow values measured
by a flowmeter.21 22 In humans, the method
results in reproducible measurements22 ; the
normal values reported in the CCA (330 mL/min in women and 375 mL/min
in men in one study21 and 376 mL/min in another
study22 ) are similar to those obtained from xenon
radionuclide methods, which estimated CCA flow rates of about 350
mL/min.28
Impaired NO synthesis and release can be demonstrated in the forearm
arteries of patients with a number of risk factors for cerebrovascular
disease.29 30 Now that we have shown that basal
CBF in humans is NO dependent, it remains to be determined whether
similar impairment of NO release is seen in the cerebral circulation of
such patients. In acute stroke, NOS inhibition may have both beneficial
and deleterious effects. Animal studies of the effect of NOS inhibition
on infarct size have shown conflicting results, but recent studies
suggest that nNOS inhibition may be protective while eNOS inhibition
may be deleterious, possibly through a fall in
CBF.31 Our study would support the use of caution
with nonspecific NOS inhibitors such as L-NMMA because the
potential reduction in tissue perfusion may offset any beneficial
neuroprotective effects, although future selective nNOS
inhibitors may be beneficial.
Received September 12, 1997;
revision received November 13, 1997;
accepted December 1, 1997.
© 1998 American Heart Association, Inc.
Original Contributions
Nitric Oxide Synthase Inhibition in Humans Reduces Cerebral Blood Flow but Not the Hyperemic Response to Hypercapnia
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Animal
studies suggest that nitric oxide (NO) is important in basal cerebral
blood flow (CBF) regulation and that it may mediate the vasodilatory
response to carbon dioxide. We investigated its role in the human
circulation using the NO synthase inhibitor
NG-monomethyl-L-arginine
(L-NMMA). 
). The pressor effect of L-NMMA was controlled for by
comparison with noradrenaline titrated to effect an
equivalent blood pressure elevation. . There was no significant change in
the CBF response to either 6% or 8% carbon dioxide after L-NMMA.
Noradrenaline produced a lesser fall in basal CCA flow
(12.0%) but had a similar effect on the hypercapnic response. after L-NMMA administration is
consistent with MCA vasoconstriction. Neuronal NO synthase
inhibition may be protective in stroke. However, our results suggest
that nonselective NO synthase inhibitors such as L-NMMA
should be used with caution because they reduce CBF.
Key Words: cerebrovascular circulation • nitric oxide • noradrenaline • ultrasonography, Doppler
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Studies in animal
models suggest that NO plays an important role in the cerebrovascular
regulation (CBF). The role of NO can be explored by the use of
inhibitors of NOS, which block the conversion of
L-arginine to L-citrulline and inhibit NO
production as assessed by both direct and indirect methods. The
most widely used are nitro-L-arginine methyl ester,
nitro-L-arginine, and L-NMMA. Such L-arginine
analogues result in a fall in CBF in a number of animal
models,1 2 3 4 5 6 without altering basal
metabolic activity,6 but the
magnitude of the effect has varied within and between species. Within
the central nervous system, two isoforms of NOS exists constitutively,
one expressed predominantly within the endothelium
(eNOS), the other in diverse cell populations within the neuronal
parenchyma (nNOS), including perivascular
nerves.7 8 L-Arginine analogues
inhibit both isoforms, but studies in mice lacking the eNOS gene
suggest that regulation of basal CBF is predominantly controlled by
eNOS, at least in mice.9
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Three separate studies, each on 6 subjects, were performed to
determine (1) the effect of different doses of L-NMMA on carotid artery
flow, (2) the effect of L-NMMA on the hyperemic response to
hypercapnia, and (3) the effect of noradrenaline (titrated
to result in a rise in blood pressure similar to that of L-NMMA) on
both basal carotid artery flow and the hyperemic response to
hypercapnia. was measured with transcranial
Doppler ultrasonography via the transtemporal route
using a 2-MHz probe.
The effect of L-NMMA at three doses (1, 3, and 10 mg/kg) on CCA
volume flow (CCA flow) and ICA volume flow (ICA flow), and MCA was
determined. L-NMMA was obtained from Glaxo Wellcome plc, and its purity
was 99.8%. During a 20-minute control interval, two sets of volume
flow measurements (each the mean of two readings) were taken. Each dose
of L-NMMA (clinical grade, supplied by Glaxo Wellcome and diluted in
0.9% NaCl) was administered as a bolus injection through an
intravenous cannula, and measurements were repeated at
5-minute intervals up to 25 minutes after dose. Following the 10 mg/kg
dose, further measurements were taken at 35 and 45 minutes after
dose.
After the dose-ranging basal CBF study, two doses of
L-NMMA were used in this study (3 and 10 mg/kg). Because of time
constraints during the administration of CO2 and
the more difficult acquisition during the increased respiratory
excursions, only CCA and not ICA measurements were made. MCA was
continuously recorded. During a 20-minute control interval, two
baseline recordings of CCA flow (each the mean of three
measurements) were made: breathing room air and then breathing 6% and
8% CO2 in air. In each case, readings were taken
after end-tidal CO2 had stabilized and always >2
minutes after CO2 had been started. After a
20-minute rest period, measurements were repeated for breathing room
air, before and 5 minutes after administration of 3 mg/kg L-NMMA, and
then after 6% and 8% CO2. This process was
repeated for 10 mg/kg L-NMMA, and an additional time point at 45
minutes after dose was included. In 4 subjects, the specificity of the
response was assessed by administration of L-arginine in
molar excess at a dose of 30 mg/kg (Clinalfa) immediately following the
45-minute post–10 mg/kg L-NMMA run, and repeating the measurements
taken at rest and after 6% and 8% CO2.
A protocol similar to that for hypercapnic hyperemia was
used. Intravenous noradrenaline (Sanofi
Winthrop, diluted in 5% dextrose to 10 µg/mL) was titrated against
resting MAP to effect a 15 to 20 mm Hg elevation (equivalent to
that observed with 10 mg/kg L-NMMA). Before noradrenaline
administration, CCA flow measurements were taken for breathing room air
and for 6% and 8% CO2. After
noradrenaline administration, once the desired MAP was
reached, baseline and hypercapnia measurements were repeated. MCA
was continuously recorded.
For the basal study, the dose-response relationships for CCA
flow, ICA flow, MCA, MAP, and pulse with L-NMMA were compared with
the control period by analysis of the AUC over the first 20
minutes after dose, followed by paired t tests (baseline
versus after dose). For the hypercapnia and noradrenaline
studies, the increase in CCA flow is expressed as an absolute value and
also as a percentage of increase relative to normocapnia after 8%
CO2, which produces a maximal vasodilatory
response in humans.23 Breathing 6%
CO2 produces a submaximal response; therefore,
CCA flow values are expressed per kilopascal of increase in end-tidal
CO2. Paired t tests were used to
compare the response after L-NMMA and noradrenaline. In the
4 subjects who received L-arginine, the hypercapnic
hyperemic responses were compared with the 45-minute post–10
mg/kg dose readings. The effects of noradrenaline and
L-NMMA on basal and stimulated flow were compared using the unpaired
t test.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Basal CBF Study
There was no change in CCA or ICA flow during the control period
(CCA 421.8±47.2 and 415.2±51.9 mL/min, P=NS; ICA
278.7±44.4 and 268.8±59.4 mL/min, P=NS). A rapid and
dose-dependent reduction in CCA and ICA volume flow after
administration of L-NMMA was observed (Fig 1
). Mean±SD CCA flow fell from
415.2±51.9 before L-NMMA to 336.5±50.2, 329.8±64.2, and 294.0±56.1
mL/min after 1, 3, and 10 mg/kg, respectively (AUC analysis,
P<.005 for all doses). This equated to a maximal reduction
of 29.5±6.8%. ICA flow fell from 268.8±59.4 before L-NMMA to
246.7±67.8, 235.8±90.1, and 226.2±72.6 mL/min after 1, 3, and 10
mg/kg, respectively (AUC analysis, P<.05 for all
doses). This equated to a maximal reduction of 14.9±21.3%. Results
from the AUC analysis are shown in Table 1. There was no significant reduction in
MCA (before L-NMMA, 64.7±7.0; 5 minutes after 1 mg/kg 62.7±7.4, 3
mg/kg 60.7±6.9, and 10 mg/kg 60.2±8.7 cm/s.
View larger version (23K):
[in a new window]
Figure 1. Effect of increasing doses of L-NMMA on CCA and
ICA volume artery flow and MAP; mean±SE in 6 subjects.
View this table:
[in a new window]
Table 1. Mean±SD Area Under CCA Flow, ICA Flow, MCA , MAP,
and Pulse Rate Dose-Response Curves for 20-Min Control Period and First
20 Min After Each Dose of L-NMMA
and Table 1) that closely mirrored the changes in CCA flow and
ICA flow. The maximal increase in MAP was observed 10 minutes after 10
mg/kg L-NMMA (101.8±9.8 versus 85.2±6.4 mm Hg; AUC
analysis, P<.01). The pulse rate fell maximally
from 59.3±8.5 min-1 before L-NMMA to 44.0±4.6
min-1 at 5 minutes after 10 mg/kg L-NMMA (AUC
analysis, P<.02). There was no significant change
in resting end-tidal CO2 after L-NMMA
administration.
There was no change in CCA during the control period (CCA,
346.5±28.4 and 340.3±42.9 mL/min, P=NS). As for the basal
CBF study, there was a dose-dependent reduction in mean±SD resting CCA
flow from 340.3±42.9 to 254.0±36.0 and 225.2±34.1 mL/min after 3 and
10 mg/kg L-NMMA, respectively (P<.01) (see Fig 2). There was no significant difference
between end-tidal CO2 levels during rest, 6% and
8% CO2 in each run of the protocol (mean values:
rest 4.88, 6% CO2 6.79, 8%
CO2 8.12 kPa).
View larger version (32K):
[in a new window]
Figure 2. Effect of L-NMMA on absolute CCA volume flow at
rest and after hypercapnia (6% and 8% CO2); mean±SE in 6
subjects. . There was no significant change in the
absolute or percent change in CCA flow after 8%
CO2 or in the percent change divided by end-tidal
CO2 rise for 6% CO2.
View this table:
[in a new window]
Table 2. Relative Hypercapnic Hyperemic Response
Before and After 3 and 10 mg/kg L-NMMA and Before and After
Noradrenaline :
before 64.7±13.0, after 3 mg/kg 63.6±11.1, and after 10 mg/kg
63.3±11.8 cm/s. There was no significant change in either 6% or 8%
CO2 MCAv reactivity. Mean±SD
reactivity to 6% was 24.9±4.5 before, 24.8±6.6 after 3 mg/kg, and
20.6±4.3%/kPa after 10 mg/kg. Mean±SD reactivity to 8% was
65.4±21.3 before, 70.9±22.9 after 3 mg/kg, and 70.1±31.4% after 10
mg/kg. ) along with the systemic
hemodynamic variables of MAP and pulse, confirming
the specificity of the effect of L-NMMA.
View this table:
[in a new window]
Table 3. Mean±SD CCA Flow (mL/min) at Rest, 45 min After 10
mg/kg L-NMMA, and After L-Arginine in 4 Subjects Who
Received L-Arginine
There was no change in CCA during the control period (CCA
435.0±79.4 and 434.5±83.4 mL/min, P=NS). The increase in
MAP produced by noradrenaline was not significantly
different from that produced by L-NMMA at 10 mg/kg (14.5±6.5 versus
18.5±12.0 mm Hg, P=.4). After
noradrenaline administration, baseline CCA flow fell from
434.5±83.4 to 379.7 ±77.1 mL/min, a percentage fall of 12.0±12.1%.
This was significantly less than the fall of 37.8±9.9% that followed
10 mg/kg L-NMMA in the hypercapnia study (P<.01). However,
there was no significant reduction in the hypercapnic hyperemia
response. There was no significant difference in the relative
hyperemic responses at either CO2 level
between the L-NMMA and noradrenaline groups (Table 2, Fig 3).
View larger version (42K):
[in a new window]
Figure 3. Mean±SE absolute CCA volume flow at rest and
after 6% and 8% CO2 and before and after
noradrenaline at a pressor dose equivalent to 10 mg/kg
L-NMMA.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
This is the first published study of which we are aware in which
the effect of NOS inhibition on human CBF has been explored. Our
results demonstrate that the nonselective NOS inhibitor
L-NMMA produces a rapid and dose-dependent fall in basal carotid artery
blood flow. This fall was reversed by L-arginine,
confirming the specificity of the NOS inhibition. In contrast, there
was no significant fall in MCA; in the face of a fall in carotid
flow, this suggests that L-NMMA resulted in MCA vasoconstriction. In
contrast to results from some studies in animals, we found no evidence
that NO contributes significantly to the hyperemia that follows
hypercapnia. is sometimes
used as a method of estimating CBF, as in the measurement of cerebral
reactivity or autoregulation.23 While this use is
valid in such situations where MCA diameter remains constant, our
results suggest that MCA diameter alters with NO inhibition. This is
consistent with indirect data suggesting that NO donors dilate
the MCA in humans.27 Therefore, this study
provides further evidence that MCA alone cannot be used to study the
effect of pharmaceutical agents on CBF if they also affect MCA
diameter.
Selected Abbreviations and Acronyms
AUC
=
area under the curve
CBF
=
cerebral blood flow
CCA
=
common carotid artery
eNOS
=
endothelial NOS
ICA
=
internal carotid artery
L-NMMA
=
NG-monomethyl-L-arginine
MAP
=
mean arterial blood pressure
MCA
=
middle cerebral artery flow velocity
nNOS
=
neuronal NOS
NO(S)
=
nitric oxide (synthase)
Acknowledgments
This work was supported by an MRC(UK) project grant (No.
G9512159). We thank Glaxo Wellcome plc for supplying
L-NG-methyl arginine
hydrochloride (546C88). The transcranial Doppler
equipment was provided by a University of London equipment grant.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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 N. Toda and T. Okamura The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels Pharmacol. Rev., June 1, 2003; 55(2): 271 - 324. [Abstract] [Full Text] [PDF]
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 A. Hassan, B. J. Hunt, M. O'Sullivan, K. Parmar, J. M. Bamford, D. Briley, M. M. Brown, D. J. Thomas, and H. S. Markus Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis Brain, February 1, 2003; 126(2): 424 - 432. [Abstract] [Full Text] [PDF]
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A. H. M. Van Mil, A. Spilt, M. A. Van Buchem, E. L. E. M. Bollen, L. Teppema, R. G. J. Westendorp, and G. J. Blauw Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans J Appl Physiol, March 1, 2002; 92(3): 962 - 966. [Abstract] [Full Text] [PDF]
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S. Joshi, H. Duong, S. Mangla, M. Wang, A. D. Libow, S. J. Popilskis, N. D. Ostapkovich, T. S. Wang, W. L. Young, and J. Pile-Spellman In Nonhuman Primates Intracarotid Adenosine, but Not Sodium Nitroprusside, Increases Cerebral Blood Flow Anesth. Analg., February 1, 2002; 94(2): 393 - 399. [Abstract] [Full Text] [PDF]
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R. Schondorf, R. Stein, R. Roberts, J. Benoit, and W. Cupples Dynamic cerebral autoregulation is preserved in neurally mediated syncope J Appl Physiol, December 1, 2001; 91(6): 2493 - 2502. [Abstract] [Full Text] [PDF]
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P. Sterzer, F. Meintzschel, A. Rosler, H. Lanfermann, H. Steinmetz, and M. Sitzer Pravastatin Improves Cerebral Vasomotor Reactivity in Patients With Subcortical Small-Vessel Disease Stroke, December 1, 2001; 32(12): 2817 - 2820. [Abstract] [Full Text] [PDF]
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M. S. Vavilala, J. S. Roberts, A. E. Moore, D. W. Newell, and A. M. Lam The Influence of Inhaled Nitric Oxide on Cerebral Blood Flow and Metabolism in a Child with Traumatic Brain Injury Anesth. Analg., August 1, 2001; 93(2): 351 - 353. [Abstract] [Full Text] [PDF]
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G. Zoccoli, D. A. Grant, J. Wild, and A. M. Walker Nitric oxide inhibition abolishes sleep-wake differences in cerebral circulation Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2598 - H2606. [Abstract] [Full Text] [PDF]
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B. J. Carey, P. J. Eames, M. J. Blake, R. B. Panerai, and J. F. Potter Dynamic Cerebral Autoregulation Is Unaffected by Aging Stroke, December 1, 2000; 31(12): 2895 - 2900. [Abstract] [Full Text] [PDF]
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C.-L. Chao and Y.-T. Lee Impairment of Cerebrovascular Reactivity by Methionine-Induced Hyperhomocysteinemia and Amelioration by Quinapril Treatment Stroke, December 1, 2000; 31(12): 2907 - 2911. [Abstract] [Full Text] [PDF]
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 G. Segarra, P. Medina, J. M. Vila, J. B. Martinez-Leon, R. M. Ballester, P. Lluch, and S. Lluch Contractile effects of arginine analogues on human internal thoracic and radial arteries J. Thorac. Cardiovasc. Surg., October 1, 2000; 120(4): 729 - 736. [Abstract] [Full Text] [PDF]
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