Nitric oxide mediates hypoxia-induced
cerebral vasodilation in humans
Annette H.M.
Van Mil 1,
Aart
Spilt 2,
Mark A.
Van Buchem 2,
Edward L.E.M.
Bollen 3,
Luc
Teppema 4,
Rudi G.J.
Westendorp 1, and
Gerard J.
Blauw 1
Departments of 1 General Internal Medicine, Section of
Gerontology and Geriatrics, 2 Radiology, 3 Neurology,
and 4 Physiology, Leiden University Medical Center, 2300RC
Leiden, The Netherlands
ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Nitric oxide (NO) plays a pivotal
role in the regulation of peripheral vascular tone. Its role in the
regulation of cerebral vascular tone in humans remains to be
elucidated. This study investigates the role of NO in hypoxia-induced
cerebral vasodilatation in young healthy volunteers. The effect of the
NO synthase inhibitor
N G -monomethyl- L -arginine
( L -NMMA) on the cerebral blood flow (CBF) was assessed
during normoxia and during hypoxia (peripheral O 2 saturation 97and 80%, respectively). Subjects were positioned in a
magnetic resonance scanner, breathing normal air (normoxia) or a
N 2 -O 2 mixture (hypoxia). The CBF was measured
before and after administration of L -NMMA (3mg/kg) by use
of phase-contrast magnetic resonance imaging techniques. Administration
of L -NMMA during normoxia did not affect CBF. Hypoxia
increased CBF from 1,049±113to 1,209±143ml/min
( P <0.05). After L -NMMA administration, the augmented CBF returned to baseline (1,050±161ml/min;
P <0.05). Similarly, cerebral vascular resistance
declined during hypoxia and returned to baseline after administration
of L -NMMA ( P <0.05for both). Use of
phase-contrast magnetic resonance imaging shows that hypoxia-induced
cerebral vasodilatation in humans is mediated by NO.
cerebrovasculature; vascular reactivity;
N G -monomethyl- L -arginine; magnetic
resonance imagery
INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
OVER A WIDE RANGE of
systemic blood pressure, perfusion of brain tissue is kept constant by
local regulation of vascular tone. This autoregulation of cerebral
blood flow (CBF) is controlled by a combination of myogenic,
neurogenic, and metabolic mechanisms ( 21 ). This complex
autoregulatory mechanism is based on a tight coupling between
O 2 supply and metabolic demand. With a constant metabolic
demand and O 2 supply, changes in blood pressure are compensated by adjustments in vasomotor tone. On the other hand, a
decrease in O 2 supply or an increase in metabolic demand
results in a decrease in vasomotor tone, causing an increase in CBF to match again with the O 2 demand of the brain ( 19,
21 ). The mechanism underlying this coupling between
O 2 supply and cerebral vascular tone remains to be
elucidated, although experimental data suggest that nitric oxide is
involved ( 15 ). In various species it has been shown that
nitric oxide synthase inhibitors attenuate hypoxia-induced cerebral
vasodilatation ( 1, 2, 16 ). Recently, it has been shown
that, in the human forearm, hypoxia-induced vasodilatation is mediated
via the release of nitric oxide ( 4 ).
From experimental studies, there is increasing evidence that nitric
oxide is involved in the regulation of cerebral vascular tone. Main
sources of nitric oxide in the brain are neurons and endothelial cells
( 12, 15 ). Recently evidence has been provided that nitric
oxide also plays a role in humans in the regulation of cerebral
vasomotor tone ( 17, 28 ). On the basis of these data, together with the observations that nitric oxide might be involved in hypoxia-induced cerebral vasodilatation, it can be hypothesized that the coupling between O 2 and cerebral
vascular tone is mediated via the nitric oxide pathway.
It was the aim of the present study to investigate the role of nitric
oxide in hypoxia-induced cerebral vascular relaxation in young healthy
volunteers, by using the competitive nitric oxide synthase inhibitor
N G -monomethyl- L -arginine
( L -NMMA) as a pharmacological tool. Phase-contrast magnetic
resonance imaging (pcMRI) techniques were used to measure total CBF and
changes in flow noninvasively ( 24 ).
METHODS
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subjects.
Eight young male healthy volunteers (mean age 24±3yr)
participated in the study. Physical and routine blood examinations, electrocardiogram (ECG), and conventional magnetic resonance imaging (MRI) of the brain (transverse relaxation time-weighted fast spin echo and fluid attenuated inversion recovery) revealed no
abnormalities. Exclusion criteria were current smoking, use of drugs or
more than three alcoholic drinks a day, a body mass index greater than 26kg/m 2, hypertension, claustrophobia, dyslipidemia,
diabetes mellitus, signs and symptoms of cardiovascular disease, or any
other significant abnormalities in physical examination, blood
analysis, ECG, or standard MRI scans. Before the start of the
experiments, subjects abstained from nonsteroidal anti-inflammatory
drugs for at least 10days and from alcoholic and caffeine-containing
beverages for at least 12h. The protocol was approved by the
Medical Ethical Committee of the Leiden University Medical Center and
conformed with the principles outlined in the Declaration of Helsinki;
all subjects gave written, informed consent.
Procedures.
During the experiments, the subjects were in the supine position with
their heads comfortably stabilized. A well-fitted face mask was applied
for administration of gas mixtures (normal pressurized air mixture and
N 2 -O 2 mixture), and a deep antecubital vein was cannulated for infusion of L -NMMA. Then the subjects were
positioned in a magnetic resonance system operating at a field strength
of 1.5T (ACS-NT15; Philips Medical Systems, Best, The Netherlands) under continuous audio and video surveillance. Heart rate was derived
from a one-lead ECG and was continuously monitored. Blood pressure was
measured semicontinuously with intervals of 3min by use of an
automatic device. Inspired O 2 (MiniOx 3000,Come Care
Medical, The Netherlands), peripheral O 2 saturation
(Sp O 2 ), breath rate, and end-tidal CO 2
(Millennia, In vivo Research, Orlando, FL) were monitored continuously.
CBF was measured noninvasively in the basilar artery and both internal
carotid arteries by use of a gradient echo pcMRI technique as described
previously with the following parameters: time to repeat/echo time 16/9
ms; flip angle 7.5°; 5mm slice thickness; field of view 250mm and
one number of signal averages ( 11 ). Triggering was
retrospective using a peripheral pulse unit. The flow measurements were
analyzed on a Sun UltraSparc 10workstation with internally developed
software package FLOW ( 26 ). Total CBF was defined as the
summed flow measured in the basilar artery and both internal carotid
arteries (expressed as ml/min). The mean values of two consecutive CBF
measurements, measured with an interval of 5min, were used for further analysis.
Study protocol.
The study was performed in a single-blinded fashion and consisted of 2study days with an interval of 1wk. On one day the effect of the
competitive nitric oxide synthase inhibitor L -NMMA on CBF
was assessed during normoxia (Sp O 2 97%), and on the
other day this was done during hypoxia (Sp O 2 80%).
The procedures were done in random order.
After they were positioned in the scanner, the subjects started
breathing ambient air through the face mask. After an equilibrium period of 20min, basal cerebral blood flow was measured twice. Subsequently, the subjects either continued breathing ambient air or
started breathing a variable N 2 -O 2 mixture. The
objective of the N 2 -O 2 mixture was to obtain a
Sp O 2 of 80%. Therefore, the N 2 -O 2 mixture was continuously adjusted for
each subject during the experiments. After 20min of a stable
Sp O 2 at either 97% or 80%, cerebral blood flow was
measured twice. Then L -NMMA (Clinalpha, Laufelfingen,
Germany) was administered intravenously in a dose of 3mg/kg in 5min,
by use of a constant-rate infusion pump (Spectris MR injector, Medrad
Europe, Beel, The Netherlands). Five minutes after this infusion, CBF
was measured twice.
Analysis.
Results are given as means±SD. Measurements of total CBF are
expressed in absolute values. Changes in cerebral vascular resistance
are expressed as percent changes from baseline. Cerebral vascular
resistance is calculated by mean arterial pressure (mmHg) divided by
total cerebral blood flow (ml/min). The Wilcoxon signed-rank test for
paired observations were used to evaluate the statistical significance
of the data. The data were analyzed blinded to the gas phase, i.e.,
normoxia and hypoxia. P values <0.05 were regarded as significant.
RESULTS
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No adverse effects of hypoxia or the administration of
L -NMMA were observed. The subjects' rating of whether they
had been exposed to hypoxia or normoxia was not better than by chance, illustrating the success of subject blinding. In one subject, the
experiments were stopped during the first 20-min stabilization period
because of claustrophobia. Therefore the data were analyzed on seven
subjects. Hypoxia was easily achieved and maintained at a
Sp O 2 level of 79.1±0.3%. Basal CBF was
comparable on the 2study days, 862±139ml/min and 907±253ml/min, respectively (not significant).
Normoxia.
During normoxia, there was no change in CBF (816±124and
825±137ml/min) or any of the other parameters (Fig.
). Administration of L -NMMA
during normoxia did not significantly affect CBF (825 ±137and
815±198ml/min, before and after L -NMMA,
respectively; not significant) heart rate, mean arterial pressure, or
end-tidal CO 2 (Fig. ). Consequently, the vascular
resistance did not change during normoxia.
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Fig. 1.
Percent change in cerebral vascular resistance, cerebral
blood flow, mean arterial pressure, and heart rate during normoxia.
L -NMMA,
N G -monomethyl- L -arginine.
Hypoxia.
Hypoxia (Sp O 2 80%) was induced by lowering the
inspired O 2 from 21.0±0.5% to 13.1±0.8%.
During hypoxia, CBF increased from 1,049±113to 1,209±143ml/min, respectively ( P <0.05; Fig.
). Hypoxia had no significant effect on
the steady-state end-tidal CO 2 (38.7±6.9vs.
38.4±5.8mmHg) or mean arterial pressure (82±8vs.
83±8mmHg). Heart rate increased from 70 ±8to 78±5beats/min ( P <0.05). The calculated cerebral
vascular resistance declined by 17±10% during hypoxia
( P <0.05; Fig. ).
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Fig. 2.
Percent change in cerebral vascular resistance, cerebral
blood flow, mean arterial pressure, and heart rate during hypoxia.
* P <0.05compared with baseline ( t =0); # P <0.05compared with values after 30min of
hypoxia (before administration of L -NMMA)
( t =30).
During hypoxia, administration of L -NMMA decreased CBF
significantly from 1,209±143to 1,050±161ml/min
( P <0.05; Fig. ). Mean arterial pressure increased
from 83±8to 88±5mmHg after administration of
L -NMMA ( P <0.05). Heart rate decreased not significantly from 78±13to 70±8beats/min.
DISCUSSION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
The main finding of the study is that acute hypoxia induced an
increase in total CBF that could be blunted by the competitive nitric
oxide synthase inhibitor L -NMMA, providing evidence that hypoxia-induced cerebral vasodilatation is mediated by the release of
nitric oxide. Because L -NMMA is a nonselective nitric oxide synthase inhibitor, acting on both endothelial and neuronal nitric oxide synthase, the present study does not provide evidence for the
source of nitric oxide mediating cerebral vasodilatation during hypoxia.
This is the first study using pcMRI to investigate hypoxia-induced
cerebral vascular reactivity in humans. To date, Doppler ultrasonography is commonly used to quantify blood flow in the common
carotid artery, internal carotid artery, and middle cerebral artery. A
clear advantage of MRI over Doppler ultrasound is the considerable
reduction of random error that can be attributed to inaccuracy in
measuring the cross-sectional area and varying angles of approach with
ultrasonography ( 13 ). Furthermore, the position of the
basilar artery makes it very difficult to perform measurements in this
artery with the use of ultrasound. Therefore, total cerebral blood flow
cannot be determined by Doppler ultrasound. Finally, because Doppler
ultrasound measures only the highest flow velocities in the center of
the vessel, the real total blood flow in the vessels is overestimated.
With the present MRI technique, the flow velocities of the total area
of the vessels measured are averaged, i.e., in the basilar artery and
both internal carotid arteries, reflecting total CBF ( 5, 11, 18,
24, 25 ).
The normal hemodynamic response to acute hypoxia is an increase in
heart rate and a slight decrease in mean arterial pressure due to a
redistribution of blood flow to organs with a greater O 2
dependency, e.g., skeletal muscles, kidneys, intestines, and the brain
( 27 ). The mechanism underlying this hypoxia-induced vasodilatation in selective vascular beds is not fully understood. In
animal experiments, it has been demonstrated that nitric oxide synthase
inhibitors attenuate hypoxia-induced cerebral vasodilatation ( 1,
2, 14, 16 ). The present data are the first to show in humans
that hypoxia-induced cerebral vasodilatation is mediated by nitric
oxide, corroborating studies in the human forearm ( 4 ). Because the cerebral vascular resistance declined during hypoxia and
returned to baseline after L -NMMA administration, the
changes in CBF cannot be attributed to blood pressure elevation.
Furthermore, myogenic autoregulatory mechanisms would cause an opposite
response by increasing vasomotor tone on blood pressure elevation to
maintain CBF constant. The hypoxia-induced vasodilatation is probably
the result of metabolic autoregulation, causing an increase in CBF and
thus an increase in O 2 supply to match the metabolic
demand. The present finding suggests that in healthy subjects nitric
oxide plays an important role in enhancing the cerebral blood flow
response to hypoxia.
The fact that the end-tidal CO 2 was not influenced by
hypoxia virtually excludes the distorting influence of changes in
P CO 2 on hypoxia-induced cerebral vasodilation
in the present study ( 28 ). Normally, the hypoxic
ventilatory response consists of an acute carotid body-mediated
increase in ventilation followed by a secondary (subacute) decrease,
the so-called hypoxic ventilatory depression, to a new steady-state
level above control. Part of the hypoxic ventilatory depression is
thought to be due to the hypoxia-induced rise in cerebral blood flow
resulting in an increased washout of CO 2 from brain tissue
( 7, 9, 10 ). In our setup, the end-tidal
P CO 2 was allowed to change with changing levels of ventilation. The fact that in our experiments the steady-state normoxic and hypoxic end-tidal P CO 2 did not
change indicates that the opposite effects of the initial increase and
secondary decrease in ventilation were cancelled out.
In contrast to normoxia, L -NMMA induced a small increase in
mean arterial pressure of 6% during hypoxia. This is probably caused
by inhibition of hypoxia-induced nitric oxide-mediated systemic
vasodilation by L -NMMA. The fact that L -NMMA
did not influence CBF during normoxia might indicate that nitric oxide plays a limited role in the maintenance of basal cerebral vascular tone
under nonpathological basal conditions. Others described a significant
fall in basal CBF after L -NMMA administration
( 29 ). Both findings are in agreement with the observation
that L -NMMA reduced basal cerebral blood flow in healthy
volunteers only at higher doses ( 17 ). Possibly we did not
achieve complete nitric oxide blockade. In the present study, the
absence of an effect of L -NMMA on the resting cerebral
blood flow and on the systemic circulation helped to interpret the
present results, because it allowed similar starting conditions during
the normoxia and hypoxia occasions. The fact that L -NMMA
blunted the hypoxia-induced cerebral vasodilatation demonstrated that
it effectively blocked the nitric oxide pathway during hypoxia in the
doses used.
An unexpected finding of this study is that basal cerebral blood flow
is significantly different between the normoxic and hypoxic conditions.
Because the study is performed in a randomized single-blind fashion,
this finding must be accidental. This is confirmed by the fact that
when baseline flows are analyzed by study day, no significant
differences are observed. Nevertheless, the present results show that
the intraindividual variation of cerebral blood flow on various
occasions is large. However, the results during normoxia clearly show
that on a specific occasion basal cerebral blood flow is remarkably
stable, even after infusion of L -NMMA.
Therefore, it can be assumed that the vascular responses observed
during hypoxia are caused by hypoxia and the subsequent administration of L -NMMA and not based on accidental
variations in cerebral blood flow.
The present finding that nitric oxide plays a role in hypoxia-induced
cerebral vasodilatation in humans may have relevant clinical
implications. To date, data on the role of nitric oxide in
ischemic brain disease are scarce. It has been suggested that after cerebral ischemia, nitric oxide initially has beneficial vascular actions of in promoting CBF ( 22 ). However, from
studies in peripheral vascular beds there is accumulating evidence that atherosclerosis impairs nitric oxide-mediated vasodilatation, probably
via endothelial damage ( 6, 8, 20, 23 ). Recently, it has
been shown that, in patients with signs and symptoms of atherosclerotic
disease, cerebrovascular responsiveness is also impaired
( 3 ). It can be speculated that this is caused by an impaired production and release of nitric oxide, by either endothelial dysfunction or neuronal damage. Further studies on the role of nitric
oxide in the maintenance of brain perfusion are important to unravel
the pathogenesis of cerebrovascular disease.
In conclusion, by using pcMRI techniques measuring cerebral blood flow,
it is shown that hypoxia-induced cerebral vasodilation in humans is
mediated by nitric oxide.
ACKNOWLEDGEMENTS
The study was supported by an unrestricted grant of the
Bristol-Myers Squibb, Princeton, NJ.
FOOTNOTES
Address for reprint requests and other correspondence: G.J.Blauw, Dept. of General Internal Medicine, Section of Gerontology &Geriatrics, C1-R, Leiden Univ. Medical Center, PO Box 9600, 2300RC
Leiden, The Netherlands (E-mail: g.j.blauw{at}lumc.nl <!--
).
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 18U.S.C. Section 1734solely to indicate this fact.
10.1152/japplphysiol.00616.2001
Received 14 June 2001; accepted in final form 8 October 2001.
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