Download Effects of supplemental oxygen administration on coronary blood

Am J Physiol Heart Circ Physiol 288: H1057–H1062, 2005;
doi:10.1152/ajpheart.00625.2004.
TRANSLATIONAL PHYSIOLOGY
Effects of supplemental oxygen administration on coronary
blood flow in patients undergoing cardiac catheterization
Patrick H. McNulty,1 Nicholas King,1 Sofia Scott,1 Gretchen Hartman,1 Jennifer McCann,1
Mark Kozak,1 Charles E. Chambers,1 Laurence M. Demers,2 and Lawrence I. Sinoway1
Departments of 1Medicine and 2Pathology, Pennsylvania State College
of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania
Submitted 23 June 2004; accepted in final form 5 October 2004
33). In this study, we used intracoronary Doppler flow recording and measurement of arterial and coronary venous concen⫺
trations of NO oxidation (NO⫺
2 and NO3 ) and peroxidation
(nitrotyrosine) products to examine this question in a group of
patients with stable CHD who underwent diagnostic cardiac
catheterization.
METHODS
ADMINISTRATION OF SUPPLEMENTAL oxygen to patients with coronary heart disease (CHD) is a common clinical practice (23).
In healthy subjects, high arterial blood oxygen tension has been
demonstrated to be a vasoconstrictor stimulus in the forearm
(7, 17) and systemic vasculatures (8, 19) and acts by a mechanism believed to involve oxidative inactivation of endotheliumderived relaxation factors including nitric oxide (NO; Refs. 7,
8, 29). Whether this mechanism operates in the human coronary circulation is not known. Indeed, it might be expected that
patients with CHD are relatively insensitive to this vasoconstrictor effect by virtue of the fact that the coronary endothelium of such patients has impaired ability to generate NO in
response to physiological and pharmacological stimuli (1, 28,
Subjects. Twenty-seven nondiabetic adult subjects (16 males and
11 females; 43–70 yr old) were studied during elective cardiac
catheterization performed to evaluate chest pain. No subject had a
coronary stenosis of ⬎50% severity by angiography, and all had a left
ventricular ejection fraction of ⬎50%. All subjects were taking both
a long-acting ␤-blocker and aspirin, and 15 subjects were taking a
statin, but none were on an angiotensin-converting enzyme inhibitor
or angiotensin receptor blocker. None of the subjects had experienced
chest pain or used nitroglycerin in any form for at least 24 h before the
study. The study protocol was approved by the Institutional Review
Board of the Pennsylvania State College of Medicine, and subjects
gave written informed consent.
Study protocol. Vascular sheaths were placed in a femoral artery
and vein under 2% xylocaine local anesthesia. A Simmons-2 catheter
was placed into the coronary sinus from the femoral vein to allow
arterial-coronary venous blood sampling. Standard transfemoral coronary angiography was performed while subjects were under midazolam and fentanyl sedation. In 12 subjects, a guiding catheter was
then placed into either the left (n ⫽ 6) or right (n ⫽ 6) coronary artery;
this was used to introduce a 0.014-in Doppler flow wire (FloMap
system; Jomed; Rancho Cordova, CA) into a major coronary branch
that was demonstrated by the angiogram to be free of obstructive
atherosclerosis. While subjects breathed room air, paired samples of
arterial and coronary venous blood were obtained for measurement of
⫺
blood gases, hemoglobin, and the NO metabolites NO⫺
2 and NO3 .
Doppler coronary flow velocity (CFV, measured in cm/s) was then
recorded with subjects at rest and after intracoronary infusion of the
endothelium-independent dilator adenosine (20 ␮g for right coronary
or 40 ␮g for left coronary studies; Fujisawa). In five subjects whose
coronary angiograms were nearly free of atherosclerosis, the effect on
CFV of the endothelium-dependent dilator ACh (Clinalfa), which was
administered by serial 3-min infusions of a 20 ␮g/ml solution through
the guiding catheter at 0.5 and 1.0 ml/min, was also measured. To
allow for conversion of CFV to coronary blood flow (CBF, measured
in cm3/min) values, we measured the diameter of the coronary
segment that held the Doppler wire from the angiogram with electronic calipers while using the diameter of the guiding catheter as a
Address for reprint requests and other correspondence: P. H. McNulty,
Division of Cardiology/H047, Penn State College of Medicine, 500 Univ. Dr.,
Hershey, PA 17033 (E-mail: [email protected]).
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.
endothelium; nitric oxide; acetylcholine; heart
http://www.ajpheart.org
0363-6135/05 $8.00 Copyright © 2005 the American Physiological Society
H1057
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McNulty, Patrick H., Nicholas King, Sofia Scott, Gretchen
Hartman, Jennifer McCann, Mark Kozak, Charles E. Chambers,
Laurence M. Demers, and Lawrence I. Sinoway. Effects of supplemental oxygen administration on coronary blood flow in patients
undergoing cardiac catheterization. Am J Physiol Heart Circ Physiol
288: H1057–H1062, 2005; doi:10.1152/ajpheart.00625.2004.—
Patients with heart disease are frequently treated with supplemental
oxygen. Although oxygen can exhibit vasoactive properties in many
vascular beds, its effects on the coronary circulation have not been
fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we
measured in 18 patients with stable coronary heart disease the effects
of breathing 100% oxygen by face mask for 15 min on CBF (via
coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator
ACh and to the endothelium-independent dilator adenosine, as well as
arterial and coronary venous concentrations of the nitric oxide (NO)
⫺
metabolites nitrotyrosine, NO⫺
2 , and NO3 . Relative to breathing room
air, breathing of 100% oxygen increased coronary resistance by
⬃40%, decreased CBF by ⬃30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF
response to ACh. Oxygen breathing elicited these changes without
affecting the diameter of large-conduit coronary arteries, coronary
⫺
venous concentrations of NO⫺
2 and NO3 , or the coronary vasodilator
response to adenosine. Administering supplemental oxygen to patients
undergoing cardiac catheterization substantially increases coronary
vascular resistance by a mechanism that may involve oxidative
quenching of NO within the coronary microcirculation.
H1058
OXYGEN AND CORONARY BLOOD FLOW
by CBF. Blood oxygen content (measured in ml/l) was calculated by
multiplying the blood hemoglobin concentration (measured in g/l) by
the oxygen-carrying capacity of hemoglobin (1.36 ml/g) and the blood
oxyhemoglobin saturation. The regional myocardial oxygen consumption rate (MV̇O2, measured in ml/min) was calculated by multiplying the arterial-coronary venous difference for blood oxygen content (in ml/l) by CBF (in l/min).
Statistical analysis. Comparisons between room air and 100%
oxygen were made using two-tailed paired Student’s t-tests. Differences were considered significant if P ⬍ 0.05.
RESULTS
Hemodynamics. Breathing 100% oxygen had no consistent
effect on heart rate, blood pressure, or the diameter of the
large-conduit coronary arteries [3.3 ⫾ 0.4 vs. 3.2 ⫾ 0.3 mm;
P ⫽ not significant (NS)] but did reduce CFV in each subject
from 20 ⫾ 6 to 14 ⫾ 6 cm/s (P ⬍ 0.01; Fig. 1). This reduction
was apparent within 5 min and corresponded to a 29% decrease
in calculated CBF (from 45 ⫾ 14 to 32 ⫾ 7 cm3/min; P ⬍
0.01) and a 41% increase in calculated CVR [from 2.2 ⫾ 0.7
to 3.1 ⫾ 0.9 mmHg/(min/cm3); P ⬍ 0.01]. In three control
subjects not exposed to 100% oxygen, CFV deviated by ⬍10%
from baseline during a 30-min period of room-air breathing.
Among subjects who were observed for 20 min after discontinuing 100% oxygen breathing, three demonstrated a prompt
(⬍5 min) return of CFV to the original baseline value, whereas
in the other three, CFV remained depressed throughout the
observation period. Individual data for CFV, CBF, and CVR
are shown in Fig. 2.
Oxygen and NO. Data for the blood gas results and MV̇O2
are shown in Table 1. Breathing 100% oxygen increased
arterial PO2 from 73 ⫾ 9 to 273 ⫾ 43 mmHg and arterial
oxygen saturation from 93 ⫾ 4 to 100%. Coronary venous
oxygen saturation simultaneously increased from 32 ⫾ 3 to
38 ⫾ 5% so that the arterial-coronary venous difference for
oxygen content did not change. Because CBF decreased during
100% oxygen breathing, calculated regional MV̇O2 decreased
from 5.2 ⫾ 0.6 to 3.8 ⫾ 0.4 ml/min. During room-air breath⫺
⫺
⫺
ing, the concentration of free NO⫺
2 and NO3 ([NO2 ⫹ NO3 ])
Fig. 1. Doppler flow signals recorded in the left anterior
descending coronary artery of one subject who sequentially
breathed room air (top) and 100% oxygen (bottom). Average
peak coronary flow velocity (APV) was 24 cm/s while subject
breathed room air and decreased to 16 cm/s after subject
breathed 100% oxygen for 15 min (left); subsequent intracoronary infusion of 40 mg adenosine increased APV to 43 cm/s
under both conditions (right).
AJP-Heart Circ Physiol • VOL
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reference. After completion of these measurements, subjects breathed
100% oxygen via a standard reservoir-bag mask for 15 min, and all
measurements were repeated. In six subjects, the 15-min period of
100% oxygen breathing was followed by a subsequent 20-min recovery period in which subjects again breathed room air. CFV was
monitored through this recovery period to examine the persistence of
hyperoxic changes in coronary resistance and blood flow. To control
for nonspecific changes in CFV over time, in three additional subjects,
CFV was monitored during a 30-min period of room-air breathing
without exposure to 100% oxygen.
Chemical analyses. Partial pressures of oxygen (PO2) and carbon
dioxide (PCO2) and pH were measured in whole blood with a Bayer
blood gas analyzer. Blood oxygen saturation was measured by reflectance oximetry. Coronary NO production was estimated by measuring
arterial and coronary venous concentrations of the NO metabolites
⫺
NO⫺
2 and NO3 with a Sievers 180i NO analyzer. With the use of this
⫺
method, NO2 [produced in vivo by direct oxidation of NO (9)] and
NO⫺
3 [produced in vivo as a product of the reaction of NO with
oxyhemoglobin (9)] are quantitatively reduced to NO by boiling in
vanadium trichloride, and the NO gas thus liberated is reacted with
ozone and quantified by chemiluminescence (36). Our assay method
attempted to account for the fact that NO released by vascular
endothelium into blood may partition between plasma and red blood
cell water (27) as well as nitrosylating blood proteins (9). Thus free
⫺
ionic NO⫺
2 and NO3 were measured in deionized water lysates of
whole blood centrifuged through a 30-kDa molecular mass filter to
remove NO bound to albumin and hemoglobin. Protein-bound NO
⫺
was then estimated as the increment in free (NO⫺
2 ⫹ NO3 ) content
produced by heating these whole blood lysates at 86°C for 30 min
before centrifugation (31). Nitrotyrosine (Kamiya Biomedical; Seattle, WA) and endothelin-1 (Assay Designs; Ann Arbor, MI) were
measured in arterial and coronary venous blood from 12 subjects
using established EIA methods. Blood was collected into glass tubes
that contained sodium EDTA and aprotinin (7 mg/tube) to inhibit
proteolysis. The minimal detection level for the nitrotyrosine ELISA
method was 2 nM and for the endothelin immunoradiometric assay
was 1 pg/ml. Between-run precision was ⬍10% for both assays.
Calculations. CBF (measured in cm3/min) was calculated by multiplying CFV (measured in cm/s) by the cross-sectional area (cm2 ⫽
␲ ⫻ arterial radius2) of the coronary artery 5 mm distal to the tip of
the Doppler wire and the factor 0.5 (1). Coronary vascular resistance
[CVR, measured in mmHg/(min/cm3)] was calculated by dividing the
difference between mean arterial pressure and coronary sinus pressure
OXYGEN AND CORONARY BLOOD FLOW
H1059
DISCUSSION
Fig. 2. Individual data for coronary flow velocity (CFV; A), coronary blood
flow (CBF; B), and coronary vascular resistance (CVR; C) in 12 subjects
during sequential room air and 100% oxygen breathing.
in arterial and coronary venous blood lysates averaged 75 ⫾ 15
and 80 ⫾ 17 ␮M, respectively (P ⫽ NS). Heating blood lysates
⫺
to release protein-bound NO increased the free [NO⫺
2 ⫹ NO3 ]
by only 10 –15%. Breathing 100% oxygen did not significantly
⫺
change arterial or coronary venous free [NO⫺
2 ⫹ NO3 ] or
protein-bound NO. As a consequence of reducing CBF, 100%
oxygen breathing did reduce absolute cardiac efflux of NO⫺
2
AJP-Heart Circ Physiol • VOL
The administration of high-flow supplemental oxygen by
facemask to patients with CHD is a common practice particularly during conscious-sedation procedures in which the performing physician perceives a risk of hypoventilation and
hypoxemia. During such procedures, the arterial oxygen content is usually estimated by monitoring transcutaneous blood
oxyhemoglobin saturation. Because this technique is insensitive to changes in oxygen tension above the level needed to
produce a 100% oxyhemoglobin saturation (PO2 of ⬃90
mmHg), the use of high-flow oxygen in this setting can lead to
unsuspected degrees of hyperoxia. In this study, administration
of supplemental oxygen by face mask to sedated patients
undergoing cardiac catheterization increased average arterial
PO2 to ⬎250 mmHg. This was associated with a prompt ⬃40%
increase in coronary resistance and a ⬃30% decrease in CBF
in the absence of any significant change in the diameter of
large-conductance coronary vessels. These results suggest that
hyperoxia is a potent vasoconstrictor stimulus to the coronary
circulation that functions at the level of microvascular resistance vessels.
ACh produces arterial dilation by stimulating the release of
NO and other mediators from the vascular endothelium (10),
whereas adenosine functions by endothelium-independent ac-
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and NO⫺
3 , which was calculated as the product of CBF and
⫺
coronary venous [NO⫺
2 ⫹ NO3 ], from 3.5 ⫾ 1.0 to 2.4 ⫾ 0.6
␮mol/min (P ⬍ 0.01).
Nitrotyrosine and endothelin-1. During room-air breathing,
arterial and coronary sinus plasma nitrotyrosine concentrations
averaged 394 ⫾ 344 (SD) and 374 ⫾ 340 nM, respectively,
and no consistent net consumption or production of nitrotyrosine was observed across the heart (coronary sinus-arterial
concentration difference, 19 ⫾ 75 nmol/l, P ⫽ NS vs. zero).
During 100% oxygen breathing, coronary sinus nitrotyrosine
concentrations rose in 10 of the 12 subjects examined (to
461 ⫾ 479 nM; P ⫽ 0.21 vs. room air), and all 12 subjects
exhibited higher nitrotyrosine levels in the coronary sinus
compared with arterial plasma levels (coronary sinus-arterial
concentration difference, 126 ⫾ 189 nmol/ml; P ⫽ 0.003 vs.
room-air breathing; Fig. 3). Plasma endothelin-1 concentrations were below the detection limit of the assay in 9 of the 12
subjects, and no consistent effects of 100% oxygen breathing
on coronary sinus endothelin-1 level or endothelin-1 arterialcoronary sinus difference were observed.
Adenosine and ACh responses. Although 100% oxygen
breathing reduced resting CBF, oxygen administration did not
affect the magnitude of the CBF response to the endotheliumindependent dilator adenosine; thus postadenosine CBF averaged 108 ⫾ 34 cm3/min with subjects breathing room air vs.
108 ⫾ 32 cm3/min with subjects breathing 100% oxygen (P ⫽
NS). In contrast, oxygen administration blunted the CBF response to the endothelium-dependent dilator ACh to the same
degree that it reduced resting CBF. Thus as shown in Fig. 4,
ACh administration produced a dose-dependent increase in
CBF during both room-air and 100% oxygen breathing, but the
absolute magnitude of this effect was blunted during 100%
oxygen breathing. The ability of 100% oxygen breathing to
quench the coronary dilator action of ACh was also evident on
coronary angiography as shown in Fig. 5.
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OXYGEN AND CORONARY BLOOD FLOW
Table 1. Arterial and coronary sinus oxygen content and myocardial oxygen consumption
Hemoglobin
Saturation, %
PO2, mmHg
Room air
100% Oxygen
Blood O2 Content, ml/l
Art
CS
Art
CS
Art
CS
Art-CS O2 Content
Difference, ml/l
Cardiac V̇O2,
ml/min
73⫾9
273⫾43*
20⫾5
23⫾4*
93⫾4
100*
32⫾3
38⫾5*
181⫾24
194⫾22*
62⫾20
73⫾21*
119⫾26
120⫾23
5.2⫾0.6
3.8⫾0.4*
Values are means ⫾ SD; n ⫽ 18 subjects. Arterial (Art) and coronary sinus (CS) oxygen partial pressure (PO2), oxyhemoglobin saturation, blood oxygen
content, arterial-coronary venous oxygen content difference, and net cardiac oxygen consumption (V̇O2; arterial-venous oxygen content difference ⫻ coronary
blood flow) values obtained during room-air and 100% oxygen breathing. Oxygen administration proportionately reduced cardiac oxygen delivery (coronary
blood flow) and cardiac oxygen consumption such that transcardiac oxygen extraction (arterial-coronary oxygen content difference) did not change. *P ⬍ 0.01
vs. room air.
Fig. 3. Arterial and coronary sinus (CS) plasma concentrations and net
coronary sinus-arterial concentration difference for nitrotyrosine in subjects
breathing room air and 100% oxygen. Data are means ⫾ SE for 12 subjects.
Breathing 100% oxygen significantly increased net cardiac nitrotyrosine washout (coronary sinus-arterial concentration difference) relative to room air
breathing.
AJP-Heart Circ Physiol • VOL
the facts that NO released into the blood by the endothelium
has several metabolic fates (15), NO metabolites are compartmentalized in the blood (26), the measurement of NO metabolites may not reflect the actual rate of NO release by the
endothelium (13, 16), and measuring small concentration differences across the high-flow coronary circulation is inherently
difficult. Nevertheless, the observation that hyperoxia reduced
resting and endothelium-dependent CBF without decreasing
⫺
coronary venous free or heat-labile [NO⫺
2 ⫹ NO3 ] would at
least appear to confirm that hyperoxic coronary constriction
does not involve a reduction in the rate of coronary endothelial
NO formation or release. More direct evidence that hyperoxiainduced NO quenching may contribute to the coronary vasoconstrictor effect of 100% oxygen is provided by the nitrotyrosine data. Nitrotyrosine can be formed in the blood by the
reaction of free tyrosine with peroxynitrite, which is itself a
product of the reaction of a superoxide radical with NO (31), as
well as by other mechanisms (24); nitrotyrosine formation thus
serves as a marker for the production of superoxide radicals
during oxidative stress and for oxidative NO quenching (5).
The observation that breathing 100% oxygen resulted in net
cardiac production of nitrotyrosine (i.e., coronary sinus concentration ⬎ arterial concentration) in our subjects suggests
that oxidative quenching of NO within the coronary microcirculation may contribute to hyperoxic coronary vasoconstriction. We note that an elevated systemic nitrotyrosine level was
recently shown (30) to be a marker for the presence of
atherosclerosis. Because all of our subjects had early coronary
atherosclerosis, it is possible that the mechanism responsible
ACh
ACh
ACh
Fig. 4. CFV recorded at baseline (ACh-0) and during intracoronary infusion of
10 and 20 ␮g/min ACh (ACh-10 and ACh-20, respectively) and 20 – 40 ␮g
adenosine in five subjects. *P ⬍ 0.05 vs. room air.
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tivation of G protein-linked smooth muscle adenosine receptors (11). Thus the observation that hyperoxia attenuated the
coronary vasodilator response to ACh but not adenosine suggests that hyperoxia-induced vasoconstriction is mediated by
an effect on coronary endothelial function. The most plausible
physiological explanation for this effect is that hyperoxia may
accelerate the oxidative degradation of coronary endotheliumderived NO by reactive oxygen species (ROS). ROS are
generated in vivo under hyperoxic conditions (12) and have
been shown to readily degrade NO in vitro (29). The recent
observation that hyperoxia-induced vasoconstriction of the
forearm vasculature can be reduced by pretreatment with an
antioxidant (17) supports the idea that this mechanism also
operates in vivo in humans.
We wanted to establish and confirm that this hyperoxiainduced vasoconstrictor mechanism also functions in hearts of
human subjects. We first determined whether hyperoxia affects
⫺
the arterial-coronary venous balance of free NO⫺
2 and NO3
ions or protein-bound NO. We were, however, unable to
demonstrate any consistent concentration gradient for these
NO species across the coronary circulation either during roomair or 100% oxygen breathing. Although the existence of such
a gradient would seem a logical consequence of coronary
endothelium NO production, we have noted inconsistent findings by other investigators in this regard (3, 14, 27, 33, 37).
This inconsistency may reflect a number of factors including
OXYGEN AND CORONARY BLOOD FLOW
H1061
Fig. 5. Right coronary angiograms performed in one subject
during intracoronary infusion of 20 ␮g/min ACh while subject
breathed room air (left) and 100% oxygen (right). During
100% oxygen (but not room-air) breathing, ACh infusion
produced diffuse constriction of the distal coronary artery
branches.
AJP-Heart Circ Physiol • VOL
(20) and increases endothelium-dependent forearm blood flow
in humans (22). Although the effects of chronic statin use on
coronary NO production in humans are unknown, it is conceivable that the use of relatively high doses of these drugs by
most of our subjects accounts for their apparently substantial
degree of endothelium-dependent coronary relaxation while
they breathed room air. Another potential explanation for our
findings was recently suggested by Cosby et al. (6), who
observed that erythrocytes traversing the forearm circulation
can lower forearm vascular resistance by reducing nitrite ions
to NO at a rate proportional to their deoxyhemoglobin contents. Were this mechanism to operate in heart (which has not
yet been confirmed), it might be predicted that breathing 100%
oxygen would tend to increase coronary resistance by increasing hemoglobin oxygen saturation and thereby lowering erythrocyte nitrate reductase activity and NO production.
Limitations. Because of inherent selection bias (we only
studied subjects with early coronary atherosclerosis who were
undergoing cardiac catheterization for a clinical indication),
the relevance of these findings for healthy subjects is uncertain.
Practical constraints imposed by the need to perform the study
in conjunction with a clinical procedure likewise prevented us
from formally characterizing baseline coronary endothelial
function in these subjects or withholding certain medications
(e.g., aspirin), which may potentially affect endothelial function. Obviously, a complete understanding of the relationship
between ambient oxygen tension and coronary resistance in
vivo will require the performance of formal dose-response
studies.
Clinical implications. The findings of this study suggest that
the common clinical practice of administering supplemental
oxygen to patients with the goal of maintaining 100% oxyhemoglobin saturation may increase CVR and reduce CBF. In
patients with severe CHD, this could potentially precipitate
myocardial ischemia and cardiac dysfunction. The routine
administration of high-flow oxygen to such patients may therefore be unwise. Because ROS may have especially adverse
effects on the ischemic myocardium (4), the routine administration of supplemental oxygen to patients suffering acute
myocardial infarction or undergoing coronary interventions
must be viewed with particular skepticism. When administering
oxygen to patients with CHD, physicians should recognize that
oxygen is itself a vasoactive substance most appropriately dispensed in precise doses titrated against the measured arterial PO2.
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for the increase we observed in coronary venous nitrotyrosine
levels in response to supplemental oxygen operates systemically in these subjects as well.
The observation that CBF and MV̇O2 decreased simultaneously and proportionately in response to hyperoxia in our
subjects (Table 1) would appear to confirm the principle that
the heart can concordantly regulate oxygen delivery and consumption to balance energy supply and utilization and prevent
cardiomyocyte oxygen toxicity (35). On the basis of observations in cultured cells and isolated perfused hearts, this phenomenon has been hypothesized to be mediated by cross-talk
between cardiac myocytes and coronary endothelial cells mediated by endothelium-derived (e.g., NO, endothelin-1) and
myocyte-derived (e.g., adenosine, angiotensin I) regulatory
factors (2, 18, 21, 25, 35). Although little is known about the
mechanisms that link CBF and MV̇O2 in humans, our observations suggest that experiments testing the effect of hyperoxia
on the coronary venous efflux of such regulatory factors might
be a novel way of examining this system in vivo. Based on the
observation of Winegrad et al. (35) that culture media from
cardiac myocytes exposed to increased PO2 in vitro elicit
endothelin-1-mediated vasoconstriction in isolated coronary
vessels, we sought to determine whether hyperoxia increased
endothelin-1 levels in coronary venous blood in our studies.
Although we were unable to detect such an increase, this does
not completely exclude a role for this molecule in mediating
hyperoxic coronary constriction. For instance, it has been
suggested (35) that under some circumstances, endothelin-1
may be released by the vascular endothelium abluminally into
the cardiac interstitial space rather than into the bloodstream.
A somewhat surprising implication of our study is that a
substantial portion (⬃30%) of CBF in our room-air breathing
subjects was hyperoxia sensitive and therefore presumably
endothelium dependent. Several studies (1, 28, 34) suggest that
the ability of the coronary endothelium to elaborate these
relaxing factors becomes compromised early in the development of coronary artery disease. Because all of our subjects
had risk factors for CHD and most (n ⫽ 24) actually had
coronary atherosclerosis severe enough to detect by angiography, it might have been expected that they would have this
impairment. One possible confounding variable, however, was
the high frequency of statin use by these subjects. Short-term
statin treatment increases coronary endothelial NO synthase
expression and coronary microvascular NO production in dogs
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OXYGEN AND CORONARY BLOOD FLOW
ACKNOWLEDGMENTS
The authors thank the staff of the Pennsylvania State Cardiovascular Center
cardiac catheterization laboratories for help in the performance of these
studies.
GRANTS
This work is supported by grants from the American Heart Association
National Center (Grant 0350681N), the National Institutes of Health (Grant
RO1 HL-70222), and the General Clinical Research Center of the Pennsylvania State University Milton S. Hershey Medical Center (Grant MO1 RR10732).
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