(Circulation. 1995;92:320-326.)
© 1995 American Heart Association, Inc.
Articles |
Contribution of Nitric Oxide to Metabolic Coronary Vasodilation in the Human Heart
From the National Institutes of Health, Cardiology Branch, NHLBI, Bethesda, Md, and the Division of Cardiology, Medical College of Virginia, Richmond (D.M.G.).
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Abstract |
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Background The vascular endothelium contributes to smooth muscle relaxation by tonic release of nitric oxide. To investigate the contribution of nitric oxide to human coronary epicardial and microvascular dilation during conditions of increasing myocardial oxygen requirements, we studied the effect of inhibiting nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) on the coronary vasodilation during cardiac pacing in patients with angiographically normal coronary arteries with and without multiple risk factors for coronary atherosclerosis.
Methods and Results In 26 patients with angiographically normal or near-normal epicardial coronary arteries, metabolic vasodilation was assessed as a change in coronary vascular resistance and diameter during cardiac pacing (mean heart rate, 141 beats per minute). Endothelium-dependent vasodilation was estimated with intracoronary acetylcholine and endothelium-independent dilation with intracoronary sodium nitroprusside and adenosine. These measurements were repeated after 64 µmol/min intracoronary L-NMMA. At rest, L-NMMA produced a 16±25% (mean±SD) increase in coronary vascular resistance (P<.05) and an 11% reduction in distal epicardial coronary artery diameter (P<.01), indicating tonic basal release of nitric oxide from human coronary epicardial vessels and microvessels. Significant inhibition of pacing-induced metabolic coronary vascular dilation occurred with L-NMMA, coronary vascular resistance was 38±56% higher (P<.03), and epicardial coronary dilation during control pacing (9±13%) was converted to constriction after L-NMMA and pacing (-6±9%, P<.04). L-NMMA specifically inhibited endothelium-dependent vasodilation with acetylcholine (coronary vascular resistance was 72% higher [P<.01]) but did not alter endothelium-independent dilation with sodium nitroprusside and adenosine. Nine patients had no major risk factors for atherosclerosis, defined as serum cholesterol >240 mg/dL, hypertension, or diabetes. The remaining 17 patients with one or more of these risk factors had depressed microvascular vasodilation during cardiac pacing (coronary vascular resistance decreased by 13% versus 36% in those without risk factors, P<.05). The inhibitory effect of L-NMMA on pacing-induced coronary epicardial and microvascular vasodilation was observed only in patients without risk factors, whereas those with risk factors had an insignificant change, indicating that nitric oxide contributes significantly to pacing-induced coronary vasodilation in patients free of risk factors and without endothelial dysfunction. Patients with risk factors also had reduced vasodilation with acetylcholine (40±28% versus 68±8% decrease in coronary vascular resistance, P<.01), but the responses to sodium nitroprusside were similar in both groups.
Conclusions During metabolic stimulation of the human heart, nitric oxide release contributes significantly to microvascular vasodilation and is almost entirely responsible for the epicardial vasodilation. This contribution of nitric oxide is reduced in patients exposed to risk factors for coronary atherosclerosis and leads to a net reduction in vasodilation during stress. An important implication of these findings is that reduced nitric oxide bioavailability during stress in patients with atherosclerosis or risk factors for atherosclerosis may contribute to myocardial ischemia by limiting epicardial and microvascular coronary vasodilation.
Key Words: endothelium-derived factors • vasodilation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The vascular endothelium plays a pivotal role in modulating smooth muscle function by releasing endothelium-derived relaxing and constricting factors.1 2 3 4 5 One important endothelium-derived relaxing factor is nitric oxide, or a compound closely related to nitric oxide.6 7 8 Nitric oxide release can be stimulated by a variety of pharmacological agents, including acetylcholine.3 5 In the presence of normal endothelial function, stimulation of nitric oxide release by acetylcholine produces vasodilation of the coronary epicardial and microvascular circulation. With development of hypercholesterolemia, hypertension, heart failure, diabetes, aging, or atherosclerosis, however, the vasodilator response to acetylcholine is attenuated, denoting the presence of endothelial dysfunction.9 10 11 12 13 14 15 16 17 Human in vitro experiments and animal studies have demonstrated that release of endothelium-derived relaxing factor is also enhanced by physiological stimuli that increase shear in blood vessels,18 19 20 and appears to be at least partly responsible for coronary vasodilation that occurs with increase in myocardial oxygen demand.21 22 23
During exercise or with cardiac pacing, human coronary arteries dilate and coronary blood flow increases, indicating epicardial and microvascular dilation with increase in myocardial oxygen requirements.14 24 25 26 27 28 Microvascular dilation is generally believed to be secondary to accumulation of local metabolic byproducts such as adenosine, lactate, or hydrogen ions.29 30 31 Recent studies have implicated an association between vascular endothelial function and vasomotion during metabolic stress by demonstrating similarities between the epicardial coronary artery behavior with acetylcholine and vasomotion associated with exercise, pacing, or mental stress.26 27 28 32 However, the contribution of nitric oxide to coronary vascular tone during physiological stress and whether this contribution, if present, is altered in the presence of endothelial dysfunction in humans have not been studied to date.
In this study, we investigated the role of nitric oxide in determining coronary epicardial and microvascular vasodilation that accompanies cardiac pacing, and we further determined whether the presence of multiple risk factors for coronary atherosclerosis altered the contribution of endothelium-derived nitric oxide to pacing-induced vasodilation. NG-monomethyl-L-arginine (L-NMMA) an analogue of L-arginine that specifically inhibits nitric oxide synthase,33 was used to inhibit production of nitric oxide, and its effect on the vasodilator response of the coronary vasculature to cardiac pacing was studied.
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Methods |
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Patients
We studied 26 patients with angiographically normal or near-normal (<5% narrowing) coronary arteries who were undergoing diagnostic cardiac catheterization for investigation of chest pain or abnormal noninvasive tests. None of the patients had vasospasm of epicardial coronary arteries in response to either ergonovine or acetylcholine. These patients formed part of a larger group of patients reported previously.17 Patients with previous myocardial infarction or valvular heart disease were excluded. The mean age was 48±12 years; there were 10 men (38%) and 16 women. Eleven patients were hypertensive (blood pressure >140/90 mm Hg) but had no echocardiographic evidence of left ventricular hypertrophy. Hypercholesterolemia (total cholesterol >240 mg/dL) was present in 8 patients, and 6 had diabetes (fasting blood glucose >140 mg/dL and on pharmacological antidiabetic therapy). Nine patients had none of these risk factors, 10 were exposed to one factor, and 7 were exposed to two or more. Cardiac medications were withdrawn for at least 48 hours before and aspirin a week before the study. The study was approved by the National Heart, Lung, and Blood Institute Investigational Review Board, and informed written consent was obtained from all patients.
Protocol
After completion of diagnostic coronary
arteriography, a 6F
guide catheter was introduced into the left main coronary artery and
blood flow velocity was measured with an 0.018-in wire equipped with a
Doppler crystal at its tip (Cardiometrics Flowire, Cardiometrics,
Inc).34 35 The Doppler flow wire was advanced into
either
the left main (n=4) or the proximal segment of a major epicardial
coronary artery (left anterior descending coronary artery in 18
patients and circumflex coronary artery in 2). The wire tip was
carefully positioned in a straight segment of the vessel that was free
of any major branches within 1 cm from the tip, produced an adequate
flow velocity signal, and could be imaged without overlap from other
vessels, thus allowing for quantitative measurements of the coronary
artery diameter. All drugs were infused directly into the left main
coronary artery via the guide catheter at infusion rates ranging from 1
to 2 mL/min. A 7F multipurpose A2 catheter was inserted via the right
internal jugular vein into the mid coronary sinus for blood sampling.
Oxygen saturation of arterial and coronary sinus venous blood was
measured with an oximeter in 19 patients at baseline and after cardiac
pacing with and without L-NMMA.
After a 5-minute infusion of dextrose
5% at 1 mL/min, baseline
coronary blood flow velocity was measured and coronary angiography
performed (Fig 1
). Rapid atrial pacing was performed in
22 patients at heart rates ranging from 115 to 150 beats per minute
(bpm). Pacing from the right ventricle was performed at 150 bpm in the
remaining 4 patients, who developed atrioventricular
Wenckebach at rates <115 bpm. Thus, the mean cardiac pacing rate was
141±11 bpm. Blood flow velocity and coronary sinus oxygen measurements
and angiography were repeated after 2 minutes of pacing.
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Endothelium-dependent vasodilation was estimated by performance of a dose-response curve with incremental infusions of intracoronary acetylcholine (Sigma Ltd) starting at 3 µg/min for 2 minutes. This was followed by 2-minute infusions of 30, 100, and 300 µg/min of intracoronary acetylcholine, with measurement of Doppler flow velocity and angiography after each increment. The dose of acetylcholine was not increased further once an infusion either produced reduced blood flow velocity or severely (>50%) narrowed the epicardial coronary vessels. Thus, all patients received the 30-µg/min dose, 14 received doses up to 100 µg/min, and 12 up to 300 µg/min. The peak flow response with acetylcholine was achieved at the 30-µg/min dose in 17 patients, at the 100-µg/min dose in 8, and at the 300-µg/min dose in 1.
Five
minutes after the dose-response curve with acetylcholine was
performed, endothelium-independent function was
estimated with sodium nitroprusside and adenosine (Fig 1
).
Intracoronary sodium nitroprusside was given at 40 µg/min for 3
minutes, followed by measurement of blood flow velocity and coronary
angiography. This was followed by administration of intracoronary
adenosine at 2.2 mg/min for 2 minutes.
After a 10-minute interval,
while dextrose 5% infusion was continued,
repeat baseline measurements of flow velocity, oxygen saturations, and
angiography were made (Fig 1). This was followed by infusion of
L-NMMA
(Calbiochem), a specific inhibitor of nitric oxide.32
L-NMMA was infused at 32 µmol/min (0.5 mL/min) for 5 minutes and then
increased to 64 µmol/min (1 mL/min) for another 5 minutes.
While
the infusion of L-NMMA at 64 µmol/min was continued, cardiac
pacing was repeated at the same rate as during the control study.
Acetylcholine was readministered at the two highest vasodilating doses
in 25 patients for 2 minutes. Eighteen patients had repeat infusion of
40 µg/min sodium nitroprusside for 3 minutes, and 2.2 mg/min
adenosine was reinfused in 15 patients for 2 minutes (Fig 1).
Blood
flow velocity was measured and coronary angiography performed after
each intervention.
Estimation of Coronary Blood Flow and Diameter
Coronary blood
flow was estimated from measurement of coronary
blood flow velocity and diameter measurements by the formula
xaverage peak velocityx0.125xdiameter2.
Coronary
vascular resistance was calculated as mean arterial pressure divided by
coronary blood flow.
For calculating flow, coronary artery diameter was measured in a 0.5-cm segment of vessel beginning 0.25 cm beyond the tip of the flow wire. Coronary angiograms were recorded with a cineangiographic system (Toshiba, Inc). Quantitative angiography was performed with ARTEK software (Quantim 200I, STATVIEW, ImageComm Systems, Inc). In addition to measurement of the diameter at the level of the Doppler flow wire, 0.5- to 1-cm segments of the proximal and distal segments of the epicardial coronary arteries were also measured by quantitative coronary angiography by readers blinded to the interventions.
Statistical Analysis
Data are expressed as mean±SD in
the text and mean±SEM in
figures. Differences between means were compared by paired or unpaired
Student's t test, as appropriate. The effects of L-NMMA on
the two doses of acetylcholine were compared by ANOVA for repeated
measures using a multiple regression model that included dummy
variables to correct for between-subject variability.36
The differences between the effects of L-NMMA in patients with and in
those without risk factors were compared by use of the percent change
from baseline for all parameters because of the baseline differences in
regional flow in the two subgroups. All probability values are
two-tailed, and a value of P<.05 was considered of
statistical significance.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Effect of L-NMMA on Resting Coronary Vascular Tone
Coronary vascular resistance increased by 16% (4.1± 3.8 to 4.6±4.1 mm Hg · mL-1 · min, P<.05) with 64 µmol/min intracoronary L-NMMA, indicating tonic release of nitric oxide from the coronary microvasculature under resting conditions. This was accompanied by a 6% (P<.01) increase in mean arterial pressure. Epicardial coronary arteries constricted with L-NMMA, resulting in a mean 8% reduction (2.8±0.8 to 2.5±0.8 mm, P<.01) in the proximal and 11% reduction (1.8±0.6 to 1.6±0.6 mm, P<.01) in the distal segments, indicating, as previously reported,17 tonic basal release of nitric oxide from the coronary epicardial vessels.
Effect of L-NMMA on Response to Cardiac Pacing
L-NMMA
produced significant inhibition of pacing-induced coronary
epicardial and microvascular dilation (Figs 2 and
3). Thus, during the control study,
cardiac pacing at 141±11 bpm produced a mean 50% increase in blood
flow, 21% reduction in coronary vascular resistance, and a 9%
increase in proximal and distal coronary artery diameters (Figs
2 and 3). After L-NMMA, cardiac pacing at
140±12 bpm produced significantly
less microvascular vasodilation; the 23% increase in coronary blood
flow and the 5% reduction in coronary vascular resistance were not
significant. Epicardial vasodilation with cardiac pacing during the
control study (18% increase in proximal epicardial coronary artery
diameter) was converted to vasoconstriction after L-NMMA (13%
reduction in diameter, Figs 2 and 3). Thus, the
baseline constriction
that occurred with L-NMMA at rest was not overcome by pacing (2.8 mm at
baseline, 2.5 mm after L-NMMA [P<.01], and 2.5 mm
after L-NMMA and pacing). The reduced vasodilation during cardiac
pacing with L-NMMA was also confirmed by the changes in arteriovenous
oxygen differences; a 6±14% narrowing of the arteriovenous oxygen
difference during the control pacing study was converted to a 5±12%
widening (P=.03) of the difference, denoting reduced
microvascular vasodilation during pacing after L-NMMA.
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, post–L-NMMA study by 
(n=26).
Data represent mean±SEM. *P<.05,
**P<.01, difference between baseline and pacing.
Comparisons of changes in these parameters with pacing before versus
after L-NMMA are stated as control vs L-NMMA.
Effect of L-NMMA on Response to Acetylcholine
During the
control study, there was progressive increase in blood
flow and reduction in coronary vascular resistance, indicating
microvascular dilation with increasing doses of acetylcholine.
Epicardial coronary artery dimension did not change significantly
compared with baseline (Fig 4). After L-NMMA, repeat
infusions of the same doses of acetylcholine produced significant
inhibition of microvascular vasodilation and vasoconstriction of
epicardial coronary arteries; coronary vascular resistance was 72%
greater at the higher dose of acetylcholine after L-NMMA compared with
the control study (Fig 4). Thus, as previously reported from
our
laboratory,17 L-NMMA inhibited both epicardial and
microvascular vasodilation in response to acetylcholine.
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Effect of L-NMMA on Responses to Sodium Nitroprusside and
Adenosine
During the control study, there was significant epicardial
and
microvascular vasodilation in response to both sodium nitroprusside and
adenosine; coronary vascular resistance decreased by 53±19% with
sodium nitroprusside and by 73±22% with adenosine in the control
study. After L-NMMA, reinfusion of sodium nitroprusside and adenosine
at the same intracoronary concentrations produced similar vasodilation
of both coronary microvascular and epicardial vessels; coronary
vascular resistance was 56±14% lower with sodium nitroprusside and
69±25% lower with adenosine after L-NMMA (both P=NS
compared with control). Proximal epicardial coronary artery diameters
with sodium nitroprusside before and after L-NMMA (3±1 to 3±1
mm) and
with adenosine before and after L-NMMA (2.9±0.9 to 2.7±0.9 mm)
were similar (P=NS). Thus, L-NMMA did not inhibit coronary
vasodilation in response to the endothelium-independent
vasodilators sodium nitroprusside and adenosine.
Impact of Risk Factors for Coronary Atherosclerosis on Response to
Cardiac Pacing
Microvascular vasodilation with pacing was greater in
patients
without risk factors (36% reduction in coronary vascular resistance)
compared with those with risk factors (13% reduction,
P<.05) (Fig 5). The mean pacing heart rate
was 137±13 bpm in those without and 146±7 bpm in those with risk
factors (P=NS). Epicardial dilation with pacing tended to be
greater in patients without risks (Fig 5), but the difference
did not
reach statistical significance (18% increase in proximal diameter in
patients without risks versus 5% in those without,
P=.09).
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Impact of Risk Factors for Coronary Atherosclerosis on Response to
Acetylcholine
The peak vasodilator response with acetylcholine was
greater in
the 9 patients without risk factors than in those with risk factors for
atherosclerosis; coronary vascular resistance decreased by 68±8% in
patients with no risk factors, compared with a decrease of 40±28% in
patients with risk factors (P<.01). However, the
vasodilator response to sodium nitroprusside was not statistically
significant (63±13% versus 55±13%, P=NS, no risk
factors
versus risk factors, respectively).
Effect of L-NMMA on Pacing Response in Patients With and Without
Multiple Risk Factors
The coronary epicardial and microvascular
vasoconstriction during
pacing after L-NMMA, compared with the initial pacing sequence, was
observed only in patients without multiple risk factors (Fig
5). Thus,
proximal epicardial coronary arteries that dilated by 18% during
control pacing constricted by 13% on pacing after L-NMMA in patients
without risk factors. Similarly, coronary vascular resistance that fell
by 36% during control pacing did not change significantly on pacing
after L-NMMA (Fig 5), indicating that nitric oxide contributes
to
pacing-induced coronary vascular dilation in this group. In contrast,
the changes in epicardial and microvascular dilation with L-NMMA in
patients with risk factors were not statistically significant,
suggesting that the contribution of nitric oxide to pacing-induced
vasodilation is minimal in these patients.
Epicardial and coronary
microvascular dilation with pacing after L-NMMA
were similar in patients with and without risk factors (Fig 5),
suggesting that the increased dilation with pacing observed during the
control pacing sequence is due to increased nitric oxide activity in
patients without risk factors.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Contribution of Nitric Oxide to Metabolic Coronary Vasodilation
Metabolic coronary vasodilation in response to increased myocardial oxygen requirements has long been recognized to be mediated by a variety of local, humoral, and neural factors.30 31 32 Microvascular dilation is believed to be primarily due to accumulation of local metabolites, including adenosine, prostaglandins, carbon dioxide, and hypoxia, and partly due to circulating catecholamines and withdrawal of sympathetic tone. Epicardial vessel dilation, on the other hand, is considered to be secondary not only to the humoral and neural factors stated above but more importantly to flow-mediated dilation. Recent experimental studies have shown that flow-mediated conductance vessel dilation is due to release of endothelium-derived relaxing factor.18 19 20 37 38 Studies in human coronary arteries have also demonstrated flow-mediated dilation of epicardial coronary arteries that is abolished in atherosclerosis.39 40 That the endothelium may also contribute to microvascular vasodilation during a metabolic stimulus such as cardiac pacing was suggested from our previous study in a similar population of patients with normal coronary angiograms.14 In that investigation, patients with a depressed vasodilator response to acetylcholine also had a depressed dilator response with atrial pacing, a finding that was confirmed in this study. To investigate whether the apparent relation between metabolic and endothelium-dependent vasodilation observed previously was due to stimulation of release of endothelium-derived nitric oxide during stress, we conducted this study using L-NMMA as a specific inhibitor of nitric oxide synthesis. Our findings demonstrate that nitric oxide contributes significantly to both epicardial and coronary microvascular vasodilation, which accompanies conditions that increase myocardial oxygen requirements. In patients without risk factors for atherosclerosis, coronary vascular resistance during pacing after L-NMMA was significantly higher compared with pacing alone, and pacing-induced epicardial vessel dilation was abolished by L-NMMA. These findings are compatible with our previous report on the contribution of nitric oxide to exercise-induced vasodilation in the forearm.41 Forearm vascular resistance was 26% higher during exercise after L-NMMA compared with exercise alone. Taken together, these studies suggest that endothelium-derived release of nitric oxide from both the coronary and peripheral vasculatures contributes to metabolic vasodilation.
Specificity of the Response to L-NMMA
As reported previously
in other vascular beds and in the coronary
circulation,17 42 43 44 45
L-NMMA inhibited both the epicardial
and microvascular vasodilator responses to acetylcholine. This
inhibition was specific for nitric oxide, because dilation in response
to sodium nitroprusside and adenosine were not affected by L-NMMA. In
light of the specificity of the effect of L-NMMA on
endothelium-dependent dilation, the attenuation of
pacing-induced vasodilation by L-NMMA indicates that cardiac pacing
produced vasodilation of epicardial and coronary microvessels at least
in part by an endothelium-dependent mechanism. Thus,
the increase in coronary vascular resistance and epicardial coronary
constriction during pacing after L-NMMA indicates that nitric oxide
contributes to coronary vascular dilation that accompanies conditions
associated with increases in myocardial oxygen demands.
Contribution of Non–Nitric Oxide Mediators to Metabolic
Coronary
Vasodilation
Our study also demonstrates that there is persistent
coronary
microvascular dilation with cardiac pacing after administration of
L-NMMA; coronary vascular resistance decreased from 4.6±4
mm Hg · mL-1 · min after L-NMMA at rest to
4.0±4.1 mm Hg · mL-1 · min after L-NMMA
and
pacing, confirming the presence of non–nitric oxide–related
mechanisms that contribute to metabolic vasodilation of the coronary
microvasculature in humans. An alternative explanation for this finding
is that L-NMMA, a competitive antagonist of nitric oxide synthase, does
not completely block production of nitric oxide from the microvascular
endothelium in the dose given. In contrast to the microcirculation,
epicardial coronary arteries did not dilate with pacing after L-NMMA
compared with pacing alone, suggesting that coronary epicardial
vasodilation during metabolic stimulation of the human heart is likely
to be mediated entirely by the endothelium-derived
release of nitric oxide.
Influence of Risk Factors for Coronary Atherosclerosis
Patients exposed to multiple risk factors for atherosclerosis had
a depressed vasodilator response to acetylcholine compared with those
without risk factors, a finding that is compatible with previous
studies.11 14 15 16 Whether
the abnormality of
pharmacological release of endothelium-derived relaxing
factor is indicative of diminished nitric oxide activity during
physiological stress was the subject of the present study. In this
study, we not only demonstrate that endothelium-derived
nitric oxide contributes to metabolic vasodilation but also show that
this contribution is significant only in patients without risk factors.
These patients had suppression of pacing-induced vasodilation with
L-NMMA. Indeed, the similarity in vascular responses to pacing after
L-NMMA in both groups suggests that the greater vasodilation in
patients without risks during control pacing was due to higher nitric
oxide activity in these patients. These observations suggest that
endothelial dysfunction manifested in patients with risk factors leads
to a net reduction in coronary vasodilation during stress due to
diminished nitric oxide activity. Diminished vasodilation during stress
may, in turn, contribute to the development of myocardial
ischemia in patients with endothelial dysfunction.
Our results are compatible with those of previous studies demonstrating that segments of epicardial coronary arteries that have a constrictor response to intracoronary acetylcholine also react abnormally in response to stress such as atrial pacing, cold pressor test, and mental stress26 27 28 29 30 and extend these findings to the coronary microcirculation. Moreover, this study, for the first time, specifically links the previously observed association between stress-induced epicardial coronary dilation and the acetylcholine response to nitric oxide activity in the human coronary epicardial and microvascular circulation.
Limitations
The exact mechanism of the depression in nitric
oxide activity
observed in our study cannot be determined from our findings. It may be
due to factors that affect the signal transduction
pathway,46 to a defect in the nitric oxide synthase enzyme
itself, or to a lower rate of synthesis of nitric oxide, which may in
turn be a result of substrate deficiency.47 48
Alternatively, it may be secondary to increased breakdown of normally
produced nitric oxide by superoxide anions.49 50 We
are
also unable to determine, in this relatively small group of patients,
whether any one or more of the risk factors are more or less important
in precipitating the abnormality in bioavailability of nitric oxide
during stress.
Implications
This study defines the physiological role of
endothelium-derived nitric oxide released from coronary
epicardial vessels and microvessels during metabolic stimulation of the
human heart. Although abnormalities in the response to acetylcholine in
epicardial coronary
arteries10 11 12 13 26 27 28 29
and in
microvessels51 has been noted in patients with
atherosclerosis, we demonstrate reduced coronary vascular nitric oxide
bioavailability, both at rest and after stress, in patients with
angiographically normal-appearing coronary arteries who have been
exposed to multiple risk factors for atherosclerosis. These findings
may have important implications: reduced coronary vasodilation in
patients with multiple risk factors and normal epicardial coronary
arteries may precipitate ischemia and might account for chest
pain in some patients with microvascular
angina.14 52 53
In patients with established atherosclerosis, also known to be
associated with endothelial dysfunction, coronary blood flow increase
during stress not only is limited by epicardial stenoses but also may
be additionally compromised by diminished microvascular dilation.
Moreover, reduced nitric oxide activity from the coronary vasculature
may contribute to accelerated progression of atherosclerosis due to an
absence in the antiproliferative effects of nitric
oxide.54 55 56
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Acknowledgments |
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The authors are grateful for the technical assistance of William Schenke, Gregory Johnson, and Rita Mincemoyer, RN.
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Footnotes |
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Reprint requests to Arshed A. Quyyumi, MD, National Institutes of Health, Cardiology Branch, NHLBI, Bldg 10, Room 7B-15, 10 Center Dr, MSC 1650, Bethesda, MD 20892-1650.
Received November 14, 1994; revision received January 19, 1995; accepted January 28, 1995.
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J. G. Diodati, N. Dakak, D. M. Gilligan, and A. A. Quyyumi Effect of Atherosclerosis on Endothelium-Dependent Inhibition of Platelet Activation in Humans Circulation, July 7, 1998; 98(1): 17 - 24. [Abstract] [Full Text] [PDF]
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K. Node, M. Kitakaze, H. Sato, Y. Koretsune, M. Karita, H. Kosaka, and M. Hori Increased release of nitric oxide in ischemic hearts after exercise in patients with effort angina J. Am. Coll. Cardiol., July 1, 1998; 32(1): 63 - 68. [Abstract] [Full Text] [PDF]
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N. Dakak, S. Husain, D. Mulcahy, N. P. Andrews, J. A. Panza, M. Waclawiw, W. Schenke, and A. A. Quyyumi Contribution of Nitric Oxide to Reactive Hyperemia : Impact of Endothelial Dysfunction Hypertension, July 1, 1998; 32(1): 9 - 15. [Abstract] [Full Text] [PDF]
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F. Costa and I. Biaggioni Role of Nitric Oxide in Adenosine-Induced Vasodilation in Humans Hypertension, May 1, 1998; 31(5): 1061 - 1064. [Abstract] [Full Text] [PDF]
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S. J. Duffy, B. T. Tran, G. New, R. N. Tudball, M. D. Esler, R. W. Harper, and I. T. Meredith Continuous release of vasodilator prostanoids contributes to regulation of resting forearm blood flow in humans Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1174 - H1183. [Abstract] [Full Text] [PDF]
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S. Husain, N. P. Andrews, D. Mulcahy, J. A. Panza, and A. A. Quyyumi Aspirin Improves Endothelial Dysfunction in Atherosclerosis Circulation, March 3, 1998; 97(8): 716 - 720. [Abstract] [Full Text] [PDF]
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A. Godecke, U. K. M. Decking, Z. Ding, J. Hirchenhain, H.-J. Bidmon, S. Godecke, and J. Schrader Coronary Hemodynamics in Endothelial NO Synthase Knockout Mice Circ. Res., February 9, 1998; 82(2): 186 - 194. [Abstract] [Full Text] [PDF]
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L. Fei, A. D. Baron, D. P. Henry, and D. P. Zipes Intrapericardial Delivery of L-Arginine Reduces the Increased Severity of Ventricular Arrhythmias During Sympathetic Stimulation in Dogs With Acute Coronary Occlusion : Nitric Oxide Modulates Sympathetic Effects on Ventricular Electrophysiological Properties Circulation, December 2, 1997; 96(11): 4044 - 4049. [Abstract] [Full Text]
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M. Kato, N. Shiode, T. Yamagata, H. Matsuura, and G. Kajiyama Bradykinin induced dilatation of human epicardial and resistance coronary arteries in vivo: effect of inhibition of nitric oxide synthesis Heart, November 1, 1997; 78(5): 493 - 498. [Abstract] [Full Text] [PDF]
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E. Giannella, H.-C. Mochmann, and R. Levi Ischemic Preconditioning Prevents the Impairment of Hypoxic Coronary Vasodilatation Caused by Ischemia/Reperfusion : Role of Adenosine A1/A3 and Bradykinin B2 Receptor Activation Circ. Res., September 19, 1997; 81(3): 415 - 422. [Abstract] [Full Text]
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T. Minamino, M. Kitakaze, K. Node, H. Funaya, and M. Hori Inhibition of Nitric Oxide Synthesis Increases Adenosine Production via an Extracellular Pathway Through Activation of Protein Kinase C Circulation, September 2, 1997; 96(5): 1586 - 1592. [Abstract] [Full Text]
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M. Kimura, I. Kurose, J. Russell, and D. N. Granger Effects of Fluvastatin on Leukocyte–Endothelial Cell Adhesion in Hypercholesterolemic Rats Arterioscler Thromb Vasc Biol, August 1, 1997; 17(8): 1521 - 1526. [Abstract] [Full Text]
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 S. Joshi, W. L. Young, J. Pile-Spellman, P. Fogarty-Mack, R. R. Sciacca, L. Hacein-Bey, H. Duong, Y. Vulliemoz, N. Ostapkovich, and T. Jackson Intra-arterial Nitrovasodilators Do Not Increase Cerebral Blood Flow in Angiographically Normal Territories of Arteriovenous Malformation Patients Stroke, June 1, 1997; 28(6): 1115 - 1122. [Abstract] [Full Text]
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R. D. Bernstein, F. Y. Ochoa, X. Xu, P. Forfia, W. Shen, C. I. Thompson, and T. H. Hintze Function and Production of Nitric Oxide in the Coronary Circulation of the Conscious Dog During Exercise Circ. Res., October 1, 1996; 79(4): 840 - 848. [Abstract] [Full Text]
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K. Egashira, Y. Katsuda, M. Mohri, T. Kuga, T. Tagawa, T. Kubota, Y. Hirakawa, and A. Takeshita Role of Endothelium-Derived Nitric Oxide in Coronary Vasodilatation Induced by Pacing Tachycardia in Humans Circ. Res., August 1, 1996; 79(2): 331 - 335. [Abstract] [Full Text]
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D. H. McDermott, J. P.J. Halcox, W. H. Schenke, M. A. Waclawiw, M. N. Merrell, N. Epstein, A. A. Quyyumi, and P. M. Murphy Association Between Polymorphism in the Chemokine Receptor CX3CR1 and Coronary Vascular Endothelial Dysfunction and Atherosclerosis Circ. Res., August 31, 2001; 89(5): 401 - 407. [Abstract] [Full Text] [PDF]
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M. A.W. Broeders, G. J. Tangelder, D. W. Slaaf, R. S. Reneman, and M. G.A. oude Egbrink Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules: Complete Reversal by L-Arginine Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 680 - 685. [Abstract] [Full Text] [PDF]
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