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(Circulation. 1999;99:491-497.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
L-Arginine Normalizes Coronary Vasomotion in Long-Term Smokers
From the Department of Molecular and Medical Pharmacology, UCLA School of Medicine, and Laboratory of Structural Biology and Molecular Medicine, University of California, Los Angeles.
Correspondence to Heinrich R. Schelbert, MD, UCLA School of Medicine, 23-120 CHS, Los Angeles, CA 90095-1735. E-mail hschelbert{at}mednet.ucla.edu
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Abstract |
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Background—Noninvasive measurements of myocardial blood flow (MBF) with PET revealed an abnormal coronary vasomotor response to cold pressor test in healthy long-term smokers. If coronary endothelial dysfunction accounted for this abnormality, we hypothesized that it could be reversed by L-arginine as the substrate for NO synthase.
Methods and Results—MBF was quantified with 13N-labeled ammonia and PET in 11 healthy smokers (age, 45±10 years; 27±10 years of smoking) and in 12 age-matched nonsmokers on 2 separate days. On day 1, MBF was measured at rest and, after intravenous L-arginine, during cold pressor test. On day 2, MBF was measured during cold pressor test and then at rest during L-arginine. Baseline rate-pressure product (RPP) (6559±1590 versus 7144±1157 bpmxmm Hg) and MBF (0.65±0.14 versus 0.73±0.13 mL · g-1 · min-1) were similar in nonsmokers and smokers. Cold pressor test increased RPP similarly in both groups (53±26% versus 46±26%), whereas MBF increased in nonsmokers (to 0.93±0.25 mL · g-1 · min-1; P<0.05) but not in smokers (0.80±0.16 mL · g-1 · min-1). The percent MBF increase differed between nonsmokers and smokers (44±25% versus 11±14%; P=0.0017). However, after L-arginine, the magnitude of MBF response to cold pressor test no longer differed between groups (48±36% versus 48±28%), whereas RPP again increased similarly in the 2 groups (59±30% versus 44±16%). L-Arginine had no effect on resting MBF in smokers or nonsmokers.
Conclusions—Our findings implicate the coronary endothelium as the major site of the abnormal vasomotor response in long-term smokers. Cold pressor test combined with PET imaging may allow the noninvasive identification of coronary endothelial dysfunction in humans.
Key Words: blood flow • smoking • cold pressor test • endothelium • tomography
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cigarette smoking is a well-recognized coronary risk factor that induces endothelial dysfunction.1 2 We previously observed an abnormal myocardial blood flow (MBF) response to cold pressor test in chronic but healthy smokers.3 The cold pressor test evokes a mixed, adrenergically mediated vasoconstrictor and vasorelaxant response; the vasorelaxant effects are thought to be mediated through ß-adrenoreceptor stimulation and, importantly, through NO release from endothelium. The cold pressor test has therefore been considered a noninvasive probe of endothelium-dependent coronary vasomotion.4 5 In the normal coronary circulation, the complex interplay between vasoconstrictor and vasorelaxant effects produces a net increase in coronary flow. However, in patients with coronary artery disease or with coronary risk factors, the cold pressor test can cause a paradoxical constriction of the epicardial vessels and an attenuated flow response.4 The reported correlation between abnormal responses to cold pressor test and to intracoronary acetylcholine in the large epicardial conduit and the resistance vessels of the coronary circulation implicate the endothelium as the primary site for the abnormal response to cold pressor test.6
If the abnormal response to cold pressor test in smokers reflects endothelial dysfunction, we postulated that intravenous L-arginine should improve or restore the flow response. L-Arginine is the substrate for NO synthase (NOS)7 and has been found to improve abnormal flow responses to intracoronary acetylcholine in patients with coronary risk factors.8 9 L-Arginine–mediated restoration of the flow response to cold pressor test would then support the hypothesis that an abnormal cold pressor test signifies endothelial dysfunction. If true, the combination of this test with PET-based measurements of MBF could offer a means for probing endothelial dysfunction noninvasively.
Therefore, it was the aim of this study to determine with 13N-labeled ammonia and PET imaging whether L-arginine modifies the MBF response to cold pressor test in healthy long-term smokers.
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Methods |
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Study Population
Twenty-three normal volunteers (11 long-term smokers and 12 nonsmokers) were studied. The group of smokers consisted of 8 men and 3 women (age, 45±10 years; range, 39 to 60 years) who had been smoking cigarettes for 27±10 years (range, 14 to 50 years; 26±17 pack-years). The group of 12 age-matched, healthy, lifelong nonsmokers (9 men, 3 women; age, 46±11 years; range, 28 to 59 years) served as controls. Four smokers and 6 nonsmokers had participated in a previous study3 and participated again a year later in the current study. Each participant was studied on 2 different days (mean interval of 8±5 days). None had hypertension, diabetes, familial hyperlipidemia, a history of coronary artery disease, or evidence of atherosclerosis (determined by absence of angina, intermittent claudication, or cerebrovascular ischemia) or was taking any medication. Long-term smoking was defined as
2 pack-years of cigarette smoking before the PET
study.1 ECGs were normal at rest, during cold pressor
test, and during L-arginine infusion in all subjects.
Smokers and nonsmokers >50 years old had either a normal treadmill or
normal pharmacological stress test. All participants refrained from
consuming caffeine-containing food or beverages for 24 hours, and
smokers refrained from smoking for 4 hours before
study.3 10 Each participant signed an informed consent
form approved by the University of California at Los Angeles Human
Subject Protection Committee.
Positron Emission Tomography
MBF was measured with 13N-labeled ammonia,
PET, and a previously validated tracer kinetic model.11
The CTI/Siemens ECAT EXACT HR+ device used in the
study acquires 63 transaxial planes with an in-plane resolution of
4.3 mm full-width half-maximum (FWHM) and a 15.5-cm axial field of
view (FOV).12 After adequate positioning of the heart in
the FOV, aided by a rectilinear transmission scan, a 20-minute
transaxial transmission scan was acquired. The images were
reconstructed with a Hann filter with a transaxial cutoff frequency of
0.093 mm-1 cycles per pixel, and an axial
cutoff frequency of 0.082 mm-1, resulting
in an effective isotropic resolution of 11 mm FWHM.
The study protocol consisted of 2 study sessions, both performed in the afternoon. On day 1, MBF was measured at rest and, after L-arginine infusion, during cold pressor test. Beginning with intravenous 13N-labeled ammonia administration (15 to 20 mCi), serial transaxial emission images were acquired (12 image frames of 10 seconds each, 2 frames of 30 seconds each, and 1 frame of 900 seconds). This was followed by intravenous infusion of L-arginine (30 g as 10% arginine hydrochloride) for 45 minutes at a rate of 6.67 mL/min. The cold pressor test was performed during the last 2 minutes of the L-arginine infusion. The patient immersed the left hand in ice water for 45 seconds before a second dose of 13N-labeled ammonia (15 to 20 mCi) was injected. The image-acquisition sequence used for the baseline study was repeated while the cold pressor test was maintained for another minute to permit trapping of 13N-labeled ammonia in the myocardium. On day 2, MBF was measured first during cold pressor test and then during the last 2 minutes of L-arginine infusion. Cold pressor test, administration of L-arginine and of 13N-labeled ammonia, and image acquisition were identical to those performed on day 1.
Heart rate, arterial blood pressure, and 12-lead ECG were recorded continuously. Heart rates and arterial blood pressures during the first 2 minutes of each image acquisition sequence were averaged and used to calculate the rate-pressure product (RPP).
Quantification of MBF
Regional MBF was quantified in the territories of the left
anterior descending, left circumflex, and right coronary
arteries.11 Thus, 69 coronary territories were
analyzed in the 23 participants (33 territories in smokers and
36 in nonsmokers). Sectorial regions of interest (ROIs; 70° to 90°
each) were placed in each coronary territory on a basal,
mid, and apical short-axis image. The same anatomic landmark (insertion
of right ventricle into the intraventricular
septum) ensured identical assignment of ROIs for the 4 study
conditions. A small ROI (25 mm2) was
centered in the left ventricular blood pool for
determination of the arterial input
function.13 The ROIs were copied to the first 120 seconds
of the serially acquired images for generation of blood pool and
myocardial time-activity curves. A single time-activity curve was
obtained for each coronary vascular territory by averaging the
time-activity data from the 3 short-axis cross sections. Because MBF
did not differ between the vascular territories, a single value of MBF
was obtained by averaging the time-activity data in the 3
coronary territories.11 14 Effects of partial
volume were corrected for with a recovery coefficient that assumed a
uniform 1-cm-thick left ventricular wall.15
Time-activity curves were corrected for physical decay and fitted with
a 2-compartment tracer kinetic model that corrects for spillover of
activity from the blood pool into the left ventricular
myocardium.16
Blood Chemistry
On day 1, total serum cholesterol and HDL
cholesterol were determined at baseline by enzymatic
methods.17 LDL cholesterol was calculated
mathematically.18 Serum concentrations of
L-arginine, citrulline, and ornithine (by
fluorescent high-performance liquid
chromatography),19 20 insulin (by
radioimmunoassay), and glucose (by standard enzymatic methods) were
measured at baseline and at 35 minutes of L-arginine
infusion on day 1 and before cold pressor test and at 35 minutes of
L-arginine infusion on day 2.
Statistical Analysis
Descriptive statistics are expressed as mean±SD.
Hemodynamic parameters and MBFs at
baseline, during cold pressor test after L-arginine, and
during cold pressor test and L-arginine infusion were
analyzed by repeated-measures ANOVA. Post hoc comparisons were
made with the Bonferroni test. Changes in serum measurements before and
after L-arginine as well as the interobserver
reproducibility of the MBF measurements were assessed by paired
t testing.
Differences in hemodynamic parameters, MBF, and serum measurements between smokers and nonsmokers were assessed with the unpaired t test. Differences between groups in the magnitude of the MBF response to cold pressor test at baseline and after L-arginine were evaluated by 2-sample Wilcoxon rank sum (Mann-Whitney) test. All probability values are 2-tailed; P<0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hemodynamic Findings
Heart rate and blood pressure measurements in smokers and nonsmokers are summarized in Table 1
. At baseline, systolic,
diastolic, and mean arterial blood pressures
(82±7 versus 84±13 mm Hg) and RPPs (6559±1590 versus
7144±1157 bpmxmm Hg) were similar in both groups. Smokers and
nonsmokers responded to cold pressor testing after
L-arginine infusion with significant increases in heart
rate, mean arterial blood pressure (to 102±14 and
100±16 mm Hg, respectively), and RPP (to 10 365±2943 and
10 208±1557 bpmxmm Hg, respectively). Also, during baseline cold
pressor testing, mean arterial blood pressure increased
similarly in both groups (to 101±11 and 109±14 mm Hg,
respectively), whereas heart rate failed to significantly increase in
nonsmokers. However, RPPs did not differ between both groups
(10 059±2911 versus 10 361±2079 bpmxmm Hg, respectively;
P=NS), indicating that cold pressor testing induced
comparable increases in cardiac work in smokers and nonsmokers.
L-Arginine infusion had no effect on heart rate
or mean arterial blood pressure (84±13 versus 84±15 bpm
and 82±7 versus 80±6 mm Hg, respectively; P=NS) at
baseline in smokers and nonsmokers, respectively. Furthermore, the
increase in cardiac work induced by cold pressor test was independent
of L-arginine in both groups (10 365±2943 bpmxmm Hg
before versus 10 059±2911 bpmxmm Hg after L-arginine
for smokers; 10 208±2911 bpmxmm Hg before versus 10 361±2079
bpmxmm Hg after L-arginine for nonsmokers;
P=NS). RPP during L-arginine
administration was similar in smokers and nonsmokers (7251±1432 versus
6969±1484 bpmxmm Hg; P=NS). Last, the resting RPP at
baseline on day 1 was similar to that at baseline before cold pressor
testing on day 2 in smokers (7144±1157 versus 7465±1698 bpmxmm Hg;
P=NS) but not in nonsmokers (6559±1590 versus 7227±1726
bpmxmm Hg; P=0.042). This finding was related to a higher
heart rate on day 2 during transmission scan than that on day 1
obtained during measurement of MBF at baseline (63±11 versus 59±12
bpm; P=0.032) despite similar systolic blood
pressures (110±9 versus 114±3 mm Hg; P=NS). However,
when heart rates during transmission imaging for both studies were
compared, they no longer differed between days (65±12 versus 63±11
bpm; P=NS). Therefore, baseline hemodynamic
conditions were comparable for the 2 sessions in smokers and
nonsmokers.
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PET Image Analysis
There were 69 coronary territories (3 per participant) in
the 23 participants. On visual examination, all 69 vascular territories
exhibited homogeneously distributed perfusion at rest,
during cold pressor test with and without L-arginine
infusion, and during L-arginine administration. There were
no rest or stress perfusion defects in any of the smokers or
nonsmokers.
MBF Measurements
MBF at rest was similar for the 2 groups (0.73±0.13 versus
0.65±0.14 mL · g-1 ·
min-1). L-Arginine infusion did not
affect resting MBF in smokers or nonsmokers (0.73±0.13 versus
0.76±0.23 mL · g-1 ·
min-1 before versus after infusion in smokers
and 0.65±0.14 versus 0.78±0.18 mL ·
g-1 · min-1 before
versus after infusion in nonsmokers; P=NS; Table 1
).
Whereas cold pressor testing increased RPPs similarly in smokers and
nonsmokers (from 7144±1157 to 10 361±2079 and from 6559±1590 to
10 059±2911 bpmxmm Hg, respectively; P<0.05), MBF
increased only in nonsmokers (from 0.65±0.14 to 0.93±0.25 mL ·
g-1 · min-1;
P<0.05) and not in smokers (from 0.73±0.13 to 0.80±0.16
mL · g-1 ·
min-1; P=NS; Table 1). The
percent MBF increase during cold pressor testing differed between
nonsmokers and smokers (44±25% versus 11±14%, respectively;
P=0.0017; Figure) despite
comparable percent increases in RPP (53±26% versus 46±26%).
However, after L-arginine infusion, the magnitude
of the MBF response to cold pressor testing no longer differed between
the 2 groups (48±36% versus 48±28%), whereas RPPs again increased
similarly in both groups (59±30% versus 44±16%; Figure).
During cold pressor test after L-arginine
administration, MBF increased similarly in smokers and nonsmokers
(1.06±0.16 versus 0.94±0.23 mL ·
g-1 · min-1;
P=NS). To remove any observer bias, MBF data were
analyzed by 2 independent observers (Dr Campisi and Dr
Schöder). Average MBF values in 6 participants did not
differ between observers (0.75±0.19 versus 0.72±0.12 mL ·
g-1 · min-1;
P=0.51).
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P=0.0044 cold pressor test vs
L-arginine plus cold pressor test in smokers.
Coronary Vascular Resistance
An index of coronary vascular resistance was calculated
from the ratio of mean arterial blood pressure
(mm Hg) to MBF (mL · g-1 ·
min-1).21 At rest, this index was
similar for smokers and nonsmokers (120±30 versus 131±20
mm Hg/mL · g-1 ·
min-1; P=NS). In smokers,
coronary vascular resistance was lower during cold pressor test
after L-arginine than during baseline cold
pressor test (97±25 versus 139±25 mm Hg/mL ·
g-1 · min-1;
P<0.05) and remained unchanged during
L-arginine infusion (117±31 mm Hg/mL
· g-1 · min-1;
P=NS). In nonsmokers, this index averaged at baseline (rest)
131±20 mm Hg/mL · g-1 · min-1 and was
lower at rest with L-arginine (106±21 mm Hg/mL ·
g-1 · min-1) and during cold pressor
testing with and without L-arginine (99±24 and 115±27
mm Hg/mL · g-1 · min-1;
P<0.05 for all versus baseline). Of note, coronary
resistance during cold pressor test was higher in smokers than in
nonsmokers (139±25 versus 115±27 mm Hg/mL ·
g-1 · min-1;
P<0.05).
Blood Chemistry
Total serum cholesterol was similar in smokers and
nonsmokers (188±40 mg/dL [range, 131 to 235 mg/dL] versus 167±45
mg/dL [range, 93 to 253 mg/dL]; P=NS). In the smoking
group, 4 participants had borderline elevated cholesterol
levels (200 to 239 mg/dL). In the nonsmoking group, 1 participant had
borderline and 1 had elevated cholesterol levels (>240
mg/dL).22 There were no differences in HDL and LDL
cholesterol levels between groups (46±19 versus 45±13
mg/dL [HDL] and 118±43 versus 99±30 mg/dL [LDL], for smokers and
nonsmokers, respectively; P=NS). HDL/LDL ratios were
similar in smokers and nonsmokers (0.47±0.34 versus 0.49±0.20;
P=NS). Serum arginine levels were similar in smokers and
nonsmokers at baseline and during L-arginine
infusion (Table 2). During
L-arginine administration, levels of citrulline
increased by 32±23% and 33±31%, respectively, and ornithine levels
increased by 468±143% and 595±277% in smokers and nonsmokers,
respectively. Insulin levels at baseline were similar in smokers and
nonsmokers and increased similarly in both groups during
L-arginine infusion (by 349±440% and
361±416%, respectively). Glucose levels remained unchanged during
L-arginine infusion in smokers and nonsmokers
(Table 2). There were no differences in serum measurements
between the 2 days of the study protocol.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The major finding of the current study is that acute administration of L-arginine as the substrate of NOS reversed the abnormal MBF response to cold pressor testing in healthy long-term smokers. This finding supports the hypothesis that the abnormal response to cold pressor test depends on endothelial dysfunction.
Cold Pressor Test and Endothelial Function
The previously reported correlation between the epicardial
vasomotor response to intracoronary acetylcholine and that to
cold pressor test in patients with mild
atherosclerosis4 indicated that the cold
pressor test could be used as a probe of
endothelium-dependent coronary
vasomotion.5 By combining cold pressor testing with
PET-based MBF measurements, we had shown that
endothelium-dependent dilation of the coronary
microcirculation could be demonstrated noninvasively. The MBF response
to cold pressor test was attenuated in healthy long-term smokers; the
degree of this impairment correlated with the number of years of
smoking.3 The current findings confirm and expand on the
previous observations. Again, the flow responses to cold pressor test
were diminished in long-term smokers. Importantly,
L-arginine reversed the abnormal response, which suggests
that the cold pressor test acted through an
endothelium-dependent mechanism. Increases in serum
citrulline during L-arginine infusion support the
possibility that the NOS pathway was stimulated. Support for this
possibility comes from Gellman et al,23 who reported that
L-arginine normalized the paradoxical coronary
resistance response to cold pressor test in patients with
coronary artery disease, suggesting again that coronary
responses to the cold pressor test involve the
L-arginine–NO pathway. Furthermore, Tousoulis et
al24 showed that the cold pressor test caused dilation of
proximal and distal artery segments in patients with normal
coronary arteriograms and that this dilation was abolished by
NG-monomethyl-L-arginine,
a competitive antagonist of NO. Our findings together with
these earlier observations support the role of the cold pressor test as
a tool to evaluate coronary endothelial
function. Cold pressor testing combined with PET imaging may thus allow
the noninvasive identification of coronary
endothelial dysfunction in humans.
L-Arginine and Endothelial Dysfunction
in Cigarette Smokers
L-Arginine is the substrate of the stereospecific
enzyme NOS.7 Several studies report a modulating effect of
L-arginine supplementation on NO production in vivo
under conditions known to be associated with
endothelial dysfunction, such as
hypercholesterolemia,8 25
hypertension,26 aging,9 and
diabetes.27 In healthy young cigarette smokers, oral
administration of L-arginine reversed the increased
monocyte–endothelial cell adhesion to
endothelial cells, an early event in
atherogenesis.28
In the current study, cold pressor test failed to increase MBF in long-term smokers despite appropriate increases in RPP and thus in cardiac work. Accordingly, coronary vascular resistance was higher in smokers than in nonsmokers but became normal after L-arginine administration. Because it continued to have no effect on the flow response to cold pressor test in nonsmokers, L-arginine appeared to act selectively in long-term smokers with endothelial dysfunction. We tested the possibility that our findings might have been attributed to a lack of reproducibility of the MBF measurements. However, mean flow values obtained in 6 participants were similar for both observers. Furthermore, Nagamachi et al29 reported no significant differences between estimates of MBF at rest either on the same day or after 26.5±18.9 days. In the present study, each participant was studied twice at an interval of 8±5 days. Thus, it is unlikely that the observations can be attributed to systematic measurement error.
It remains uncertain how L-arginine administration increases NO production. One explanation is that L-arginine supplementation enhances the availability of intracellular substrate for endothelial NOS. However, because intracellular levels of L-arginine exceed the Km of NOS, administration of the substrate is unlikely to affect NO production.30 Nevertheless, total cellular L-arginine concentration might not necessarily reflect the concentration in microdomains of the cell (for example, in the plasmalemmal caveolae as the site of endothelial production of NO).30 31 L-Arginine levels in endothelial cells can be modulated by the enzyme arginase, which degrades L-arginine to ornithine and urea.32 This reaction has also been reported in hepatocytes,33 macrophages,34 and neurons.35 According to Wu and Meininger,36 arginase and not NOS is the major pathway of arginine metabolism in normal endothelial cells. Therefore, it is possible that catabolism of arginine independent of NOS (ie, arginase) may play a role in regulating intracellular arginine levels. In the current study, serum ornithine levels increased more than citrulline levels during L-arginine infusion in both smokers and nonsmokers. The increases were similar for both groups. Therefore, arginine appears to degrade mainly by the arginase pathway.
Another possibility is that vascular effects of L-arginine could be mediated by release of endogenous substances. L-Arginine stimulates insulin release from pancreatic ß-cells. The hormone possesses vasoactive properties possibly mediated by endogenous NO release.37 The increase in serum insulin during L-arginine raises the possibility of an insulinotropic effect of L-arginine for normalizing the MBF response to cold pressor test. Creager et al25 demonstrated that infusion of L-arginine in hypercholesteremic individuals induced an increase in insulin levels and in brachial blood flow. In contrast, the enantiomer D-arginine (which is not a substrate for NOS) also induced insulin release, although without affecting brachial artery blood flow. Thus, despite enhanced insulin release during L- or D-arginine infusions, the reversal of endothelial dysfunction in hypercholesterolemia or long-term cigarette smokers, as observed in the present study, may be related to a specific action of L-arginine. However, Giugliano et al37 reported that vascular responses to L-arginine are mediated in part by endogenous insulin secretion in healthy individuals. In particular, octreotide inhibition of basal insulin secretion diminished the vasodilating effect of L-arginine. Studies are needed to clarify this important issue. Alternatively, L-arginine may enhance NO release by reversing the inhibitory effect of L-glutamine in receptor-mediated NO release38 or might overcome the effects of endogenous NOS antagonists such as asymmetric dimethyl arginine.39 Finally, L-arginine might exert its beneficial effect on the vascular system through antioxidative properties.40 Cigarette smoke contains oxidants, and recent reports described a role of oxygen-derived free radicals in mediating endothelial dysfunction.41 Thus, L-arginine may decrease NO catabolism by smoke-enhanced oxygen-derived free radicals.42
Study Limitations
The blood flow measurements in long-term smokers could have been
affected by acute nicotine effects. Nicotine evokes the release of
catecholamines, with subsequent adrenergically mediated
increases in cardiac work and coronary blood flow. However,
smokers abstained from smoking before the PET study for 4 hours,
which is sufficient to reduce serum nicotine to nearly unmeasurable
levels.3 10
Abnormalities in total cholesterol levels might have affected the MBF response to cold pressor test. However, only 5 of the 23 participants had borderline values, and 1 had elevated cholesterol levels. Of note, average total cholesterol levels did not differ between smokers and nonsmokers. Furthermore, HDL/LDL ratio, not total cholesterol, is a predictor of the blood flow response to cold pressor test.3 In our study, HDL/LDL ratios were similar for both groups.
Flow-limiting coronary stenoses might have affected MBF responses to cold pressor testing in long-term smokers. Coronary artery disease could have been ruled out with certainty only by use of coronary arteriography, which seemed unjustified in these asymptomatic individuals. However, none of the 23 volunteers had a history of coronary artery disease or of atherosclerosis (determined by absence of angina, intermittent claudication, and cerebrovascular ischemia). In addition, smokers and nonsmokers >50 years old had either a previous normal treadmill or normal pharmacological stress test.
Corrections for partial volume effects, which assumed a uniform myocardial wall thickness of 1 cm, might have introduced a systematic error in the MBF measurements.15 On the basis of phantom studies, partial volume effects were corrected with a recovery coefficient of 0.73. Assuming a constant wall thickness between studies, a systematic error in correcting for partial volume would have equally affected all 4 MBF estimates.
Conclusions
Acute administration of L-arginine as the precursor of
NO reversed the abnormal MBF response to cold pressor test in healthy
long-term smokers. This finding supports the hypothesis that the
abnormal response to cold pressor test depended on
endothelial dysfunction in long-term smokers. Cold
pressor test combined with PET imaging may allow the noninvasive
identification of coronary endothelial
dysfunction in humans.
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Acknowledgments |
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The Laboratory of Structural Biology and Molecular Medicine, University of California, Los Angeles, is operated for the US Department of Energy by the University of California under contract No. DE-FC03-87ER60615. This study was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington, DC; by research grant HL-33177, National Institutes of Health, Bethesda, Md; and by an Investigative Group Award, American Heart Association, Los Angeles (Calif) Affiliate. The authors thank Ron Sumida, Larry Pang, Francine Aguilar, Der-Jenn Liu, Priscilla Contreras, and Sumon Wongpiya for their excellent assistance in performing the PET studies and N. Satyamurthy and his cyclotron staff for production of the 13N-labeled ammonia. We also thank Deborah Dorsey, RN, for her assistance; Diane Martin and David Twomey for preparing the artwork; and Eileen Rosenfeld for preparing this manuscript.
Received April 9, 1998; revision received September 22, 1998; accepted October 22, 1998.
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