(Circulation. 1995;92:24-30.)
© 1995 American Heart Association, Inc.
Articles |
17ß-Estradiol Attenuates Acetylcholine-Induced Coronary Arterial Constriction in Women but Not Men With Coronary Heart Disease
From the National Heart and Lung Institute and Royal Brompton National Heart and Lung Hospital, London, UK; Yale University School of Medicine, New Haven, Conn (P.M.S.); and Novo Nordisk, Bagsvaerd, Denmark (L.U.).
Correspondence to Dr Peter Collins, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK.
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Abstract |
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Background Women are protected from coronary artery disease until the menopause. Ovarian hormones are vasoactive substances that influence both hemodynamic parameters and atheroma formation. Intravenous ethinyl estradiol has been shown to reverse acetylcholine-induced vasoconstriction in cynomolgus monkeys and humans, and 17ß-estradiol improves exercise-induced myocardial ischemia in female patients. We investigated the effect of the naturally occurring estrogen 17ß-estradiol on the coronary circulation in postmenopausal women and men with coronary artery disease.
Methods and Results We studied nine postmenopausal women 59±3 years old, mean±SEM, and seven men 52±4 years old with proven coronary artery disease. They underwent measurement of coronary artery diameter and coronary blood flow after intracoronary infusion of acetylcholine 1.6 and 16 µg/min before and 20 minutes after intracoronary administration of 2.5 µg of 17ß-estradiol into atherosclerotic, nonstenotic coronary arteries. Changes in coronary artery diameter were measured by quantitative angiography, and changes in coronary blood flow were measured with an intracoronary Doppler catheter. In female patients, acetylcholine 1.6 and 16 µg/min caused constriction before the administration of 17ß-estradiol (-6±2% and -8±5%, respectively, compared with baseline). This constrictor response was converted to dilatation after intracoronary administration of 17ß-estradiol (+8±2% and +9±3%, respectively; P<.01 before versus after estrogen). Acetylcholine 1.6 and 16 µg/min increased coronary blood flow before and after the infusion of 17ß-estradiol. However, the mean acetylcholine-induced increases in coronary flow were significantly greater (P<.009) after (126±37% and 248±89%, respectively) than before (94±31% and 143±49% mL/min, respectively) the administration of 17ß-estradiol. 17ß-Estradiol alone had no significant effect on coronary diameter or coronary blood flow (P>.05). Isosorbide dinitrate (1 mg) caused dilatation of the coronary arteries by 11±2% (P<.005). In men, acetylcholine 1.6 and 16 µg/min caused constriction both before and after the administration of 17ß-estradiol and caused similar increases in coronary blood flow both before and after the intracoronary administration of 17ß-estradiol. Infusion of intracoronary placebo in six female control patients 55±3 years old and six male control patients 56±3 years old did not change coronary diameter responses or coronary blood flow responses to acetylcholine.
Conclusions 17ß-Estradiol modulates acetylcholine-induced coronary artery responses of female but not male atherosclerotic coronary arteries in vivo. These human data confirm reports from studies in cynomolgus monkeys that estrogen modulates the responses of atherosclerotic coronary arteries. An enhancement of endothelium-dependent relaxation by natural estrogen (as used in most hormone replacement therapy) may be important in postmenopausal women with established coronary heart disease and may contribute to the acute effect of 17ß-estradiol on blood flow and its long-term protective effect on the development of coronary artery disease.
Key Words: hormones • arteries • circulation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Women appear to be protected, until the menopause, from the development of coronary artery syndromes. This protective effect seems to be due to the beneficial effect of ovarian hormones, in particular 17ß-estradiol, since estrogen replacement therapy reduces the incidence of coronary artery disease and the progression of coronary artery lesions.1 2 3 4 5 6 7 A number of potential mechanisms for the protective effect of estrogens on coronary arteries have been proposed. Estrogen has a beneficial effect on plasma lipoproteins, increasing HDL cholesterol and decreasing LDL cholesterol.8 Although early studies suggested that >50% to 60% of the protective effect of estrogens on coronary artery disease was due to the favorable change in plasma lipids,9 more recent data suggest that this figure is closer to 25%.3 10 Estrogens also appear to inhibit cholesterol deposition in the arterial wall.11 Other potential protective mechanisms of estrogen action include calcium antagonism12 and hormone-induced release of endothelium-derived relaxing factor(s) and suppression of contracting factors.13 14 15 16
Acute hemodynamic effects of estrogens reported in both animal and human studies include increases in cardiac output and uterine and peripheral blood flow.17 18 17ß-Estradiol has been shown to induce relaxation of precontracted coronary artery rings and to inhibit calcium influx in isolated cardiac myocytes.19 20 21 Intravenous ethinyl estradiol reverses acetylcholine-induced vasoconstriction in cynomolgus monkeys22 and in humans.23 A recent study showed that 17ß-estradiol improves exercise-induced myocardial ischemia in postmenopausal women with angiographically proven coronary artery disease.24
Therefore, it is plausible that the increase in incidence of coronary artery events after the menopause is due not only to the progression of coronary atherosclerosis but also to abnormalities of coronary vasodilator reactivity as a consequence of the decreased plasma levels of ovarian hormones.
The aim of the present study was to assess the effect of intracoronary administration of 17ß-estradiol and to evaluate its mechanism of action in female and male patients with angiographically proven coronary artery disease.
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Methods |
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Population of Patients
The study population consisted of nine female patients 59±3 years old and seven male patients 52±4 years old with angiographically proven coronary artery disease. The female patients were all postmenopausal (11±3 years), three had had a hysterectomy, and none were receiving or had ever received hormone therapy. Patients with primary valvar heart disease, complete heart block, or uncorrected hypokalemia and female patients on chronic hormone replacement therapy were excluded. A group of six female patients 55±3 years old with angiographically proven coronary artery disease served as female control patients. The female control patients were all postmenopausal (7±3 years), one had had a hysterectomy, and none were receiving or had ever received hormone therapy. Six male patients 56±3 years old with angiographically proven coronary artery disease served as male control patients.
Study Design
Patients were studied off antianginal therapy
for at least 24
hours. Caffeine-containing beverages and nicotine were avoided on the
day of study. Patients arrived in the catheterization laboratory in the
fasting state and underwent diagnostic left heart catheterization and
coronary angiography using a standard percutaneous femoral approach.
The coronary angiograms were reviewed, and those patients with
documented coronary atheroma were included in the study. The study
vessel was atheromatous but not stenotic (no lesion >50% occlusive),
and suitable angiographic views were determined.
Full anticoagulation was maintained with intravenous heparin. A bipolar temporary pacing wire was positioned in the right ventricle, and the pacemaker was set on demand at 10 beats per minute less than the patient's resting heart rate. An 8F guiding catheter (Medtronic) was positioned in the left or right coronary ostium, and a 3F 20-MHz Doppler flow probe (Schneider) was passed over a 0.014-in guide wire into the proximal coronary artery. The Doppler catheter was connected to a Millar velocimeter (Millar Instruments Inc) for continuous recordings of mean and phasic coronary artery blood flow velocities onto a chart recorder (Lectromed). The catheter was calibrated on a 0- to 40-cm/s scale, and the position and range gating were adjusted to optimize the audio velocity signal and the phasic flow velocity waveform. The Doppler position was maintained throughout the study protocol and checked at regular intervals. The ECG, heart rate, and mean and phasic arterial blood pressures were measured continuously.
Intracoronary Infusion Protocols
All solutions were infused
through the Doppler probe by use of
an infusion pump (Becton Dickinson UK Ltd) at a rate of 1 mL/min. A
2-minute control infusion of 5% dextrose in sterile water was given.
Two-minute infusions of acetylcholine (1.6 and 16 µg/min) in 5%
dextrose were then selectively administered into the coronary artery
through the lumen of the Doppler flow probe. Next, 2.5 µg of
17ß-estradiol (dissolved in ethanol; final concentration of ethanol,
0.04%; Novo Nordisk A/S) was infused into the coronary artery over a
period of 1 minute. The acetylcholine infusion procedure was then
repeated 20 minutes after the administration of 17ß-estradiol.
Finally, 1 mg of isosorbide dinitrate was infused into the coronary
artery. An identical protocol was used in the control patients with
estradiol vehicle (0.04% ethanol) instead of estradiol.
Quantitative Coronary Angiography
Coronary angiograms were
taken at the start of the protocol and
at peak mean velocity response during each infusion or at the end of
the infusion if no change in velocity was detected. A resting period
was observed between infusions until all measured parameters had
returned to baseline. Coronary angiograms were performed before and at
10 and 20 minutes after the estradiol infusion. All angiograms were
performed with nonionic contrast media (Omnipaque, Nycomed AS; iodine
content, 350 mg/mL) at an injection rate of 7 mL/s. The view that best
displayed the coronary artery segment for analysis in the isocenter
was selected, and the x-ray gantry position was maintained throughout
the study. A 4- to 5-mm length of vessel was measured in up to three
consecutive end-diastolic frames at the tip of the Doppler
probe and at a fixed anatomic point from the Doppler probe, and the
results were then averaged. The quantitative analyses were performed
independently and in a blinded fashion by an observer who was unaware
of the infusion protocols.
Angiographic image data were acquired digitally in a 512x512 matrix with 10-bit depth per pixel on a real-time digital image acquisition and analysis system (Digitron III VACI, Siemens AG) at 25 frames per second (dose rate, 25 µR per frame) with gap filling, using a 12-cm nominal input field and 0.8-mm2 focal spot. A low-lag, 1249-line progressive-scan video camera (Videomed C) was directly coupled to the image intensifier. The analog output of the video camera was digitized in real time with a linear lockup table relating radiographic density to gray level, with parallel transfer via a solid-state buffer, to be stored on 4x690-megabyte Fujitsu hard disks. To correct for geometric magnification, calibration was determined from the diameter of the guiding catheter, which was measured with hand-held micrometer calipers after each study. Both algorithms for automatic edge-detection of digital data (directly acquired or from the digitized cinefilm image) used the weighted sum of the first and second derivatives to detect the vessel edge. The methods of acquisition and analysis were validated by use of contrast-filled polymethyl methacrylate phantoms of cylindrical wells ranging from 1.5 to 4.0 mm in diameter.
Area, Velocity, and Flow Measurements
Area measurements were
calculated from the mean luminal
diameter. Measurements were made before infusion and at peak velocity
change. Coronary blood flow in milliliters per minute was estimated
from the product of the mean coronary blood flow velocity and the
cross-sectional area of the arterial segment under investigation.
Statistical Analysis
Patient and control data were compared
by unpaired Student's
t tests. Serial changes in coronary artery diameter and
coronary blood flow were compared by means of the Wilcoxon test for
paired data.25 A two-tailed probability level of
P<.05 was considered to be significant. Values are
expressed as mean±SEM.
Informed Consent
Written informed consent was obtained from
every patient by the
senior investigator (P.C.) in accordance with institutional guidelines,
and the studies were performed by the same person. The protocol had the
approval of the Royal Brompton National Heart and Lung Hospital Ethics
Committee.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Characteristics of the Patients
All patients had coronary atherosclerosis. Eight female patients had stenoses of >50% in one or more major coronary arteries. One patient had irregular coronary arteries, four patients had one-vessel disease, and four patients had two-vessel disease. In three patients the left anterior descending coronary artery was studied, in three patients the left circumflex coronary artery was studied, and in three patients the right coronary artery was studied.
All the male patients had coronary atherosclerosis and stenoses of >50% in one or more major coronary arteries. Three patients had one-vessel disease, and four patients had two-vessel disease. In one patient the left anterior descending coronary artery was studied, in three patients the left circumflex coronary artery was studied, and in three patients the right coronary artery was studied.
All the female control patients had coronary atherosclerosis. Four patients had stenoses of >50% in one or more major coronary arteries. Two patients had irregular coronary arteries, two had one-vessel disease, and two had two-vessel disease. In three control patients the left anterior descending coronary artery was studied, and in three control patients the right coronary artery was studied.
All the male control patients had coronary atherosclerosis and stenoses of >50% in one or more major coronary arteries. Three patients had one-vessel disease, and two had two-vessel disease. In three control patients the left anterior descending coronary artery was studied, and in three control patients the right coronary artery was studied.
There
were no significant differences between the groups with respect
to factors that might influence the coronary response to acetylcholine
(Table
). These include age, levels of total and LDL
cholesterol, triglycerides, blood glucose, blood pressure, heart rate,
and coronary atherosclerosis. Blood pressure and heart rate did not
change during any of the intracoronary infusions.
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Plasma 17ß-estradiol levels were the same before versus after intracoronary infusion of 2.5 µg 17ß-estradiol. The 17ß-estradiol level in women was 52±8 pmol/L before intracoronary estrogen and 67±7 pmol/L after intracoronary estrogen (P=NS) (postmenopausal 17ß-estradiol level <200 pmol/L). In men it was 123±3 pmol/L before intracoronary estrogen and 197±54 pmol/L after intracoronary estrogen (P=NS).
Changes in Coronary Artery Diameter
Female Patients
There was no difference in coronary artery diameter between
baseline and at 10 or 20 minutes after the infusion of 2.5 µg
17ß-estradiol (2.91±0.15, 2.88±0.18, and 2.82±0.15
mm,
respectively, P=NS). Before intracoronary infusion of
estrogen, coronary artery diameter decreased from baseline after
infusion of acetylcholine (1.6 and 16 µg/min) from 2.91±0.3 to
2.73±0.26 and 2.69±0.3 mm, respectively. Twenty minutes after
the
intracoronary infusion of 2.5 µg 17ß-estradiol, the same
concentrations of acetylcholine induced an increase in coronary artery
diameters from 2.82±0.15 to 3.08±0.26 and 3.11±0.3 mm,
respectively
(P<.01 compared with acetylcholine response before versus
after estradiol, Fig 1). A 1-mg dose of isosorbide
dinitrate caused dilatation of the coronary arteries studied to
3.31±0.26 mm (P<.001 compared with baseline).
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Male Patients
There was no difference in coronary
artery diameter between
baseline and at 10 or 20 minutes after the infusion of 2.5 µg
17ß-estradiol (2.85±0.24, 2.90±0.26, and 2.85±0.26
mm,
respectively, P=NS). The effect of acetylcholine (1.6 and 16
µg/min) on coronary artery diameter was no different before (from
2.91±0.24 [baseline] to 2.66±0.2 and 2.63±0.3
mm, respectively)
and 20 minutes after the intracoronary infusion of 2.5 µg
17ß-estradiol (from 2.85±0.24 [baseline] to
2.73±0.26 and
2.65±0.3 mm, respectively, P=NS compared with
acetylcholine
response before versus after estradiol). A 1-mg dose of isosorbide
dinitrate caused dilatation of the coronary arteries studied to
3.30±0.24 mm (P<.01 compared with baseline).
Female Control Patients
Placebo administration did
not change coronary artery diameter
from baseline at 10 and 20 minutes after the infusion (2.65±0.15,
2.59±0.19, and 2.66±0.17 mm, respectively,
P=NS). The
effect of acetylcholine (1.6 and 16 µg/min) on coronary artery
diameter was no different before (from 2.65±0.15 [baseline]
to
2.40±0.13 and 2.54±0.14 mm, respectively) and 20 minutes after
placebo (from 2.66±0.17 [baseline] to 2.46±0.17 and
2.46±0.12 mm,
respectively, P=NS compared with acetylcholine response
before versus after placebo). A 1-mg dose of isosorbide dinitrate
caused dilatation of the coronary arteries studied to 3.05±0.16 mm
(P<.005 compared with baseline).
Male Control
Patients
Placebo administration did not change coronary artery
diameter
from baseline at 10 and 20 minutes after the infusion (2.85±0.18,
2.92±0.24, and 2.79±0.19 mm, respectively,
P=NS). The
effect of acetylcholine (1.6 and 16 µg/min) on coronary artery
diameter was no different before (from [baseline] 2.84±0.18
to
2.54±0.14 and 2.63±0.14 mm, respectively) and 20 minutes after
placebo (from [baseline] 2.79±0.19 to 2.64±0.16 and
2.66±0.12 mm,
respectively, P=NS compared with acetylcholine response
before versus after placebo). A 1-mg dose of isosorbide dinitrate
caused dilatation of the coronary arteries studied to 3.20±0.11 mm
(P<.005 compared with baseline).
Changes in Coronary Blood Flow
Female Patients
There were no significant correlations between coronary blood flow
and changes in blood pressure, heart rate, or the blood pressure–heart
rate product. There was no difference in coronary blood flow from
baseline at 10 or 20 minutes after the infusion of 17ß-estradiol
(63±12, 71±16, and 68±31 mL/min, respectively,
P=NS).
Acetylcholine (1.6 and 16 µg/min) increased coronary blood flow both
before (94±31 and 143±49 mL/min, respectively) and after
(126±37 and
248±89 mL/min, respectively) the administration of 17ß-estradiol.
However, there were significant differences in the increases in flow
response to acetylcholine after intracoronary 17ß-estradiol
(P<.009 compared with acetylcholine response before versus
after estradiol, Fig 2). A 1-mg dose of isosorbide
dinitrate caused a significant increase in coronary blood flow to
219±53 mL/min (P<.01 compared with baseline).
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) and after
(
) estrogen. The dose-dependent increases in coronary blood flow
induced by acetylcholine were significantly greater after estrogen (*
indicates P<.009 before vs after estrogen, Wilcoxon test).
Increase in male coronary blood flow evoked by acetylcholine (right)
before (
Male Patients
In male patients there was no change
in coronary blood flow from
baseline at 10 or 20 minutes after the infusion of 17ß-estradiol
(75±10, 74±8, and 77±11 mL/min, respectively,
P=NS). The
effect of acetylcholine (1.6 and 16 µg/min) on coronary artery blood
flow was no different before (from [baseline] 75±8 to
90±22 and
137±39 mL/min, respectively) and 20 minutes after the infusion of
17ß-estradiol (from [baseline] 77±11 to 95±19 and
142±27 mL/min,
respectively, P=NS compared with acetylcholine response
before versus after placebo). A 1-mg dose of isosorbide dinitrate
caused an increase in coronary blood flow to 237±41 mL/min
(P<.005 compared with baseline).
Female Control
Patients
Placebo administration did not change coronary blood flow
from
baseline at 10 or 20 minutes after the infusion (76±17, 75±19,
and
79±20 mL/min, respectively, P=NS). The effect of
acetylcholine (1.6 and 16 µg/min) on coronary artery blood flow was
no different before (from [baseline] 76±17 to 103±27
and 146±48
mL/min, respectively) and 20 minutes after placebo infusion (from
[baseline] 88±24 to 104±39 and 154±49 mL/min,
respectively,
P=NS compared with acetylcholine response before versus
after placebo). A 1-mg dose of isosorbide dinitrate caused an increase
in coronary blood flow to 184±44 mL/min (P<.005 compared
with baseline).
Male Control Patients
Placebo
administration did not change coronary blood flow from
baseline at 10 or 20 minutes after the infusion (84±15, 78±12,
and
77±12 mL/min, respectively, P=NS). The effect of
acetylcholine (1.6 and 16 µg/min) on coronary artery blood flow was
no different before (from 84±15 [baseline] to 102±13
and 133±17
mL/min, respectively) and 20 minutes after placebo infusion (from
84±17 [baseline] to 94±18 and 118±11 mL/min,
respectively,
P=NS compared with acetylcholine response before versus
after placebo). A 1-mg dose of isosorbide dinitrate caused an increase
in coronary blood flow to 200±46 mL/min (P<.001 compared
with baseline).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study demonstrates that in postmenopausal female patients with documented coronary artery disease, the vascular responses of atherosclerotic coronary arteries to acetylcholine were converted from net constriction to net dilatation within 20 minutes of exposure of the coronary arteries to 17ß-estradiol. This effect was not apparent in men of a similar age with coronary heart disease. 17ß-Estradiol also enhances the coronary flow response to acetylcholine, suggesting an additional effect on the coronary resistance vessels. Acetylcholine causes a release of endothelium-derived relaxing factor (now known to be nitric oxide or a closely related substance)26 27 28 29 and has both an indirect dilator action via the release of endothelium-derived nitric oxide and a direct constrictor effect via muscarinic receptors on vascular smooth muscle. Acetylcholine accounts for the endothelium-dependent vasodilation in human epicardial coronary arteries with normally functioning endothelium.28 In coronary arteries that have been damaged or in which the endothelium has been removed, the constrictor smooth muscle response to acetylcholine predominates, resulting in vasoconstriction.30 Acetylcholine causes paradoxical constriction of atherosclerotic and dilatation of angiographically normal coronary arteries, suggesting that atherosclerosis impairs endothelium-mediated dilatation of coronary arteries in vivo. However, it has not yet been definitively established to what extent the constrictor response of atherosclerotic coronary arteries to acetylcholine is due to an abnormality of nitric oxide release from the endothelium. In human atherosclerotic coronary arteries, endothelial dysfunction may result in an increased sensitivity to the constrictor effects of catecholamines.31 Atherosclerosis appears to disturb the normal vasomotor response of large coronary arteries to mental stress; paradoxical coronary constriction occurs during mental stress, particularly at points of stenosis.32 This vasomotor response correlates with the extent of atherosclerosis in the artery and with the response to an infusion of acetylcholine. In this study, acetylcholine had a preferential dilator effect on the microvascular coronary arterial bed, since despite a small degree of constriction of the epicardial coronary arteries (except after intracoronary 17ß-estradiol in the female patients), increases in coronary flow occurred in the absence of systemic hemodynamic changes. This is in accord with similar results for intracoronary infusions of acetylcholine published by other workers.32 33 34 35 The increase in flow induced by isosorbide dinitrate involved both epicardial coronary arterial and microvascular coronary arterial dilation, which may suggest that mechanisms other than nitric oxide are involved in the response to acetylcholine. The fact that estrogen reversed the epicardial constriction induced by acetylcholine in the female patients would suggest enhancement of nitric oxide effects or the inhibition of acetylcholine-induced epicardial coronary constriction either at the smooth muscle muscarinic receptor or by the inhibition of the release of or response to acetylcholine-induced vasoconstrictor signals.
Previous studies in estrogen-deficient female monkeys show that atherosclerosis impairs acetylcholine-mediated vascular responses.22 36 Long-term (2 years)36 estrogen replacement therapy protects against impaired vascular responses of atherosclerotic coronary arteries in postmenopausal female monkeys. However, even animal models have yet to provide any information with regard to mechanisms of action of estrogen. Suggested possible mechanisms are long-term effects on plasma lipids and atherogenesis or direct short-term effects on the endothelium. In a short-term study, coronary angiography in monkeys with coronary atherosclerosis demonstrated that arteries constricted in response to intracoronary infusion of acetylcholine before estrogen treatment but dilated 20 minutes after intravenous infusion of ethinyl estradiol.22 The vascular responses were not associated with variations in plasma lipid concentrations, blood pressure, heart rate, or plaque size. Our study shows almost identical responses in human atherosclerotic coronary arteries. An acute effect would argue against an effect on plasma lipid and lipoprotein concentrations. Long-term estrogen replacement therapy in surgically induced menopausal female monkeys inhibits the progression of atherosclerosis, reducing plaque size11 ; however, the effects of long-term estrogen therapy on vascular responses were not directly associated with the effect of estrogen on plaque content.36 A 20-minute exposure of the arteries to 17ß-estradiol would be very unlikely to change plaque size. Plasma lipids can modulate endothelium-dependent dilatation of coronary arteries,37 38 but it is unlikely that an acute change in plasma lipoprotein levels would occur in such a short period of time, as confirmed in an animal study.22 Recent evidence suggests that cells or cell breakdown products in atherosclerotic arteries may increase the breakdown of nitric oxide.39 Estrogen has been shown to be a potent antioxidant of lipids,40 and oxidized lipids inhibit nitric oxide.37 41 A reduction in lipid peroxidation in the atherosclerotic arterial wall may be one of the mechanisms whereby estrogen protects against the breakdown of endothelium-derived nitric oxide.
Estrogen may modulate the function of muscarinic receptors on endothelial or smooth muscle cells. It may facilitate the release or response of endothelium-derived relaxing factor(s) or inhibit the release of constricting factors,16 or there may be a combination of these effects. Estrogen can inhibit constrictor responses to endothelin-1 in rabbit coronary and basilar arteries.20 42 It is therefore possible that the rapid effects of estrogen on vascular responses could be explained by an inhibitory effect on endothelin-1 constrictor responses in the coronary artery. Increases in plasma endothelin-1 levels after intracoronary acetylcholine infusions in pigs with coronary artery atherosclerosis have been reported.43 An inhibition of endothelin-1 by estrogen may contribute to the reversal of the constrictor effect of acetylcholine in human atherosclerotic coronary arteries.
We previously showed a direct relaxing effect of estrogen on the vascular smooth muscle of rabbit coronary arteries.19 20 Concentrations of estrogen used in these experiments were above physiological concentrations (10-6 and 10-5 mol/L). Physiological concentrations of estrogen do not appear to have direct coronary vasodilator effects in vivo in monkeys,22 although a physiological long-term calcium antagonistic effect of estrogen on the coronary artery may explain some of its beneficial effect on atherosclerotic disease.12 Our study was designed to expose the artery to estrogen acutely in an attempt to avoid any direct continuous effect on the vessel at the time of the acetylcholine infusion. The concentration of estrogen used was the same as that used in a short-term study in the uterine circulation of ewes.17
The objective of the present study was to determine the effect of acute 17ß-estradiol on acetylcholine responses in human female and male atherosclerotic coronary arteries. The coronary arteries constricted in response to the infusion of acetylcholine before estrogen treatment, but in women they dilated 20 minutes after the intracoronary administration of 2.5 µg of 17ß-estradiol. 17ß-Estradiol also enhanced the flow-dependent responses to acetylcholine at concentrations of 1.6 and 16 µg/min in these women. These data confirm reports of a similar effect in the coronary arteries of atherosclerotic female monkeys. This is the first report of such an effect of naturally occurring estrogen (17ß-estradiol) in human female and male coronary arteries in vivo, and it confirms a similar beneficial effect of synthetic and natural estrogen in women.23 44 Short-term estrogen administration, therefore, may affect coronary endothelium-mediated dilatation in women in vivo, and rapid effects can occur. Such rapid effects may be of clinical benefit in the short- and long-term treatment of atherosclerotic coronary heart disease in postmenopausal women.
The lack of effect in male coronary arteries would argue against a nonspecific effect of estrogen. It may indicate that estrogen is working via a mechanism that is more sensitive in female coronary arteries than in those of men. Recent data show that acutely estrogen-withdrawn female rabbits demonstrate coronary arterial relaxation to estrogen that is endothelium- and nitric oxide–dependent.45 The acute exposure of estrogen-deficient women to estrogen may enhance the release of or response to nitric oxide synthase by acetylcholine. Animal data support this hypothesis. Femoral arteries from rabbits treated with 17ß-estradiol show an enhanced endothelium-dependent relaxation to acetylcholine at small concentrations (3x10-9 to 3x10-8 mol/L).13 An increased basal release of nitric oxide in endothelium-intact aortic rings from female rabbits compared with those from males has been reported.14 It has also been demonstrated that estrogen-induced increases in blood flow in the uterine artery can be antagonized by nitric oxide synthase inhibition.15 Recent work shows that estrogen can stimulate constitutive nitric oxide synthase in cultured bovine endothelial cells.46 This effect in vitro, however, is not acute and takes 16 to 24 hours. There are also conflicting data showing no effect on nitric oxide synthase in cultured bovine aortic endothelial cells.47 An acute effect on the constitutive enzyme in vivo cannot be ruled out, and an acute effect on the inducible enzyme is possible. An in vivo study in guinea pigs examined the effects of estrogen on nitric oxide synthase activity in heart, kidney, and skeletal muscle. Estradiol increased nitric oxide in female guinea pigs after 5 days of treatment; however, this occurred in males only after 10 days of estrogen exposure.48 It was suggested that the number or availability of estrogen receptors in male tissues is initially too low, requiring a period of estrogen priming.
In this study, single-plane angiograms were used, assuming that at the site measured, the coronary artery was circular. Minor errors could result from this; however, the coronary artery diameter was assessed at more than one site, which would decrease potential errors.
We recently showed a beneficial effect of sublingual estrogen on myocardial ischemia in women with established coronary artery disease.24 The mechanism of this effect is unknown, but an improvement in blood supply to the myocardium is likely, since the beneficial effect of estrogen was associated with an increased heart rate at 1-mm ST-segment depression compared with placebo. The results of the present study support the hypothesis that an acetylcholine-induced increase in coronary blood flow by estrogen may be due, in part, to a facilitation of endothelium-dependent relaxation, which may be gender specific.
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Acknowledgments |
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This study was supported by a grant from the British Heart Foundation. We are indebted to the patients who participated in this study; to D. Clarke, Sister G. Maketo and the catheter laboratory staff, P. Allibone, S. Pearson, L. Haskell, and the staff on the Paul Wood and York wards at the Royal Brompton Hospital. Without their help and cooperation this study would not have been possible.
Received October 3, 1994; revision received December 27, 1994; accepted January 2, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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K. J. Mather, E. G. Norman, J. C. Prior, and T. G. Elliott Preserved Forearm Endothelial Responses with Acute Exposure to Progesterone: A Randomized Cross-Over Trial of 17-{beta} Estradiol, Progesterone, and 17-{beta} Estradiol with Progesterone in Healthy Menopausal Women J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4644 - 4649. [Abstract] [Full Text]
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S. Vehkavaara, J. Westerbacka, T. Hakala-Ala-Pietilä, A. Virkamäki, O. Hovatta, and H. Yki-Järvinen Effect of Estrogen Replacement Therapy on Insulin Sensitivity of Glucose Metabolism and Preresistance and Resistance Vessel Function in Healthy Postmenopausal Women J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4663 - 4670. [Abstract] [Full Text]
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C. M. Webb, M. A. Ghatei, J. G. McNeill, DCRR, and P. Collins 17{beta}-Estradiol Decreases Endothelin-1 Levels in the Coronary Circulation of Postmenopausal Women With Coronary Artery Disease Circulation, October 3, 2000; 102(14): 1617 - 1622. [Abstract] [Full Text] [PDF]
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G W Lloyd, N R Patel, E McGing, A F Cooper, D Brennand-Roper, and G Jackson Does angina vary with the menstrual cycle in women with premenopausal coronary artery disease? Heart, August 1, 2000; 84(2): 189 - 192. [Abstract] [Full Text] [PDF]
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L. P. Thompson, G. Pinkas, and C. P. Weiner Chronic 17{beta}-Estradiol Replacement Increases Nitric Oxide-Mediated Vasodilation of Guinea Pig Coronary Microcirculation Circulation, July 25, 2000; 102(4): 445 - 451. [Abstract] [Full Text] [PDF]
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J. G. Murphy and R. A. Khalil Gender-specific reduction in contractility and [Ca2+]i in vascular smooth muscle cells of female rat Am J Physiol Cell Physiol, April 1, 2000; 278(4): C834 - C844. [Abstract] [Full Text] [PDF]
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C. S. Hayward, R. P. Kelly, and P. Collins The roles of gender, the menopause and hormone replacement on cardiovascular function Cardiovasc Res, April 1, 2000; 46(1): 28 - 49. [Full Text] [PDF]
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L. R. Peterson, M. Courtois, L. F. Peterson, M. R. Peterson, V. G. Dávila-Román, R. J. Spina, and B. Barzilai Estrogen Increases Hyperemic Microvascular Blood Flow Velocity in Postmenopausal Women J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2000; 55(3): 174M - 179. [Abstract] [Full Text]
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G. W. de Valk-de Roo, C. D.A. Stehouwer, P. Meijer, V. Mijatovic, C. Kluft, P. Kenemans, F. Cohen, S. Watts, and C. Netelenbos Both Raloxifene and Estrogen Reduce Major Cardiovascular Risk Factors in Healthy Postmenopausal Women : A 2-Year, Placebo-Controlled Study Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2993 - 3000. [Abstract] [Full Text] [PDF]
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G. New, S. J. Duffy, R. W. Harper, and I. T. Meredith Estrogen improves acetylcholine-induced but not metabolic vasodilation in biological males Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2341 - H2347. [Abstract] [Full Text] [PDF]
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C. M. Webb, J. G. McNeill, C. S. Hayward, D. de Zeigler, and P. Collins Effects of Testosterone on Coronary Vasomotor Regulation in Men With Coronary Heart Disease Circulation, October 19, 1999; 100(16): 1690 - 1696. [Abstract] [Full Text] [PDF]
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K. Sudhir and P. A. Komesaroff Cardiovascular Actions of Estrogens in Men J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3411 - 3415. [Full Text] [PDF]
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A. P. V. Dantas, R. Scivoletto, Z. B. Fortes, D. Nigro, and M. H. C. Carvalho Influence of Female Sex Hormones on Endothelium-Derived Vasoconstrictor Prostanoid Generation in Microvessels of Spontaneously Hypertensive Rats Hypertension, October 1, 1999; 34(4): 914 - 919. [Abstract] [Full Text] [PDF]
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J. K. Crews, J. G. Murphy, and R. A. Khalil Gender Differences in Ca2+ Entry Mechanisms of Vasoconstriction in Wistar-Kyoto and Spontaneously Hypertensive Rats Hypertension, October 1, 1999; 34(4): 931 - 936. [Abstract] [Full Text] [PDF]
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G. A. Figtree, Y.-q. Lu, C. M. Webb, and P. Collins Raloxifene Acutely Relaxes Rabbit Coronary Arteries In Vitro by an Estrogen Receptor–Dependent and Nitric Oxide–Dependent Mechanism Circulation, September 7, 1999; 100(10): 1095 - 1101. [Abstract] [Full Text] [PDF]
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D. Waters Cholesterol Lowering : Should It Continue to Be the Last Thing We Do? Circulation, June 29, 1999; 99(25): 3215 - 3217. [Full Text] [PDF]
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 M. E. Mendelsohn and R. H. Karas The Protective Effects of Estrogen on the Cardiovascular System N. Engl. J. Med., June 10, 1999; 340(23): 1801 - 1811. [Full Text] [PDF]
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 V M Miller Gender and vascular reactivity Lupus, June 1, 1999; 8(5): 409 - 415. [Abstract] [PDF]
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D. M. Herrington, B. L. Werbel, W. A. Riley, B. E. Pusser, and T. M. Morgan Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease J. Am. Coll. Cardiol., June 1, 1999; 33(7): 2030 - 2037. [Abstract] [Full Text] [PDF]
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G. M. C. Rosano, F. Leonardo, P. Pagnotta, F. Pelliccia, G. Panina, E. Cerquetani, P. L. della Monica, B. Bonfigli, M. Volpe, and S. L. Chierchia Acute Anti-Ischemic Effect of Testosterone in Men With Coronary Artery Disease Circulation, April 6, 1999; 99(13): 1666 - 1670. [Abstract] [Full Text] [PDF]
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H. Teoh, S. W.S. Leung, and R. Y.K. Man Short-term exposure to physiological levels of 17{beta}-estradiol enhances endothelium-independent relaxation in porcine coronary artery Cardiovasc Res, April 1, 1999; 42(1): 224 - 231. [Abstract] [Full Text] [PDF]
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R. M. Goetz, H. S. Thatte, P. Prabhakar, M. R. Cho, T. Michel, and D. E. Golan Estradiol induces the calcium-dependent translocation of endothelial nitric oxide synthase PNAS, March 16, 1999; 96(6): 2788 - 2793. [Abstract] [Full Text] [PDF]
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 L. A. Stephenson and M. A. Kolka Esophageal temperature threshold for sweating decreases before ovulation in premenopausal women J Appl Physiol, January 1, 1999; 86(1): 22 - 28. [Abstract] [Full Text] [PDF]
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W. H. Kaesemeyer, R. B. Caldwell, J. Huang, and R. W. Caldwell Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions J. Am. Coll. Cardiol., January 1, 1999; 33(1): 234 - 241. [Abstract] [Full Text] [PDF]
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A. Huang, D. Sun, A. Koller, and G. Kaley Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide Am J Physiol Regulatory Integrative Comp Physiol, November 1, 1998; 275(5): R1571 - R1577. [Abstract] [Full Text] [PDF]
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M. Gerhard, B. W. Walsh, A. Tawakol, E. A. Haley, S. J. Creager, E. W. Seely, P. Ganz, and M. A. Creager Estradiol Therapy Combined With Progesterone and Endothelium-Dependent Vasodilation in Postmenopausal Women Circulation, September 22, 1998; 98(12): 1158 - 1163. [Abstract] [Full Text] [PDF]
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 J. K. Liao Endothelium and acute coronary syndromes Clin. Chem., August 1, 1998; 44(8): 1799 - 1808. [Abstract] [Full Text] [PDF]
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H. T. Westerveld, J. E. R. van Lennep, H. W. O. R. van Lennep, A.-H. Liem, J. A. J. de Boo, Y. T. van der Schouw, and D. W. Erkelens Apolipoprotein B and Coronary Artery Disease in Women : A Cross-sectional Study in Women Undergoing Their First Coronary Angiography Arterioscler Thromb Vasc Biol, July 1, 1998; 18(7): 1101 - 1107. [Abstract] [Full Text] [PDF]
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M. Kahonen, J.-P. Tolvanen, K. Sallinen, X. Wu, and I. Porsti Influence of gender on control of arterial tone in experimental hypertension Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H15 - H22. [Abstract] [Full Text] [PDF]
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Y. Nakano, T. Oshima, H. Matsuura, G. Kajiyama, and M. Kambe Effect of 17ß-Estradiol on Inhibition of Platelet Aggregation In Vitro Is Mediated by an Increase in NO Synthesis Arterioscler Thromb Vasc Biol, June 1, 1998; 18(6): 961 - 967. [Abstract] [Full Text] [PDF]
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A. A. Nekooeian and C. C. Y. Pang Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H2094 - H2099. [Abstract] [Full Text] [PDF]
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L. A. Fitzpatrick and M. D. Editorial: Coronary Artery Disease in Women--an Equal Opportunity Killer J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 719 - 720. [Full Text]
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P. J. Nestel, T. Yamashita, T. Sasahara, S. Pomeroy, A. Dart, P. Komesaroff, A. Owen, and M. Abbey Soy Isoflavones Improve Systemic Arterial Compliance but Not Plasma Lipids in Menopausal and Perimenopausal Women Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3392 - 3398. [Abstract] [Full Text]
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T. Caulin-Glaser, G. Garcia-Cardena, P. Sarrel, W. C. Sessa, and J. R. Bender 17ß-Estradiol Regulation of Human Endothelial Cell Basal Nitric Oxide Release, Independent of Cytosolic Ca2+ Mobilization Circ. Res., November 19, 1997; 81(5): 885 - 892. [Abstract] [Full Text]
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K. Sudhir, T. M. Chou, K. Chatterjee, E. P. Smith, T. C. Williams, J. P. Kane, M. J. Malloy, K. S. Korach, and G. M. Rubanyi Premature Coronary Artery Disease Associated With a Disruptive Mutation in the Estrogen Receptor Gene in a Man Circulation, November 18, 1997; 96(10): 3774 - 3777. [Abstract] [Full Text]
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V. Guetta, A. A. Quyyumi, A. Prasad, J. A. Panza, M. Waclawiw, and R. O. Cannon III The Role of Nitric Oxide in Coronary Vascular Effects of Estrogen in Postmenopausal Women Circulation, November 4, 1997; 96(9): 2795 - 2801. [Abstract] [Full Text]
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G. M.C. Rosano, A. M. Caixeta, S. Chierchia, S. Arie, M. Lopez-Hidalgo, W. I. Pereira, F. Leonardo, C. M. Webb, F. Pileggi, and P. Collins Short-term Anti-Ischemic Effect of 17ß-Estradiol in Postmenopausal Women With Coronary Artery Disease Circulation, November 4, 1997; 96(9): 2837 - 2841. [Abstract] [Full Text]
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S. M. Herman, J. T.C. Robinson, R. J. McCredie, M. R. Adams, M. J. Boyer, and D. S. Celermajer Androgen Deprivation Is Associated With Enhanced Endothelium-Dependent Dilatation in Adult Men Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 2004 - 2009. [Abstract] [Full Text]
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B. Bruck, U. Brehme, N. Gugel, S. Hanke, G. Finking, C. Lutz, N. Benda, F. W. Schmahl, R. Haasis, and H. Hanke Gender-Specific Differences in the Effects of Testosterone and Estrogen on the Development of Atherosclerosis in Rabbits Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 2192 - 2199. [Abstract] [Full Text]
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T. Akasaka, K. Yoshida, A. Yamamuro, T. Hozumi, T. Takagi, S. Morioka, and J. Yoshikawa Phasic Coronary Flow Characteristics in Patients With Constrictive Pericarditis : Comparison With Restrictive Cardiomyopathy Circulation, September 16, 1997; 96(6): 1874 - 1881. [Abstract] [Full Text]
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N. H. Bjarnason, J. Haarbo, I. Byrjalsen, R. F. Kauffman, and C. Christiansen Raloxifene Inhibits Aortic Accumulation of Cholesterol in Ovariectomized, Cholesterol-Fed Rabbits Circulation, September 16, 1997; 96(6): 1964 - 1969. [Abstract] [Full Text]
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S. Oparil, R. L. Levine, S.-J. Chen, J. Durand, and Y.F. Chen Sexually Dimorphic Response of the Balloon-Injured Rat Carotid Artery to Hormone Treatment Circulation, March 4, 1997; 95(5): 1301 - 1307. [Abstract] [Full Text]
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H. Schunkert, A.H. J. Danser, H.-W. Hense, F. H.M. Derkx, S. Kurzinger, and G. A.J. Riegger Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women Circulation, January 7, 1997; 95(1): 39 - 45. [Abstract] [Full Text]
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E. Barrett-Connor Sex Differences in Coronary Heart Disease: Why Are Women So Superior? The 1995 Ancel Keys Lecture Circulation, January 7, 1997; 95(1): 252 - 264. [Full Text]
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Y. D. Kim, B. Chen, J. Beauregard, P. Kouretas, G. Thomas, M. Y. Farhat, A. K. Myers, and D. E. Lees 17ß-Estradiol Prevents Dysfunction of Canine Coronary Endothelium and Myocardium and Reperfusion Arrhythmias After Brief Ischemia/Reperfusion Circulation, December 1, 1996; 94(11): 2901 - 2908. [Abstract] [Full Text]
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