(Circulation. 2001;103:1992.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Flow-Induced Dilation of Human Coronary Arterioles
Important Role of Ca2+-Activated K+ Channels
From the VA Medical Center, the Department of Medicine, and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee (H.M., Y.L., F.R.L., D.D.G.); the VA Medical Center, Iowa City, and the Department of Internal Medicine and Anesthesia, University of Iowa College of Medicine, Iowa City (R.E.W.); and the 2nd Department of Internal Medicine, Akita University, Akita, Japan (T.S., M.M.).
Correspondence to David D. Gutterman, MD, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail dgutt{at}mcw.edu
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Abstract |
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Background—Flow-induced vasodilation (FID) is a physiological mechanism for regulating coronary flow and is mediated largely by nitric oxide (NO) in animals. Because hyperpolarizing mechanisms may play a greater role than NO in the microcirculation, we hypothesized that hyperpolarization contributes importantly to FID of human coronary arterioles.
Methods and
Results—Arterioles from atria or ventricles
were cannulated for videomicroscopy. Membrane potential of vascular
smooth muscle cells (VSMCs) was measured simultaneously.
After constriction with endothelin-1, increases in flow induced an
endothelium-dependent vasodilation.
N
-Nitro-L-arginine
methyl ester
10-4 mol/L
modestly impaired FID of arterioles from patients without
coronary artery disease (CAD), whereas no inhibition was seen
in arterioles from patients with CAD. Indomethacin
10-5 mol/L was
without effect, but 40 mmol/L KCl attenuated maximal FID.
Tetraethylammonium
10-3 mol/L but
not glibenclamide
10-6 mol/L
reduced FID. Charybdotoxin
10-8 mol/L
impaired both FID (15±3% versus 75±12%,
P<0.05) and
hyperpolarization (-32±2 mV [from -28±2 mV
after endothelin-1] versus -42±2 mV [-27±2 mV],
P<0.05). Miconazole
10-6 mol/L or
17-octadecynoic acid
10-5 mol/L
reduced FID. By multivariate analysis, age was
an independent predictor for the reduced
FID.
Conclusions—We conclude that shear stress induces endothelium-dependent vasodilation, hyperpolarizing VSMCs through opening Ca2+-activated K+ channels in human coronary arterioles. In subjects without CAD, NO contributes to FID. NO and prostaglandins play no role in patients with CAD; rather, cytochrome P450 metabolites are involved. This is consistent with a role for endothelium-derived hyperpolarizing factor in FID of the human coronary microcirculation.
Key Words: blood flow • vasodilation • microcirculation
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Introduction |
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Flow-induced vasodilation (FID) is a physiologically important mechanism regulating coronary microvascular tone. FID has been demonstrated in a variety of vessels from different species,1 2 3 4 5 including humans.6 7 An endothelium-dependent mechanism for FID has been demonstrated,1 2 3 5 although the endothelial factor varies, depending on species, vascular bed, and vessel size. Three principal dilator compounds are released from endothelial cells: nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF).8 9 10 Animal studies have reported that FID is mediated by either NO,2 4 PGI2,5 or both.11 FID is prominent in resistance3 as well as conduit vessels.6
NO or other factors contribute to FID of large epicardial coronary arteries in patients.12 13 In the human coronary microcirculation, agonist-induced dilation largely involves mechanisms independent of the formation of NO.10 14 There is little direct evidence that FID is endothelium-dependent in humans.
This study investigates the role of endothelial factors in the vascular response to flow in human coronary arterioles, focusing on the contributions of NO, prostaglandins, and K+ channel activation, because K+ channels are normally responsible for membrane hyperpolarization in vascular smooth muscle cells (VSMCs).
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Nethods |
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TopAbstractIntroductionNethodsResultsDiscussionReferences |
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Fresh specimens of right atrial appendage and ventricle, obtained from 77 patients who were undergoing cardiac surgery, were placed in oxygenated Krebs solution (4°C) of the following composition (in mmol/L): NaCl 118, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 20, Na2EDTA 0.026, and dextrose 11, pH 7.4. Under microscopic guidance, coronary arterioles were carefully dissected from the endocardial surface of atrial appendage or from the epicardial surface of ventricle. Arterioles were transferred to a 20-mL organ chamber containing Krebs solution, cannulated with glass micropipettes (30 to 40 µm; identical internal diameters), and secured with ophthalmic suture (10-0). The preparation was transferred to the stage of an inverted microscope (CK2, Olympus) coupled to a CCD camera (WV-BL200, Panasonic) and video micrometer (VIA-100K, Boeckeler Instruments, Inc). Micropipettes were connected to independent hydrostatic reservoirs, each raised 81.6 cm H2O (60 mm Hg) above the vessel. Krebs solution in the chamber was continuously recirculated at 30 mL/min (Masterflex pump, Cole Parmer Instrument Co), aerated with 20% O2, 5% CO2, and 75% N2, and maintained at 37°C. Intraluminal flow was monitored with a flowmeter (model 4552, Gilmont Instruments, Inc). Vessel preparations with leaks (flow>0) were discarded.
Flow was produced by simultaneously changing the heights of the reservoirs in equal and opposite directions to generate a pressure gradient, as described previously by Kuo et al.3 Because the tip sizes of the 2 pipettes were similar, simultaneous changes in the heights of the reservoirs induced increases in flow without change in intraluminal pressure according to Hagen-Poiseuille’s law. The pressure gradients used in these studies correspond to those used by others.3
After 30-minute equilibration, vessels were transiently constricted with 75 mmol/L KCl. Vessels that failed to constrict >30% were discarded.
At the end of each experiment, ADP 10-4 mol/L (an endothelium-dependent vasodilator) was applied to confirm endothelial integrity.15 Maximal vascular diameter was determined by addition of sodium nitroprusside (SNP, 10-4 mol/L).
Experimental Protocols
After 30 minutes of stabilization, endothelin-1
10-10 to
5x10-10 mol/L
was added to increase resting tone to 30% to 50% of passive diameter,
because human coronary arterioles develop varying degrees of
spontaneous myogenic tone (10% to 50%). Internal vessel diameter was
then examined at different flows corresponding to pressure gradients of
5, 10, 20, and 100 cm H2O in the absence or
presence of
N-nitro-L-arginine
methyl ester (L-NAME)
10-4 mol/L (an
NO synthase inhibitor) or indomethacin
(INDO) 10-5
mol/L (a cyclooxygenase inhibitor). In
some experiments, miconazole
10-6 mol/L (a
cytochrome P450 inhibitor) or 17-octadecynoic acid
(17-ODYA) 10-5
mol/L (a chemically distinct and selective cytochrome P450
inhibitor) was applied.
To examine whether membrane hyperpolarization contributed to FID, KCl 40 mmol/L rather than endothelin-1 was used to constrict vessels. In separate studies, the effect of tetraethylammonium (TEA) 10-3 mol/L (a blocker of Ca2+-activated K+ channels [KCa]) or glibenclamide 10-6 mol/L (a blocker of ATP-sensitive K+ channels [KATP]) was tested.
After the second flow-response relationship was completed, in the presence of SNP 10-4 mol/L, the diameter at a gradient of 100 cm H2O was measured first in one direction, then with the gradient reversed. Vessel diameter always varied by <2 µm, verifying matched cannula resistances.
Measurement of Membrane Potential
Flow-induced changes in diameter and membrane
potential (Em) of VSMCs were examined
simultaneously, as described
previously.10
Em was measured with a glass microelectrode (50
to 100 M
) filled with 3 mol/L KCl and connected to a high-impedance
amplifier (Axoprobe, Axon Instruments). The microelectrode was manually
advanced perpendicular to the long axis of the vessel and through the
adventitial side.
Criteria for successful impalements included an abrupt drop
in Em, a steady-state value for >10 seconds,
and a rapid return to baseline on electrode
withdrawal.16 Successful
impalements of 
3 cells were averaged to obtain
Em for a single experimental
protocol.10 16
To examine the role of KCa, flow-induced changes in Em and/or diameter were measured in the presence of charybdotoxin (CTX) 10-8 mol/L.
Endothelial Denudation
Endothelium was mechanically denuded
by injection of 2 mL of air through the vessel, then flushing with
Krebs solution. Denudation was confirmed by observation of preserved
dilation to SNP and markedly reduced dilation to ADP
10-5
mol/L.15
Materials
Endothelin-1 was obtained from Peninsula
Laboratories. Other agents were obtained from Sigma Chemical Co. All
pharmacological agents except 17-ODYA (applied intraluminally) were
added to the external bathing solution, and the concentrations stated
represent the final molar concentrations in the organ
chamber.
Patient Data
Demographic data and diagnoses were obtained from
hospital patient information recorded at the time of surgery.
Protocols were approved by both the University of Iowa and Medical
College of Wisconsin Institutional Review Boards.
Statistical Analyses
FID or dilation to SNP is expressed as a percentage,
with 100 representing the change from the constricted
diameter (endothelin-1 or KCl) to the maximal diameter. Statistical
comparisons of maximal percent vasodilation and
Em values under different treatments were
performed by paired or unpaired Student’s
t test. A 2-factor
repeated-measures ANOVA was used to compare dose-response relationships
between treatment groups. Corollary dose-specific contrasts were tested
with the Bonferroni-adjusted t
test whenever the interactions were statistically significant. Multiple
stepwise regression analyses were used to detect the influence
of underlying diseases, age, and sex on FID. Regression models were
constructed for all doses. All procedures were performed with "proc
mixed" and "proc reg" programs of SAS for Windows, version 8.
Statistical significance was defined as a value of
P<0.05. All data are described
as mean±SEM. For all data, n indicates the number of
patients.
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Results |
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A total of 99 atrial and 4 ventricular vessels with a mean internal diameter of 91±4 µm and a range of 40 to 212 µm were dissected (n=103).
Figure 1
shows that flow is a potent dilator of both atrial
and ventricular coronary arterioles. Pressure
gradients of 5, 10, 20, and 100 cm H2O elicited
intraluminal flows of 1.1±0.3, 2.9±0.6, 5.4±1.1, and 13.7±1.9
µL/min, respectively. Corresponding vasodilation was 9±2%, 27±4%,
49±4%, and 69±4% in atrial tissue and 9±6%, 36±12%, 63±15%,
and 72±13% in ventricular tissue
(P=NS, ventricular
versus atrial).
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Patient demographics and diagnoses are summarized in the
Table.
FID was significantly reduced by aging but not by underlying diseases
(diabetes, hypertension, hypercholesterolemia,
congestive heart failure, coronary artery disease [CAD], and
myocardial infarction) or sex
(P<0.05).
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The effect of endothelial denudation on FID
is shown in
Figure 2. FID in human coronary arterioles was
abolished in denuded vessels, which established the necessary role of
the endothelium. Denudation was confirmed by reduced
dilation to ADP (4±6%, n=5,
P<0.05 versus intact vessels,
86±5%, n=14, unpaired t
test).
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The effect of inhibiting NO synthase is shown in
Figure 3. Treatment with L-NAME
(10-4 mol/L)
did not reduce FID (68±8% versus control 60±7% at 100
cm H2O;
P=NS, n=11). In the subgroup of
patients without CAD, however, L-NAME modestly decreased FID
(Figure 3A; dilation at 5, 10, 20, and 100
cm H2O gradient=20±11%, 46±8%, 56±8%, and
73±7% before and 2±2%, 19±6%, 31±7%, and 69±9% after L-NAME,
P<0.05, n=5). L-NAME did not
affect FID in the subgroup of patients with CAD
(Figure 3B; 3±2%, 26±10%, 47±9%, and 49±10% before
and 10±3%, 27±7%, 48±10%, and 67±10% after L-NAME,
P=NS, n=6). Thus, NO synthesis
contributes partially to FID in "normal" human coronary
arterioles, whereas other factors may compensate for the loss of NO in
the presence of CAD.
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Because cyclooxygenase products
mediate FID in rat cremaster muscle
arterioles,5 we tested the
effect of INDO. INDO did not alter FID
(Figure 4A, 63±7% versus control 67±15% at 100
cm H2O gradient,
P=NS).
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Arachidonic acid can be metabolized by
cytochrome P450 to produce
EDHF.8 9 17
We examined the effect of inhibiting cytochrome P450 on FID. Miconazole
reduced FID
(Figure 4B
, maximum dilation reduced from 72±8% to
18±12%, P<0.05). 17-ODYA
markedly reduced FID in the presence of L-NAME and INDO
(Figure 4C, 24±5% versus control 69±8% at 100
cm H2O gradient,
P<0.05).
Activation of K+ channels with
concomitant hyperpolarization of VSMCs has been
described as an important mechanism underlying vasodilation, especially
in
arterioles.8 10 18
When KCl instead of endothelin-1 was used to constrict vessels to 30%
to 50% of resting diameter, FID was reduced
(Figure 5, P<0.05 at
20 and 100 cm H2O). Dilation to SNP was similar
when vessels were constricted with either KCl (86±6%) or endothelin-1
(95±2%; P=NS).
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We next evaluated the contribution of both
KATP and KCa channels to
FID. Both KATP and KCa
channels are present on human coronary
arteries.19 Glibenclamide,
however, had no effect on FID
(Figure 6A; 74±8% after glibenclamide versus control
72±9% at 100 cm H2O gradient,
P=NS). Treatment with TEA
reduced FID (P<0.05 at 10, 20,
and 100 cm H2O,
Figure 6B) but did not alter vasodilation to SNP (92±3%
versus control 88±3%, P=NS).
These findings suggest that FID involves activation of
KCa in human coronary
arterioles.
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To examine the role of
hyperpolarization, we simultaneously
measured changes in both Em and vascular
diameter.
Figure 7A shows a series of sample Em
traces from microelectrode impalements of VSMCs. Endothelin-1
constricted the vessel and caused a depolarization of VSMCs. Flow
produced graded vasodilation and hyperpolarization,
with the maximal effect occurring at 100
cm H2O. In separate vessels, addition of CTX
attenuated both hyperpolarization and vasodilation
(Figure 7B). CTX inhibited both effects of flow but did not
alter the vasodilation to SNP (87±4% versus control 94±3%,
P=NS).
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Discussion |
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This study is the first to directly examine FID in human coronary arterioles. The major new findings are 4-fold. First, flow induces a potent vasodilation in both atrial and ventricular coronary arterioles. Second, FID is endothelium-dependent and requires cytochrome P450 metabolites but not prostaglandins. NO contributes modestly to FID in arterioles from patients without CAD but does not play a role in arterioles from patients with CAD. Third, FID occurs as a result of membrane hyperpolarization consequent to the opening of KCa in VSMCs. Fourth, age is significantly correlated with reduced FID. Taken together, these findings indicate that endothelium-derived vasodilator metabolites of cytochrome P450 play an important role in FID in human coronary arterioles. This substance is most likely EDHF.
Although other studies have examined FID in several vascular beds, both animal and human,1 2 3 4 5 6 7 11 12 13 this is the first direct demonstration of FID in human coronary resistance vessels. This is also the first demonstration of FID due to EDHF in the coronary microcirculation. In vivo experiments on the coronary microcirculation are complicated by the confounding influences of cardiac metabolism, extravascular compressive forces, and neurohumoral agents. Our findings provide clear evidence that FID is an intrinsic property of both atrial and ventricular coronary arterioles.
FID Is
Endothelium-Dependent
Animal studies have demonstrated that an intact
endothelium is necessary for
FID.1 2 3 4 5 11
Effluent from a porcine coronary arteriole with an intact
endothelium subjected to flow induces vasodilation in
an endothelium-denuded
vessel.4 The
perfusate from flow-stimulated cultured
endothelial cells also evokes vasorelaxation in rabbit
iliac arteries.20 These
findings confirm that an endothelium-derived
transferable factor is responsible for FID.
NO,4 7 13 PGI2,5 or both11 have been proposed as mediators of FID. In the rat, NO is the mediator of FID in cerebral arterioles,21 and PGI2 is the mediator in cremaster muscle arterioles,5 and both contribute to FID in gracilis muscle arterioles.11
In the present study, we demonstrated that L-NAME slightly reduced endothelium-dependent FID of arterioles from patients without CAD, whereas no inhibition was seen in patients with CAD. Development of CAD decreases NO formation at rest and in response to acetylcholine in the human coronary circulation.22 A recent study in vivo shows that vasorelaxing factors other than NO primarily mediate FID of nonatherosclerotic human conduit coronary arteries.12 INDO did not affect FID in the present study, suggesting that some factor other than NO or PGI2 is involved in FID in human coronary arterioles. We speculate that this factor may act as a compensatory mechanism for impaired bioavailability of NO in diseases.
Endothelium-Derived
Hyperpolarizing Factor
Endothelium-dependent vasodilation is
often mediated by a transferable substance distinct from NO or
PGI2. This unidentified vasoactive substance has
been called "endothelium-derived hyperpolarizing
factor" (EDHF) because the dilation is associated with
hyperpolarization of VSMCs. EDHF activates
K+ channels, leading to
hyperpolarization and
vasodilation.8 10 17
Although the chemical nature of EDHF is not firmly established, strong
evidence suggests that it is a metabolite of
arachidonic acid derived from cytochrome
P450.8 9 10 17
Inhibition by miconazole and 17-ODYA in the present study is
consistent with the concept that EDHF mediates FID in the
diseased human heart. Inhibition of FID by blockers of
KCa and demonstration of flow-induced
hyperpolarization supports a role for
EDHF.10
K+ Channels
Several lines of evidence implicate
KCa in the response to flow. FID was greatly
attenuated when KCl instead of endothelin-1 was used to constrict the
vessels. By depolarizing the membrane, KCl may have already
activated voltage-dependent Ca2+
channels that were involved in the flow-induced response. In addition,
flow-induced activation of K+ channels in
the presence of high external K+
concentration may have been less effective in causing membrane
hyperpolarization, because the
K+ equilibrium potential was lowered to a
value close to the resting Em. FID was also
attenuated by TEA and CTX but not glibenclamide. Nevertheless,
TEA-sensitive K+ channels probably do not
account fully for FID in human coronary arterioles, because
substantial dilation remained in the presence of the
inhibitor. Distinct K+ channels
or other mechanisms (eg,
Na+-K+ exchange,
alternative arachidonic acid
derivatives23 ) may play a
role in the dilation.
Potential Limitations
Animal studies have demonstrated that NO-mediated FID
is impaired in coronary arterioles of diet-induced
atherosclerotic swine.24
Human in vivo studies have also reported that FID is impaired in
atherosclerotic conduit coronary
arteries.6 Because most
vessels used in these experiments were from patients with CAD, our
results may have been skewed toward identifying a reduced role of NO
and a more prominent, perhaps compensatory, role for EDHF in
FID.25 This would be
consistent with the observation that hyperpolarizing mechanisms
may be preserved or even enhanced in
hypercholesterolemia, where NO bioavailability
is reduced.25 This idea is
also supported by the observation that in subjects without CAD, there
is a significant contribution of NO to FID of coronary
arterioles.
It is reported that aging selectively causes endothelial dysfunction of coronary arterioles, whereas endothelial dysfunction is restricted to conduit coronary arteries in age-matched patients with angiographic evidence of coronary atherosclerosis.26 In most of our patients, NO did not contribute substantially to FID; thus, it may be expected that risk factors would not have the same detrimental influence on FID.
It is possible that the prominent FID in human coronary arterioles from subjects with CAD indicates that we are interrogating a portion of the vasculature that contributes minimally to resistance. In conditions in which flow reserve is reduced, such as maximal dilation or in the presence of an epicardial stenosis, resistance may be shifted to small-caliber vessels. Although this possibility cannot be excluded, the vessels we examined are identical in size to those that contribute most to coronary resistance in animal models.27
Hyperpolarizing mechanisms may be especially important in the microvasculature, because the contribution of EDHF to endothelium-dependent vasorelaxation increases inversely with vessel size.18 Thus, in human coronary resistance vessels, EDHF may contribute more than NO to FID. It is important to note that although FID was observed in both atrial and ventricular arterioles, because of tissue availability, the mechanisms involved were tested only in atrial tissue. We cannot exclude the possibility that a different mechanism of dilation occurs in ventricular arterioles.
It is possible that NO or PGI2 may have contributed to vasodilation and hyperpolarization in this preparation because of insufficient inhibition of NO synthase or cyclooxygenase. This is unlikely, however, because the concentrations of inhibitors used were sufficiently high to inhibit these enzymes in similar in vitro studies.4 5 7 11 13 It has been reported that millimolar doses of NO synthase inhibitors may be necessary to block formation of NO in some vessels.28 Even 10-3 mol/L L-NAME, however, did not alter FID in vessels from subjects with CAD (data not shown).
The K+ channel blockers used in these experiments, such as CTX, may act on the endothelium as well as VSMCs, potentially blocking the release or synthesis of endothelium-derived relaxing factors. We cannot exclude this possibility in the present study. Flow-stimulated increases in endothelial K+ efflux and [Ca2+]i are not altered, however, by high K+ concentrations or K+ channel–blocking agents, such as tetrabutylammonium and CTX.29 30 Furthermore, CTX does not inhibit shear stress–dependent release of NO in rabbit femoral arteries.31
In addition to inhibition of cytochrome P450, miconazole has been reported to inhibit K+ channels and tyrosine kinase activity,32 33 suggesting the nonspecific effects of miconazole on FID. In contrast, 17-ODYA does not directly affect these activities.34
Clinical Implications
Porcine coronary resistance arteries between 80
and 150 µm in diameter are more sensitive to flow than either larger
or smaller arteries.35
Furthermore, the magnitude of FID in large conduit arteries appears to
be less than that in resistance
arteries.1 35 The
vessels used in this study had an average diameter of 91 µm and were
quite sensitive to flow, consistent with an important role for
flow in the regulation of human coronary vascular
resistance.
The prominent role of EDHF in coronary arteriolar FID distinguishes the human from the animal models and suggests a mechanism for preserving myocardial perfusion in conditions such as diabetes, CAD, and hypertension, in which NO bioavailability is reduced. This is in contrast to conduit vessels, in which the presence of similar disease states results in reduced FID.
Conclusions
An increase in luminal flow induces potent
endothelium-dependent vasodilation of human
coronary arterioles. The human coronary
microvasculature appears to be unique in that FID is associated largely
with hyperpolarization of VSMCs and
KCa
opening.
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Acknowledgments |
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This study was supported by a Fellowship Grant from the American Heart Association, Iowa Affiliate; a VA Merit Review Award; and grants from the NIH (HL-62852) and the Gutterman Trust.
Received September 5, 2000; revision received November 2, 2000; accepted November 3, 2000.
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