Department of Internal Medicine and Cardiovascular Center, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52242
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ABSTRACT |
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Previous studies
showed that nitric oxide (NO) plays an important role in coronary
arteriolar dilation to increases in myocardial oxygen consumption
(MO2). We sought to evaluate coronary
microvascular responses to endothelium-dependent and to
endothelium-independent vasodilators in an in vivo model.
Microvascular diameters were measured using intravital
microscopy in 10 normal (N) and 9 hyperglycemic (HG; 1 wk alloxan,
60 mg/kg iv) dogs during suffusion of acetylcholine (1, 10, and 100 µM) or nitroprusside (1, 10, and 100 µM) to test the effects on
endothelium-dependent and -independent dilation. During administration
of acetylcholine, coronary arteriolar dilation was impaired in HG, but
was normal during administration of nitroprusside. To examine a
physiologically important vasomotor response, 10 N and 7 HG control, 5 HG and 5 N during superoxide dismutase (SOD), and 5 HG and 4 N after
SQ29,548 (SQ; thromboxane A2/prostaglandin H2
receptor antagonist) dogs were studied at three levels of
M
O2: at rest, during dobutamine (DOB; 10 µg · kg
1 · min
1 iv), and during
DOB with rapid atrial pacing (RAP; 280 ± 10 beats/min). During
dobutamine, coronary arterioles dilated similarly in all groups, and
the increase in M
O2 was similar among
the groups. However, during the greater metabolic stimulus (DOB+RAP),
coronary arterioles in N dilated (36 ± 4% change from diameter
at rest) significantly more than HG (16 ± 3%, P < 0.05). In HG+SQ and in HG+SOD, coronary arterioles dilated similarly
to N, and greater than HG (P < 0.05).
M
O2 during DOB+RAP was similar among
groups. Normal dogs treated with SOD and SQ29,548 were not different
from untreated N dogs. Thus, in HG dogs, dilation of coronary
arterioles is selectively impaired in response to administration of the
endothelium-dependent vasodilator acetylcholine and during increases
in M
O2.
coronary microcirculation; diabetes; dobutamine; superoxide; SQ29,548; superoxide dismutase
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INTRODUCTION |
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DIABETES MELLITUS IS ASSOCIATED with increased morbidity and mortality, largely as a result of cardiac events. Although patients with diabetes mellitus have an increased incidence of atherosclerosis, not all cardiac complications can be explained by atherosclerosis of coronary conduit vessels (17). Patients with diabetes mellitus have a higher incidence of exercise intolerance than nondiabetic patients (1). Nahser et al. (22) reported that, in patients without significant coronary artery disease, coronary flow reserve and coronary vascular responses to pacing are impaired in diabetic patients compared with nondiabetic patients. Thus coronary vasodilation induced by metabolic stimuli is impaired by diabetes through mechanisms that cannot be explained by obstructive coronary artery disease.
The normal response of the coronary circulation to increases in metabolic demand is a reduction in coronary vascular resistance. We have recently demonstrated that coronary arteriolar dilation during increases in myocardial oxygen consumption are mediated in large part by release of nitric oxide (NO), an endothelium-derived relaxing factor (9), suggesting that the endothelium plays a pivotal role in metabolic arteriolar dilation. Studies in diabetic animals (19, 21, 26, 29, 32) and of diabetic patients (12, 24) have shown impaired endothelium-dependent relaxation. Endothelial dysfunction in diabetes may be mediated by several different mechanisms including increased release of an endothelium-derived constricting factor (21, 29, 30) and increased production of reactive oxygen species (26, 31), which may interfere with NO (11, 25) or may alter arachidonic acid metabolism, favoring production of vasoconstricting, rather than vasodilatory, prostanoids (15). Vasoconstrictor prostanoids are produced in excess in diabetes (21, 29, 32) and attenuate endothelium-mediated dilation in rabbit aorta (30, 32). Administration of scavengers of oxygen radicals restores normal vasodilation to endothelium-dependent agents both in vitro (26, 31) and in vivo (2). It is not entirely clear which radical species are involved, but superoxide anion reacts directly with NO to produce the less potent dilator peroxynitrite (28). More recently, Katusic et al. (15) have shown that superoxide generation with xanthine/xanthine oxidase causes production of thromboxane A2/prostaglandin H2.
Because metabolic coronary dilation is mediated in part by
endothelium-dependent mechanisms and because endothelial dependent mechanisms are impaired in diabetes, we considered the possibility that
the coronary arteriolar response to metabolic stimuli is impaired
during prolonged hyperglycemia. Thus the first objective of this study
was to examine endothelium-mediated dilation during hyperglycemia in
our in vivo model. Next, we sought to test the hypothesis that coronary
microvascular dilation during increases in myocardial oxygen
consumption (MO2) is impaired with
prolonged hyperglycemia. Because vasoconstrictor prostanoids and
reactive oxygen species are involved in impaired endothelium-dependent vasodilatation in diabetes, our final objective was to test the hypothesis that vasoconstrictor prostanoids and/or reactive oxygen species mediate the impaired coronary microvascular responses to
increases in M
O2 during prolonged hyperglycemia.
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METHODS |
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Model of Prolonged Hyperglycemia
Adult mongrel dogs (n = 26, body wt 3-8 kg) were injected with a single injection of alloxan monohydrate (60 mg/kg iv). Alloxan was prepared as a 6% solution in a citrate buffer (pH 4.0-4.5), as described by Engerman et al. (10) and as previously used in our laboratory (16). Animals were allowed only water during the 24 h before injection and were fed immediately afterward. Hydration status, serum electrolytes, blood urea nitrogen (BUN), creatinine, and blood glucose were closely monitored between injection and experimental day. All experiments involving hyperglycemic animals were performed 6-8 days after alloxan injection. Animals were included in the hyperglycemia group if their glucose was >200 mg/dl when tested 3-4 days after alloxan injection. All animals studied were free from volume depletion, electrolyte disturbances, and renal dysfunction.General Surgical Preparation
Dogs were sedated with ketamine (15 mg/kg sc) and acepromazine (0.2 mg/kg sc), and anesthetized withA left thoracotomy was performed, and the heart was suspended in a pericardial cradle. Catheters (PE-150) were inserted into the coronary sinus via the left jugular vein and into the left atrial appendage for administration of fluorescein-labeled dextran and radiolabeled microspheres. A 5-French catheter (Millar Instruments, Houston, TX) was placed in the left ventricle via the left atrial appendage for recording left ventricular pressure and dP/dt. Snares were placed around the descending thoracic aorta and the inferior vena cava to control arterial pressure. Pacing electrodes were attached to the left atrial appendage and connected to a Grass stimulator (Grass Instruments, Quincy, MA), which was used to control heart rate. The epicardial surface was kept moist by suffusion of warmed oxygenated Krebs solution (in mM: NaCl 118.3, KCl 4.7, CaCl2 2.5, MgPO4 1.2, NaHCO3 25, KH2PO4 1.2) at 2 ml/min bubbled with 20% oxygen, 5% carbon dioxide, and 75% nitrogen. Body temperature was maintained (37 ± 1°C) with a servo-controlled thermal blanket.
Microvascular Preparation
Coronary microvascular diameters were measured by intravital microscopy (Zeiss, Germany) with epi-illumination of the cardiac surface by a computer-controlled strobe (Chadwick Helmuth, Almonte, CA). The strobe was triggered using the left ventricular dP/dt signal to flash once per cardiac cycle in late diastole. Fluorescein isothiocyanate dextran (mol wt 487,000, Sigma Chemical, St. Louis, MO) was injected into the left atrium to illuminate the microvascular lumen and to differentiate arterioles from venules by sequence of illumination. A Zeiss Neufluora (6.3X, n.a. = 0.02) objective was used; when coupled with a 6.3X relay lens, microvascular diameters can be measured with 2.5-µm resolution. Digital images were captured with a video camera and stored on computer disk. Images were later recalled on a high-resolution monitor, and the microvascular diameters were measured using a digitizing tablet and a computer to calculate the internal vessel diameter in micrometers. Details of the system have been described previously (4, 5, 18). All vessel measurements represent the mean of at least three images obtained at steady state for each experimental condition.Myocardial Perfusion and Oxygen Consumption
Myocardial perfusion was measured with the radiolabeled microsphere technique, as previously described (5). Radiolabeled microspheres (15.5 µm: 141Ce, 95Nb, 46Sc, 113Sn, 85Sr) were injected into the left atrial appendage during withdrawal of two reference samples from the aorta via the femoral artery catheters at a fixed rate (1.4-2.5 ml/min). At the end of the experiment, the heart was excised, and left ventricular tissue samples, excluding the papillary muscles, were obtained from the region of the studied vessels. The radioactivity contained in each sample was counted by a germanium crystal gamma counter (Canberra Industries, Meriden, CT). Myocardial blood flow (ml/min) was calculated with the formula
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Left ventricular arterio-venous oxygen difference
(avO2D, ml/l) was determined with the formula
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Drugs
Sodium nitroprusside, acetylcholine (Sigma), and superoxide dismutase (SOD, EC 1.15.1.1, Cu/Zn from bovine erythrocytes, 4,000 U/mg protein, Sigma) were prepared in normal saline stock solutions. Acetylcholine and nitroprusside were administered by superfusion onto the surface of the heart via a side port in the suffusion solution to achieve final concentrations of 1, 10, and 100 µM. SOD was suffused to achieve a final concentration of 250 U/cc. The thromboxane A2/prostaglandin H2 receptor antagonist, SQ29,548, was initially dissolved in 95% ethanol to achieve a concentration of 10 mg/ml and was stored in aliquots atProtocols
After the general surgical preparation, at least 30 min was allowed for stabilization of monitored variables. The microvascular field of study was identified, and coronary arterioles were verified by injection of fluorescein-labeled dextran. Baseline measurements of hemodynamics, microvascular diameters, blood gases, and blood glucose were performed.Protocol 1: endothelium-dependent dilation. Steady-state cumulative dose-response curves were constructed using acetylcholine and nitroprusside (1, 10, and 100 µM) applied topically to the surface of the heart. After stabilization of the monitored variable, either acetylcholine or nitroprusside responses were tested in a randomized fashion. After 10 min of topical application of the vasodilator, hemodynamics and microvascular diameters were measured. Similar measurements were made with the other doses of the agents. At least 40 min elapsed between the two different vasodilator agents. Ten normal and nine diabetic animals were studied under this protocol.
Protocol 2: microvascular response to increases in myocardial
oxygen consumption.
The next series of experiments was used to investigate the hypothesis
that coronary microvascular responses to increases in MO2 are impaired during prolonged
hyperglycemia. After initial baseline measurements, sodium
nitroprusside (100 µM, topically) was administered to establish that
the preparation had vascular tone; vessels dilating <20% in response
to 100 µM nitroprusside were excluded from analysis. After a washout
period (
30 min), repeat baseline measurements of hemodynamics, blood
glucose, blood gases, microvascular diameters, myocardial perfusion,
and arterial and coronary sinus oxygen saturations were made. A
dobutamine infusion (10 µg · kg
1 · min
1 iv) was started,
and, after 10 min, hemodynamics, blood glucose, blood gases,
microvascular diameters, myocardial perfusion, and arterial and
coronary sinus oxygen saturation measurements were repeated. Next,
during the dobutamine infusion, the left atrium was paced at rates up
to 300 bpm, or to the point just before atrio-ventricular block
occurred, and after 10 min, all monitored variables were obtained a
third time. Thus measurements were made at three levels of myocardial
metabolism: at rest, during dobutamine, and during dobutamine with
rapid atrial pacing (RAP). This protocol was used in 10 normal and 7 hyperglycemia (HG) dogs.
Protocol 3: role of endoperoxides in impaired metabolic dilation.
To test the hypothesis that endoperoxides (thromboxane A2
and prostaglandin H2) are responsible for impaired
responses to increases in MO2 during
hyperglycemia, the effect of the endoperoxide receptor antagonist
SQ29,548 was investigated in five HG and four normal dogs. After
assessment of microvascular tone with nitroprusside, SQ29,548 (2 mg/kg
iv) was given (8). After 10 min, the dobutamine and RAP
protocol described in protocol 2 was performed.
Protocol 4: role of superoxide anion in impaired metabolic
dilation.
To test the hypothesis that oxygen-derived free radicals are
responsible for the impaired microvascular response to increases in
MO2 during prolonged hyperglycemia, SOD
(250 U/ml, topically) was applied to the microvascular field. A
previous study from our laboratory had suggested that topically applied
free radical scavengers restore normal endothelial function in diabetes
(2). After assessment of microvascular tone with
nitroprusside, SOD (250 U/ml, topically) was applied. In this protocol,
five diabetic and five normal dogs were studied. After 10 min, the
dobutamine and RAP protocol described in protocol 2 was performed.
Statistical Analysis
Microvessels (<100 µm) were included in the analysis if they met two a priori-determined criteria: 1) the nitroprusside response was >20%; and 2) the vessel regained tone within 15% of baseline after washout of nitroprusside. One vessel from the normal group and two vessels from the HG group were excluded, because the response to nitroprusside was <20%. Three of the normal, none of the HG, two of the SQ29,548-treated diabetic, and one of the SOD-treated diabetic vessels were excluded because of a failure to regain tone after nitroprusside washout.All values are presented as means ± SE. One-way analysis of
variance was used to evaluate the changes in hemodynamic variables, blood gases, blood glucose, and MO2
among the experimental preparations and in diameters among the studied
vessels. Student-Newman-Keuls post hoc testing was performed where
appropriate. A P < 0.05 was considered statistically significant.
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RESULTS |
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Endothelial Function Protocol (Protocol 1)
Serum electrolytes, BUN, Cr, blood gases, and hemodynamics for both the normal and prolonged hyperglycemia animals studied under protocol 1 were not significantly different between the groups and were within the range of normal (data not shown). Microvascular diameters at baseline were not different between the groups (normal, 97 ± 10 µm; HG, 111 ± 12 µm). During suffusion of acetylcholine (1, 10, and 100 µM) the arterioles in normal animals dilated significantly more than those in diabetic animals (Fig. 1A). During suffusion of nitroprusside (1, 10, and 100 µM) the arterioles dilated to a similar degree in both groups (Fig. 1B).
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Metabolic Stress Protocols (Protocols 2-4)
Baseline microvascular diameters were similar among the groups (Normal, 60 ± 3 µm; HG, 70 ± 5 µm; SQ29,548-treated HG, 66 ± 5 µm; SQ29,548-treated Normal, 62 ± 4 µm; SOD-treated HG, 60 ± 5 µm; SOD-treated normal: 58 ± 6 µm; P = NS). Bicarbonate (day 1, 17 ± 1 meq/l; experiment day, 18 ± 1 meq/l), BUN (day 1, 14 ± 1 mg/dl; experiment day, 17 ± 1 mg/dl), Cr (day 1, 0.9 ± 0.1 mg/dl; experiment day, 0.8 ± 0.1 mg/dl) remained normal in the alloxan-treated animals during the week before experimentation. Only blood glucose (day 1, 76 ± 3 mg/dl; experiment day, 275 ± 37 mg/dl, P < 0.05) was substantially elevated in the HG animals.Hemodynamics, Blood Glucose, Blood pH, and Blood Gases
As shown in Table 1, heart rate was similar among the groups at each level of metabolic stimulation. Mean arterial pressure was kept constant, and there was no difference among groups at any time when measurements were made. Blood glucose was significantly and similarly elevated at each level of metabolic stimulation in the three HG groups compared with the three normal groups of animals. There was no difference in arterial pH or pO2 among the groups at each level of stimulation. In the SOD-treated diabetic group, pCO2 was slightly greater than that in the SQ29,548-treated HG and normal groups during dobutamine, but the values remained within the normal physiological range.
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MO2 and Perfusion
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Microvascular Diameters
Responses to increases in MO2 in
normal and HG dogs: Protocol 2.
In normal animals, coronary microvascular diameters progressively
increased with increasing M
O2 (Fig.
3). In animals with prolonged
hyperglycemia, during dobutamine infusion, coronary arteriolar dilation
was similar to that seen in normal animals. During dobutamine and RAP,
coronary arterioles in normal animals (treated or untreated with
SQ29,548 or SOD) dilated significantly compared with both baseline and
dobutamine measurements. However, during dobutamine and RAP, coronary
arterioles from diabetic animals did not dilate further (Fig. 3),
despite a further rise in M
O2 similar to
that seen in normal animals.
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Effect of SQ29,548 treatment in diabetes: protocol 3.
After treatment with SQ29,548, baseline diameters did not change
[HG+SQ, 2 ± 3; N+SQ,
5 ± 10%, P = not
significant (NS)]. In these animals, during dobutamine, coronary
arterioles dilated to a similar degree to those from normal and
untreated diabetic animals. During combined dobutamine and RAP,
however, coronary arterioles from SQ29,548-treated diabetic and normal
animals dilated similarly and significantly more than arterioles from
untreated diabetic dogs (Fig. 3).
Effect of SOD treatment in diabetes: protocol 4.
After treatment with topical SOD, baseline diameters did not change
(HG+SOD, 4 ± 1; N+SOD,
6 ± 6%, P = NS). In these dogs, coronary arterioles dilated to a similar degree to
those from normal and untreated HG animals (Fig. 3) during dobutamine.
With dobutamine and RAP, however, coronary arterioles from HG animals treated with topical SOD dilated similarly to those from normal animals
but significantly more than those from untreated HG animals (Fig. 3).
During dobutamine and RAP, arteriolar dilation was similar in SQ29,548-
and SOD-treated HG dogs.
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DISCUSSION |
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There are three major findings in this study. First, in vivo
coronary arteriolar responses to increases in
MO2 are impaired in dogs with prolonged
hyperglycemia. Second, our study importantly showed that blockade of
endoperoxide receptors with SQ29,548 prevents this impaired dilation to
marked metabolic stimulation, suggesting a role for thromboxane
A2 and/or prostaglandin H2. Third, we showed restoration of dilator function during prolonged hyperglycemia with
topical administration of superoxide dismutase, indicating that the
superoxide anion plays a role in this impaired response. Thus, in dogs
with prolonged hyperglycemia, dilation of coronary arterioles is
impaired in response to endothelium-dependent vasodilators and during
increases in M
O2. Coronary dilation
during increases in MVO2 in hyperglycemic dogs may be
restored with either blockade of endoperoxide receptors or with
superoxide scavengers.
Endothelium-Dependent Vasodilation in Diabetes
Endothelium-dependent vasodilation has been shown to be impaired in diabetic animals (26, 32) in vitro. Our data clearly demonstrate that coronary arteriolar dilation to acetylcholine is impaired in in vivo with exposure to prolonged hyperglycemia (Fig. 1A). However, impaired dilation during hyperglycemia is selective for endothelium-mediated dilation, because dilatory responses were similar to normal animals during administration of the endothelium-independent vasodilator nitroprusside (Fig. 1B). Several mechanisms for endothelial dysfunction have been proposed (26), not all of which directly involve nitric oxide. There may be increased release of an endothelium-derived constricting factor (EDCF), most likely a prostanoid. Additionally, oxygen-derived free radical production is increased in diabetes, which may have two effects. First, nitric oxide may be destroyed by superoxide anion. Second, the presence of free radicals may alter the metabolism of arachidonic acid through the cyclooxygenase pathway to favor production of vasoconstricting, rather than vasodilatory, prostanoids.Our failure to observe a difference in baseline diameter after pretreatment with SOD or SQ29,548 was unexpected. However, this result is consistent with that of Tesfamariam and colleagues (30, 32), who noted enhanced thromboxane production only during stimulation with acetylcholine. The measurements of thromboxane were not abnormal in basal states but were elevated in diabetes or hyperglycemia during stimulated states. This suggests that the diabetic milieu lowers the threshold for stimulation-induced elevation in endoperoxides.
Mechanism of Coronary Vasodilation During Increases in
MO2 in Normal Animals
Jones et al. (13) have recently reported that nitric oxide
participates in coronary microvascular dilation during increased metabolic demand with rapid atrial pacing. In addition, our laboratory demonstrated that coronary microvascular dilation during increases in
MO2 with a dobutamine and pacing
protocol is virtually abolished by nitric oxide synthase inhibition
(9). In contrast to the findings of Jones et al. and
Embrey et al. (9), some investigations have shown that
increases in coronary flow due to increased metabolic demand are due to
ATP-sensitive potassium channels and not to a nitric oxide-mediated
pathway. In a study by Narishige et al. (23), using
anesthetized open-chest dogs and a model of metabolic stimulation
(
1-adrenoceptor stimulation), found that glibenclamide prevented increases in coronary blood flow associated with increases in
M
O2. Their results using either
isoproterenol or denopamine demonstrated a role for
KATP+ in mediating increases in coronary
blood flow during increases in oxygen consumption. In similar
preparations in awake exercising dogs, others have not reproduced these
findings (3, 6, 7).
Role of Endoperoxides and Free Radicals in Impaired Microvascular
Dilation During Increased MO2
Our data support the concept that release of an EDCF and/or (see next paragraph) free radicals participate in impaired metabolic dilation during hyperglycemia. Interestingly, reversal of either of these mechanisms permits normal vasodilation to increasing metabolic demand.
There are two possible explanations for either thromboxane
A2/prostaglandin H2 receptor blockade or
superoxide scavenging to restore normal dilator function of arterioles
during increased MO2. First, there may
be coexistent pathways for superoxide production and for endoperoxide
production in the diabetic state. If both pathways are required to
achieve inhibition of endothelium-mediated dilation, inhibition of
either would allow for normal dilation to occur. The second possibility
is that superoxide production and endoperoxide production are
sequentially linked (15).
Clinical Implications
This study provides insight into potential mechanisms for the observed decreased exercise tolerance in diabetic patients. Our study provides direct evidence that endoperoxides and oxygen-derived free radicals play a role in impaired coronary microvascular dilation during increases in MIn summary, this study provides evidence that vasoconstrictor eicosanoids and oxygen-derived free radicals mediate impaired coronary arteriolar dilation during increased myocardial oxygen consumption during prolonged hyperglycemia.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institutes of Health NHLBI RO1 HL-51308 and the Veterans Affairs/Juvenile Diabetes Foundation Diabetes Research Center. Dr. Ammar was a recipient of an American Heart Association, Iowa Affiliate, Postdoctoral Fellowship Award. Drs. Gutterman and Dellsperger are Established Investigators of the American Heart Association.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. C. Dellsperger, VA Medical Center, Highway 6 West, Iowa City, IA 52246 (E-mail: kevin.dellsperger{at}med.va.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 19 January 2000; accepted in final form 17 May 2000.
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