© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Elevation of an endogenous inhibitor of nitric oxide synthesis in experimental congestive heart failure
aCardiology Research Laboratory, London Health Sciences Centre, Departments of Medicine, Pharmacology and Toxicology, University of Western Ontario, Victoria Campus, 375 South Street, London, Ontario, Canada N6A 4G5
bDepartment of Clinical Pharmacology, University of Gothenburg, Gothenburg, Sweden
cCardiology Research Laboratory, Department of Physiology University of Western Ontario, London, Ontario, Canada
* Corresponding author. Tel.: (+1-519) 685 8300X5502; fax: (+1-519) 432 7367; e-mail: qfeng@julian.uwo.ca
Received 10 February 1997; accepted 16 September 1997
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Abstract |
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Objective: NG,NG-dimethylarginine (asymmetric dimethylarginine, ADMA) is an important endogenous substance with potent inhibitory actions on nitric oxide (NO) synthesis. The present study was designed to determine circulating ADMA levels and endothelium-dependent, NO mediated vasodilation in a rat model of congestive heart failure (CHF). Methods: CHF was induced in rats by coronary artery ligation. Sham-operated rats served as normal controls. Plasma ADMA was determined by high performance liquid chromatography with fluorescence detection. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by the clearance of inulin and p-aminohippuric acid, respectively. Endothelial function of the aorta was assessed in an organ bath. Results: Plasma levels of ADMA in rats with CHF (0.94±0.05 µmol/l) were significantly increased compared with sham-operated controls (0.75±0.06 µmol/l, p<0.05). Plasma levels of ADMA was negatively correlated with GFR (r=–0.65, p<0.05). Decreased endothelium-dependent relaxation to acetylcholine in the aorta of CHF was completely restored by L-arginine (300 µM) (p<0.01) while endothelium-independent relaxation to nitroprusside was not altered. ADMA potently inhibited endothelium-dependent relaxation in thoracic aorta of normal and CHF rats. The effect of ADMA was completely antagonized by L-arginine in both groups (p<0.01). Moreover, L-arginine improved endothelium-dependent relaxation in CHF rats in the presence of ADMA. Conclusions: An endogenous NO synthesis inhibitor ADMA is increased in the circulation of rats with CHF. The increased plasma levels of ADMA may contribute to the decreased endothelium-dependent relaxation in CHF, which is restored by L-arginine, possibly by competitive antagonism of ADMA.
KEYWORDS Asymmetric dimethylarginine (ADMA); L-Arginine; Nitric oxide synthase Inhibitor; Nitric oxide; Endothelium; Renal function; Congestive heart failure; Rat
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Endothelium-derived nitric oxide (NO) is an important mediator involved in the regulation of vascular tone [1, 2]. NO is synthesized from L-arginine by nitric oxide synthase (NOS) [3]. This reaction is competitively inhibited by analogs of L-arginine which are substituted at the terminal guanidino nitrogen [4]. Methylated arginines such as NG-monomethyl-L-arginine (L-NMMA) and dimethylarginines including NG,NG-dimethylarginine (asymmetric dimethylarginine, ADMA) and NG,N'G-dimethylarginine (symmetric dimethylarginine, SDMA) are naturally occurring substances [5, 6]. In the human circulation, concentrations of dimethylarginines are ten times greater than that of L-NMMA [7]. ADMA but not SDMA has been shown to inhibit NO synthesis in vitro and in vivo experiments in animals and in man [7]. Furthermore, ADMA dose-dependently inhibits vascular endothelium-dependent relaxations [8]. Thus, accumulation of endogenous ADMA has the potential to impair NO synthesis and increase vascular tone.
Congestive heart failure (CHF) is associated with increased peripheral vascular resistance [9, 10]. This increased vascular resistance in the later stage of CHF is detrimental and may contribute to symptoms and the high mortality of this disease. Although sympathetic and neurohormonal activation contributes significantly to this increased vascular tone [9, 11], endothelial dysfunction also plays an important role [12]. Recent studies have shown that CHF is associated with a decreased endothelium-dependent, NO mediated vasodilation [12–15]. However, the mechanisms of the impaired endothelium-dependent relaxation in CHF are not well understood. It is not known if endogenous ADMA plays a role in the impaired endothelial function. In the present study we tested the hypothesis that circulating ADMA levels are increased in a rat model of CHF induced by myocardial infarction. The effects of ADMA on endothelium-dependent relaxation in CHF were determined in the presence and absence of L-arginine. Since ADMA is excreted from the urine [7], the relationship between plasma ADMA and renal function was also studied.
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2 Methods |
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2.1 Experimental animals
The experiments were conducted on male Sprague–Dawley rats (200–300 g). All animals were maintained on normal rat chow and given water ad libitum in a 12-hour light/dark cycle. Animals were caged individually after surgical operation. The study protocol was approved by the Council on Animal Care at the University of Western Ontario.
2.2 Induction of congestive heart failure
During sodium pentobarbital (50 mg/kg, i.p.) anaesthesia the rats were intubated and artificially ventilated with a respirator (SAR-830, CWE, Inc., Ardmore, PA). A left thoracotomy was performed, exposing the left side of the heart. The left coronary artery was ligated by positioning a suture between the pulmonary artery out-flow tract and the left atrium as previously described [16, 17]. The lungs were thereafter hyper-inflated using positive end-expiratory pressure and the thorax immediately closed. After coronary artery ligation 24% died within several hours of the operation. Those surviving this initial period had 12% mortality within 8 weeks, which was similar to a previous report [18]. Sham-operated rats underwent the same surgical procedure without coronary artery ligation. Rats were randomly assigned to the following experiments 6–8 weeks after coronary artery ligation or sham-operation.
2.3 Hemodynamic monitoring in conscious rats
CHF (n=6) and Sham rats (n=5) were anaesthetized with sodium pentobarbital (50 mg/kg, i.p.) for cannulation. A polyethylene catheter (PE-50) was inserted into the left ventricle via the right carotid artery to measure left ventricle end-diastolic pressure (LVEDP). The first derivative of the left ventricular pressure (dP/dt) was determined by a differentiator with a frequency response linear to 100 Hz. For measurement of cardiac output (CO), a thermodilution probe (2.5F, Baxter, Mississauga, Ontario) was inserted from the right femoral artery so that its tip was at the aortic arch and another catheter (PE-50) was inserted in the superior vena cava via the right jugular vein for injection of saline [19]. The tail artery was cannulated for measurements of blood pressure and heart rate. Catheters were tunnelled subcutaneously to an exit site between the scapulae. Experiments were performed in conscious animals 2–3 h after surgery. Pressures and heart rate were measured by using a Hewlett-Packard pressure transducer (model 1290A) connected to a pressure monitor and recorded on a Gould recorder (model 2400S). CO was measured by a cardiac computer (American Edwards Laboratories, CA) by injection of 0.2 ml saline at 21–22°C and the average of triplicate measurements was taken. Cardiac index (CI)=CO/body weight (ml/min/100 g).
2.4 Measurement of glomerular filtration rate and renal blood flow
During pentobarbital anaesthesia, the left carotid artery and vein were cannulated. The abdomen was incised and the bladder was cannulated for urine collection. The rats (n=5 in each group) were infused intravenously with a solution of 10% inulin (Eastman Chemical Co) and 0.25% p-aminohippuric acid (PAH) (Sigma) in normal saline at a rate of 1.5 ml/h. After approximately 60 min of equilibration, urine samples were collected under oil in preweighed vials for 3 sequential 20 min periods. Blood samples (150 µl) were obtained at the midpoint of each clearance period. Urine volume was calculated gravimetrically. Hematocrit was calculated by the microcapillary tube method. Urine and plasma samples were assayed for inulin and PAH by standard colorimetric methods. Glomerular filtration rate (GFR) and renal blood flow (RBF) were calculated as the clearance of inulin and PAH, respectively [20]. At the end of the experiment, the rat was euthanized with an over-dose pentobarbital, and the kidney was removed, decapsulated, cut in half, blotted dry, and weighed. GFR and RBF were expressed as per gram kidney weight. At the end of the last clearance period, 5 ml of blood were drawn for measurement of plasma ADMA levels.
2.5 Determination of plasma ADMA and concentrations
The rats were anaesthetized with sodium pentobarbital (50 mg/kg, i.p.). Blood (5 ml) drawn from carotid artery was collected into heparinised tubes and centrifuged at 2500 g for 15 min to separate plasma. All plasma samples were kept at –70°C until analysis.
Samples from CHF (n=10) and Sham rats (n=10) were analyzed using high-performance liquid chromatography (HPLC) and fluorescence detection, a method recently developed in our laboratory [21]. Briefly, ADMA and SDMA were extracted from the plasma samples with a cation exchange column, Isolute-SCX (100 mg). The column was activated with 1 ml methanol, conditioned with 2 ml TCA (2%) and applied with 1.5 ml plasma. The column was subsequently rinsed with 1 ml TCA (2%), 3 ml phosphate buffer (pH 8) and 1 ml methanol. ADMA and SDMA were eluted in 2 ml methanol containing 30% distilled water and 2% fresh triethylamine prepared daily. The eluent was then evaporated to dryness at 60°C under nitrogen. The dried extract was dissolved in distilled water and passed through a 0.22 µm filter. ADMA and SDMA were converted to fluorescent derivatives with o-phthalaldehyde in an alkaline medium and separated on a 3 µm Ultracarb 3 ODS (20) (150x4.6 mm) column (Phenomenex, Torrance, CA, USA) with a multigradient elution. A Waters 420-AC fluorescence detector (Millipore Co, Milford, MA) with a 338 nm bandpass excitation filter, and a 425 nm longpass emission filter and a flow cell of 8 µl was used for detection. The recoveries of ADMA and SDMA were over 80% and the detection limit was 0.2 µmol/l.
2.6 Assessment of vascular endothelial function in vitro
Thoracic aortae were isolated and cut into rings 
3 mm in length. Aortic rings were mounted between two stainless steel wires in 5 ml organ baths containing Krebs solution (in mM: 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4·H2O, 1.2 K2PO4, 11 dextrose, and 22 NaHCO3; pH 7.4). The Krebs solution was aerated with 95% O2–5% CO2 and maintained at 37°C. A resting tension of 1 g, determined as the optimal resting tension during preliminary investigation, was applied to the aortic rings. One wire was fixed to a brass manipulator and the other was attached to a FTO3 isometric force transducer (Grass Instruments, Quincy, MA) and a Grass model 79E polygraph for the continuous recording of tension. The contractile capacity of each vessel segment was examined by exposure to KCl (100 mM). Contractile response to prostaglandin F2
(PGF2, 10–8 to 3x10–5 M) was assessed in CHF (n=5) and Sham (n=4) rats. In the subsequent experiments, all vessels were preconstricted with PGF2 (10–5 M) and endothelium-dependent relaxation was assessed with increasing concentrations of acetylcholine (10–9–10–5 M). Endothelium-independent relaxation was assessed with increasing concentrations of nitroprusside (10–10–10–7 M).
In CHF (n=8) and Sham rats (n=7), after control responses to acetylcholine and nitroprusside were obtained, the vessels were treated with L-arginine (300 µM) in the organ bath for 15 min. The assessment of relaxations to acetylcholine and nitroprusside was repeated in the presence of L-arginine (300 µM), a concentration which has been shown to inhibit the effects of ADMA in vitro [7]. In normal control rats (n=12), responses to acetylcholine and nitroprusside were assessed in the presence and absence of increasing concentrations of ADMA (30 to 300 µM, pretreated for 15 min) in the organ bath. In rats with CHF (n=5), relaxation responses to acetylcholine and nitroprusside were assessed in the presence and absence of ADMA (300 µM, pretreated for 15 min) in the organ bath. In order to see if L-arginine antagonizes the effects of ADMA, responses to acetylcholine and nitroprusside were obtained in the presence of L-arginine (300 µM) and ADMA (300 µM) in both groups.
2.7 Measurement of infarct size
The heart was dissected out, weighed and cut into four transverse slices of equal thickness. Photographs were taken for each heart slice. The endocardial circumferences of fibrotic and normal areas were quantitated with a distance meter. Infarct size was expressed as a fraction of the total cross-sectional circumference of the left ventricle [16, 17].
2.8 Data analysis
Data are expressed as mean±SEM. EC50 values were calculated by GraphPad Prism computer program using non-linear sigmoid curve fitting and are expressed as –log(M). Unpaired Student's t-test or two-way analysis of variance (ANOVA) followed by unpaired Student's t-test and linear regression were used. Two-tailed p value <0.05 was considered statistically significant.
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3 Results |
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3.1 General characteristic of CHF
The infarct size of coronary artery ligated rats (n=24) was 40.8±1.5% of the left ventricle (Table 1). No myocardial infarction was observed in sham-operated control rats (n=22). In CHF, the weight of the heart, heart to body weight ratio, left and right ventricles were significantly increased compared to sham-operated rats (p<0.01). Cardiac index and developed pressures of the left ventricle were decreased while left ventricular end-diastolic pressure and total peripheral resistance were significantly increased in CHF rats (p<0.05) (see Table 1). These hemodynamic changes in coronary artery ligated rats formed a picture characteristic of clinical congestive heart failure.
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3.2 Plasma ADMA in CHF
Plasma levels of ADMA in rats with CHF were significantly increased by 25.3% compared to sham-operated controls (p<0.05) (Fig. 1). Plasma levels of SDMA were 0.39±0.04 and 0.38±0.03 µmol/l in CHF and sham rats, respectively (p=n.s.). The ADMA/SDMA ratio was slightly higher in CHF (2.48±0.15) compared with sham-operated rats (2.10±0.22), but not statistically significant (p=0.18).
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3.3 Correlation between GRF and ADMA
GFR and RBF were measured in 5 CHF and 5 sham-operated rats which also had plasma ADMA measurements. Both GFR and RBF were similar between CHF (1.01±0.09 and 6.78±0.56 ml/min/g kidney weight) and sham-operated rats (1.04±0.05 and 7.04±0.60 ml/min/g kidney weight) (p=n.s.). However, GFR was significantly and negatively correlated with plasma levels of ADMA (r=–0.65, p<0.05) (Fig. 2). RBF was not significantly correlated with ADMA plasma levels (r=0.17, p=n.s.). No significant correlations were present between ADMA and other parameters such as infarct size (p=n.s.).
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3.4 ADMA and endothelium-dependent relaxation
PGF2
elicited concentration-dependent responses in aortic rings of both CHF (n=5) and sham-operated rats (n=4). EMAX of PGF2 (in % of KCl constriction) was 153±11 in CHF and 173±18 in sham rats (p=n.s.). EC50 values of PGF2 were similar between CHF and sham rats (5.69±0.11 vs. 5.61±0.10, p=n.s.). Since contractile response to PGF2 was similar between CHF and sham rats, PGF2 was used to preconstrict all vessel rings in the subsequent experiments. In aortic rings, endothelium-dependent relaxation to acetylcholine was significantly decreased in CHF (n=8) compared to sham-operated rats (n=7, p<0.01) (Table 2, Fig. 3). EC50 of acetylcholine was significantly increased in CHF compared with sham-operated rats (p<0.01). However, endothelium-independent relaxation to nitroprusside was not different between CHF and sham-operated rats (p=n.s.) (Fig. 3, Table 2). With L-arginine treatment, the decreased endothelium-dependent relaxation to acetylcholine in CHF was restored to the response similar to sham-operated rats (p<0.01) (Fig. 4, Table 2). L-arginine did not alter endothelium-dependent relaxation to acetylcholine in Sham rats or relaxation to nitroprusside in both CHF and Sham rats (p=n.s.) (Fig. 4, Table 2).
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In order to see if ADMA contributes to decreased endothelium-dependent relaxation, aortic rings were treated with increasing concentrations of ADMA. In normal control animals, ADMA showed concentration-dependent inhibition of endothelium-dependent relaxation to acetylcholine (p<0.01) with no effects on endothelium-independent relaxation to nitroprusside (p=n.s.) (Fig. 5, Table 3). The effect of ADMA (300 µM) was completely restored by L-arginine (300 µM) (Fig. 5, Table 3). In rats with CHF (n=5), ADMA (300 µM) inhibited endothelium-dependent relaxation to acetylcholine in aortic rings with significant attenuation in EMAX (p<0.05) (Fig. 6, Table 3). Moreover, L-arginine (300 µM) shifted the acetylcholine response curve to the right of CHF control response (p<0.05) in the presence of ADMA (Fig. 6, Table 3). Neither L-arginine nor ADMA changed the response to nitroprusside in CHF (p=n.s.) (Fig. 6, Table 3).
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4 Discussion |
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Endothelium-dependent, NO-mediated vascular relaxation is decreased in CHF. Decreased endothelium-dependent relaxation has been documented in the peripheral arteries of a pacing-induced CHF dog model [14], and in thoracic aorta and hindquarter resistance arteries in a CHF rat model induced by myocardial infarction [12, 13]. Smith and co-workers have demonstrated a reduced mRNA and protein expression of endothelial NOS in the pacing-induced CHF dog model [22]. We have recently demonstrated that constitutive NOS activity is decreased in the aortae of CHF rats [23]. However, the mechanism of the decreased endothelium-dependent relaxation and NOS expression is not fully understood [22]. CHF is associated with increased production of cytokines [24, 25]that have been shown to downregulate endothelial NOS mRNA expression [26]. Pulsatility is believed to be a potent stimulus for NO [27], which may be decreased in CHF due to decrease in cardiac output and vascular blood flow. In addition, increased oxidative stress may also play a role in the decreased endothelium-dependent relaxation in CHF, as oxygen free radicals may inactivate NO [28]. In the present study, we demonstrate for the first time that an endogenous NO synthesis inhibitor ADMA is increased in the circulation of rats with CHF. Since ADMA inhibits endothelium-dependent relaxation in a concentration-dependent manner, the increased plasma levels of ADMA may be one of the factors that contribute to the decreased endothelium-dependent relaxation and NO production in CHF.
ADMA is a major endogenous NOS inhibitor [7, 29]. Previous studies have shown that ADMA inhibits NO production and endothelium-dependent relaxation [8]. This is confirmed in the present study in normal control and CHF rats. Furthermore, we demonstrated that the inhibitory effects of ADMA on endothelium-dependent relaxation were completely restored by L-arginine, indicating the balance between L-arginine and ADMA is important in normal endothelial function. In rats with CHF, plasma levels of ADMA were increased. Since methylarginines are concentrated within the cell [30], a moderate increase (25.3%) in plasma ADMA concentration in CHF rats as observed in the present study may mirror a much higher increase of the compound in the vicinity of the NO synthase and thus results in decreased endothelium-dependent relaxation in CHF. ADMA/SDMA ratio has been demonstrated to be increased in patients with chronic renal failure [7, 29]. In the present study, ADMA/SDMA ratio was not significantly increased in CHF rats. Since SDMA does not affect endothelial function, the ADMA/L-arginine ratio rather than ADMA/SDMA ratio might be a better index for endothelial function. In this regard, we have recently measured plasma L-arginine level and found it was decreased in CHF rats (unpublished observations). These data and the results from the present study suggest an increased ADMA/L-arginine ratio and thus nitric oxide synthase inhibition in CHF.
L-Arginine has been demonstrated to improve endothelial function in vivo by several investigators. Hirooka and co-workers showed intra-arterial L-arginine administration improves endothelium-dependent and ischemic vasodilation in the forearm of patients with CHF [31]. Furthermore, acute L-arginine treatment has beneficial hemodynamic effects in pulmonary hypertension [32], and short-term oral supplementation of L-arginine improves functional status in patients with CHF [33]. However, the exact mechanisms of the effects of L-arginine are not clear. Although administration of L-arginine has been demonstrated to increase NO production [34], the release of insulin and pituitary growth hormone may also mediate the effects of L-arginine in vivo [35, 36]. In the present study, acute L-arginine treatment in organ bath in a concentration (300 µM) that is very close to the normal physiological levels of plasma L-arginine (200 µM) in rats [37]restored endothelium-dependent relaxation in the aorta of rats with CHF. Since L-arginine treatment in vitro is not likely to cause release of insulin and growth hormones in the aortic rings, the results support the notion that L-arginine antagonizes the inhibitory effect of ADMA in the vicinity of the NO synthase, which may be increased in CHF, and thus improves endothelial function.
ADMA is synthesized by methylation of arginine residues in proteins and subsequent hydrolysis of the arginine residues in proteins [38]. Thus the amounts of ADMA produced may reflect rates of protein methylation and degradation. The removal of ADMA might occur by metabolism or excretion. Rat kidney contains dimethylarginase that metabolizes ADMA to citrulline [39]. Human endothelial cells possess an enzyme that has similar properties to dimethylarginase [30]. Impairment in this metabolizing pathway would also increase dimethylarginine concentrations. A recent study demonstrated that ADMA is increased in the regenerated endothelial cells 6 weeks after endothelium denudation, and may contribute to decreased endothelium-dependent relaxation in the endothelial damaged vessels [8]. Whether ADMA is increased in the vascular endothelial cells in CHF requires further investigation.
In the present study, measurements of GFR and RBF in rats with CHF were similar with those of sham-operated control animals. The results suggest that the renal function is well preserved at basal conditions in these CHF rats. Our results are consistent with a previous study showing that GFR and RBF are normal in rats with infarct size 10–40% of the left ventricle [40]. Even in rats with infarcts greater than 40%, GFR and RBF show only mild reductions of borderline significance (p=0.053) under basal conditions [40]. However, rats with infarcts 10–40% exhibit a distinct impairment in their ability to excrete sodium in response to an acute sodium load [40, 41]. A significant correlation between plasma ADMA levels and GFR observed in the present study supports the notion that endogenous ADMA is excreted in the urine [7]. Since basal GFR and RBF are not altered, it is possible that urinary excretion of ADMA may be normal in these CHF animals. However, it is not known whether there are changes in ADMA production and/or metabolism in CHF. Therefore, the exact mechanisms of increased circulating levels of ADMA in CHF require further investigation.
A major limitation of the present study is that we did not measure ADMA concentrations within the endothelial cells or tissue levels in the aorta. Although our HPLC method is highly sensitive for plasma ADMA measurements, it is not possible to determine intracellular or tissue levels of ADMA in the aorta due to the limited number of cells or tissues we could harvest from a rat. Therefore, a more sensitive assay is needed to measure directly endothelial as well as tissue ADMA levels in CHF rats.
In summary, ADMA an endogenous NO synthesis inhibitor is increased in the circulation of rats with CHF. ADMA inhibits endothelium-dependent relaxation in both normal and CHF rats. This effect of ADMA is completely antagonized by L-arginine. Furthermore, in vitro L-arginine treatment restores endothelium-dependent relaxation in CHF rats. We therefore conclude that the increased plasma levels of ADMA may contribute to the decreased endothelium-dependent relaxation in CHF.
Time for primary review 22 days.
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Acknowledgements |
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This research was supported by the Heart and Stroke Foundation of Ontario (Grant-in-aid #NA2983). We thank Mr. S. Dukacz for technical assistance.
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