Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries

2001 ◽  
Vol 280 (2) ◽  
pp. H925-H928 ◽  
Author(s):  
Alison Stirrat ◽  
Marie Gallagher ◽  
Stephen A. Douglas ◽  
Eliot H. Ohlstein ◽  
Colin Berry ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Function ◽  
Pulmonary Arteries ◽  
Systemic Resistance ◽  
Internal Diameter ◽  
Urotensin Ii ◽  
Resistance Arteries ◽  
Pulmonary Vessels ◽  
Potent Vasodilator ◽  
Abdominal Arteries

The peptide human urotensin-II (hUT-II) and its receptor have recently been cloned. The vascular function of this peptide in humans, however, has yet to be determined. Vasoconstrictor and vasodilator responses to hUT-II were investigated in human small muscular pulmonary arteries [∼170 μm internal diameter (ID)] and human abdominal resistance arteries (∼200 μm ID). Vasodilator responses were investigated in endothelin-1 (3 nM) precontracted vessels and, in the small pulmonary vessels, compared with the known vasodilators adrenomedullin, sodium nitroprusside, and acetylcholine. In human small pulmonary arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [−log M concentration causing 50% of the maximum vasodilator effect (pIC50) 10.4 ± 0.5; percentage of reduction in tone ( E max) 81 ± 8% (vs. 23 ± 11% in time controls), n = 5]. The order of potency for vasodilation was human urotensin-II = adrenomedullin (pIC50 10.1 ± 0.4, n = 6) > sodium nitroprusside (pIC50 7.4 ± 0.2, n = 6) = acetylcholine (pIC50 6.8 ± 0.3, n = 6). In human abdominal arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [pIC50 10.3 ± 0.7; E max96 ± 8% (vs. 43 ± 16% in time controls), n = 4]. This is the first report that hUT-II is a potent vasodilator but not a vasoconstrictor of human small pulmonary arteries and systemic resistance arteries.

Influence of hypoxia and serotonin on small pulmonary vessels

1994 ◽  
Vol 76 (1) ◽  
pp. 56-64 ◽  
Author(s):  
A. al-Tinawi ◽  
G. S. Krenz ◽  
D. A. Rickaby ◽  
J. H. Linehan ◽  
C. A. Dawson
Keyword(s):  
Size Range ◽  
Pulmonary Arteries ◽  
The Other ◽  
Internal Diameter ◽  
Total Response ◽  
Pulmonary Vessels ◽  
X Ray ◽  
Diameter Range ◽  
Maximum Decrease ◽  
Potential Impact

X-ray angiograms obtained from isolated perfused dog lungs were used to measure changes in the internal diameter of small intraparenchymal pulmonary arteries (150–1,600 microns) and veins (200–1,000 microns) in response to hypoxia or intra-arterial serotonin [5-hydroxytryptamine (5-HT)] infusion. The diameter changes in response to the two stimuli were measured over a range of stimulus-induced increases (delta Pa) in the total arteriovenous pressure drop. When the resulting delta Pa was small, all arteries in the diameter range studied constricted in response to either stimuli. The maximum decrease in diameter was approximately 25% with hypoxia and 36% with 5-HT. However, when delta Pa was large, arteries with a control diameter larger than approximately 800 microns distended with hypoxia. On the other hand, 5-HT constricted all the arteries in the size range studied regardless of the resulting magnitude of delta Pa. Hypoxia caused a small (approximately 9%) constriction in all veins in the diameter range studied independent of diameter or the magnitude of delta Pa, whereas in the concentration range studied 5-HT had no significant influence on these veins. An analysis of the potential impact of these vessels on total pulmonary vascular resistance suggested that although vessels in the size range studied contributed significantly to the total response to these two stimuli, vessels smaller than those studied also made a major contribution to the total response.

Abstract P500: Activation of the Heterodimeric Erythropoietin /β-Common Receptor Impairs Acetylcholine Mediated Vasodilation in Mouse Mesenteric Arterioles

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Cody R Kilar ◽  
YanPeng Diao ◽  
Larysa Sautina ◽  
Sivakumar Sekharan ◽  
Shahar Keinan ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Complications ◽  
Mesenteric Arteries ◽  
No Production ◽  
Resistance Arteries ◽  
Inhibitory Peptide ◽  
Receptor Complexes ◽  
Common Receptor ◽  
Potent Vasodilator ◽  
Selective Impairment

Erythropoietin (EPO) increases systemic vascular resistance and blood pressure. However, endothelial cells cultured in the presence of EPO demonstrate increased production of the potent vasodilator, nitric oxide (NO). The mechanism by which EPO causes vasoconstriction despite stimulating NO production may be dependent on its ability to differentially activate the two receptor complexes, the homodimeric EPO (EPOR 2 ) and the heterodimeric EPOR/β-common receptor (βCR). Objective: The purpose of this study was to investigate the contribution of the EPOR 2 and βCR receptor to the vasoactive properties of EPO. Methods: First order, mesenteric arteries isolated from 16-week old male C57BL/6 mice were cannulated and perfused using a pressure arteriography system. To determine the contribution of each receptor complex, arteries were incubated with EPO stimulating peptide (ESP) which binds and activates only the heterodimeric EPOR/βCR complex or EPO which activates both receptors, 20 min prior to evaluation of vasoconstrictor (phenylephrine and potassium chloride), endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (sodium nitroprusside) vasodilator responses. Additionally, we studied the effect of a novel βCR inhibitory peptide (βIP) which was developed in silico and validated by demonstrating that it selectively inhibits binding of ligands to the βCR. Results: Acetylcholine induced vasodilation was impaired in arteries pretreated with EPO or ESP by 100% and 60%, respectively. EPO and ESP did not affect endothelium-dependent vasodilation by Bradykinin or A23187, endothelium-independent vasodilation by sodium nitroprusside, or vasoconstriction by phenylephrine and KCl. The βIP prevented the impairment of acetylcholine-induced vasodilation by EPO and ESP. Conclusion: Together, our findings suggest that activation of the heterodimeric EPOR/βCR leads to selective impairment of ACh-mediated vasodilator response in mouse mesenteric resistance arteries. Thus the βCR might have a role in mediating hypertensive effects of EPO. Therapeutic inhibition of the βCR might prevent vascular complications of EPO without affecting erythropoiesis.

Calcitonin gene-related peptide vasodilation of human pulmonary vessels

1989 ◽  
Vol 67 (3) ◽  
pp. 1265-1270 ◽  
Author(s):  
D. G. McCormack ◽  
J. C. Mak ◽  
M. O. Coupe ◽  
P. J. Barnes
Keyword(s):  
Pulmonary Arteries ◽  
Calcitonin Gene Related Peptide ◽  
Human Calcitonin ◽  
Organ Bath ◽  
Pulmonary Vessels ◽  
Functional Studies ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Potent Vasodilator ◽  
Arteries And Veins

Human calcitonin gene-related peptide (CGRP) is localized to sensory neurons in pulmonary vessels and is a potent vasodilator. We have characterized the effects of CGRP in human pulmonary vessels and localized the receptors for this peptide by autoradiography. Fresh human lung tissue was obtained from eight patients undergoing surgery and small (200–400 microns ID) pulmonary arteries and veins were dissected free of surrounding connective and pulmonary tissue. Pairs of vessels were studied and in one of each pair the endothelium was left intact and from the other of each pair the endothelium was removed by gentle abrasion. For functional studies arteries (n = 9) and veins (n = 9) were suspended in an organ bath, precontracted with 1 microM prostaglandin F2 alpha. CGRP (10 pM to 10 microM) was added in a cumulative manner. CGRP caused a dose-dependent relaxation of endothelium intact human pulmonary arteries and veins with log EC50 values of -8.01 +/- 0.35 and -8.70 +/- 0.40, respectively (not significant). Removal of the endothelium did not diminish the vasodilator potency of CGRP in either vessel. For autoradiographic studies, cryostat sections of the small human pulmonary vessels with or without endothelium were used. 125I-CGRP densely labeled CGRP receptors on vascular smooth muscle and endothelial removal did not have any effect on grain density. We concluded that CGRP is a potent vasodilator of human pulmonary arteries and veins that is not dependent on an intact endothelium. These functional studies correlate with the distribution of CGRP receptors as localized by autoradiography.

Vagally and acetylcholine-mediated constriction in small pulmonary vessels of rabbits

1987 ◽  
Vol 63 (4) ◽  
pp. 1601-1609 ◽  
Author(s):  
K. Sada ◽  
M. Shirai ◽  
I. Ninomiya
Keyword(s):  
Nerve Stimulation ◽  
Pulmonary Arteries ◽  
Stimulus Frequency ◽  
Vagal Nerve ◽  
Internal Diameter ◽  
Specific Stimulus ◽  
Pulmonary Vessels ◽  
X Ray ◽  
Branching Points ◽  
Arteries And Veins

Using a new X-ray TV system, we analyzed effects of vagal nerve stimulation (VNS; 1–30 Hz) and intravenous injection of acetylcholine (Ach; 0.3–0.9 microgram) on the internal diameter (ID; 100–1,500 microns) of small pulmonary arteries and veins in anesthetized rabbits. In selective segments of the arteries, ID decreased abruptly and maximally by 50–70% in a specific stimulus frequency to the vagal nerve and a dose of ACh. The vasoconstrictor sites were distributed near the branching points of the arteries, particularly those downstream, and their numbers increased with an increase in the stimulus frequencies and ACh doses. The relative frequencies of occurrences were 15.3% with VNS (30 Hz) and 5.3% with ACh (0.9 microgram). In nonselective segments with VNS, ID decreased frequency dependently by 0, 4, 12, and 26% at 1, 4, 15, and 30 Hz, respectively, and with ACh, decreased dose dependently by 21 and 35% with 0.3 and 0.9 microgram, respectively. The vasoconstriction in response to VNS and ACh was attenuated by atropine, enhanced by eserine, and not affected by phentolamine. That vasoconstriction to VNS was abolished by hexamethonium. No selective constriction was found in veins and the ID was decreased uniformly by 1–2% with VNS and ACh.

scholarly journals Mitochondria-regulated formation of endothelium-derived extracellular vesicles shifts the mediator of flow-induced vasodilation

2017 ◽  
Vol 312 (5) ◽  
pp. H1096-H1104 ◽  
Author(s):  
Julie K. Freed ◽  
Matthew J. Durand ◽  
Brian R. Hoffmann ◽  
John C. Densmore ◽  
Andrew S. Greene ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Extracellular Vesicles ◽  
Vascular Function ◽  
Plasminogen Activator Inhibitor ◽  
Internal Diameter ◽  
Resistance Arteries ◽  
Plasminogen Activator Inhibitor 1 ◽  
Vascular Effect ◽  
Higher Doses ◽  
Pai 1

To examine the effect of endothelium-derived extracellular vesicles (eEVs) on the mediator of flow-induced dilation (FID), composition, formation, and functional effects on the mediator of FID were examined from two different eEV subtypes, one produced from ceramide, while the other was produced from plasminogen-activator inhibitor 1 (PAI-1). Using video microscopy, we measured internal-diameter changes in response to increases in flow in human adipose resistance arteries acutely exposed (30 min) to eEVs derived from cultured endothelial cells exposed to ceramide or PAI-1. FID was significantly impaired following exposure to 500K/ml (K = 1,000) of ceramide-induced eEVs (Cer-eEVs) but unaffected by 250K/ml. FID was reduced in the presence of PEG-catalase following administration of 250K/ml of Cer-eEVs and PAI-1 eEVs, whereas Nω-nitro-l-arginine methyl ester (l-NAME) had no effect. Pathway analysis following protein composition examination using liquid chromatography tandem mass spectrometry (LC-MS/MS) demonstrated that both subtypes were strongly linked to similar biological functions, primarily, mitochondrial dysfunction. Flow cytometry was used to quantify eEVs in the presence or absence of l-phenylalanine-4′-boronic acid (PBA) and mitochondria-targeted [93-boronophenyl)methyl]triphenyl-phosphonium (mito-PBA), cytosolic and mitochondrial-targeted antioxidants, respectively. eEV formation was significantly and dramatically reduced with mito-PBA treatment. In conclusion, eEVs have a biphasic effect, with higher doses impairing and lower doses shifting the mediator of FID from nitric oxide (NO) to hydrogen peroxide (H2O2). Despite differences in protein content, eEVs may alter vascular function in similar directions, regardless of the stimulus used for their formation. Furthermore, mitochondrial ROS production is required for the generation of these vesicles. NEW & NOTEWORTHY The vascular effect of endothelium-derived extracellular vesicles (eEVs) is biphasic, with higher doses decreasing the magnitude of flow-induced dilation (FID) compared with lower doses that shift the mediator of FID from nitric oxide to H2O2. eEVs may cause vascular dysfunction via similar pathways despite being formed from different stimuli, although both require mitochondrial reactive oxygen species for their formation.

Mechanisms of Direct Inhibitory Action of Isoflurane on Vascular Smooth Muscle of Mesenteric Resistance Arteries

2003 ◽  
Vol 99 (3) ◽  
pp. 666-677 ◽  
Author(s):  
Takashi Akata ◽  
Tomoo Kanna ◽  
Jun Yoshino ◽  
Shosuke Takahashi
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Reactivity ◽  
Channel Blocker ◽  
Isometric Force ◽  
Systemic Resistance ◽  
Resistance Arteries ◽  
Voltage Gated ◽  
Fura 2 ◽  
Force Relation

Background Isoflurane has been shown to directly inhibit vascular reactivity. However, less information is available regarding its underlying mechanisms in systemic resistance arteries. Methods Endothelium-denuded smooth muscle strips were prepared from rat mesenteric resistance arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2-loaded strips, whereas only the force was measured in the beta-escin membrane-permeabilized strips. Results Isoflurane (3-5%) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine (0.5 microM) or KCl (40 mM). These inhibitions were similarly observed after depletion of intracellular Ca2+ stores by ryanodine. Regardless of the presence of ryanodine, after washout of isoflurane, its inhibition of the norepinephrine response (both [Ca2+]i and force) was significantly prolonged, whereas that of the KCl response was quickly restored. In the ryanodine-treated strips, the norepinephrine- and KCl-induced increases in [Ca2+]i were both eliminated by nifedipine, a voltage-gated Ca2+ channel blocker, whereas only the former was inhibited by niflumic acid, a Ca2+-activated Cl- channel blocker. Isoflurane caused a rightward shift of the Ca2+-force relation only in the fura-2-loaded strips but not in the beta-escin-permeabilized strips. Conclusions In mesenteric resistance arteries, isoflurane depresses vascular smooth muscle reactivity by directly inhibiting both Ca2+ mobilization and myofilament Ca2+ sensitivity. Isoflurane inhibits both norepinephrine- and KCl-induced voltage-gated Ca2+ influx. During stimulation with norepinephrine, isoflurane may prevent activation of Ca2+-activated Cl- channels and thereby inhibit voltage-gated Ca2+ influx in a prolonged manner. The presence of the plasma membrane appears essential for its inhibition of the myofilament Ca2+ sensitivity.

scholarly journals Lack of synergistic interaction between quercetin and catechin in systemic and pulmonary vascular smooth muscle

2010 ◽  
Vol 105 (9) ◽  
pp. 1287-1293 ◽  
Author(s):  
Carmen Menendez ◽  
Rosario Jimenez ◽  
Laura Moreno ◽  
Pilar Galindo ◽  
Angel Cogolludo ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Pulmonary Arteries ◽  
Rat Aorta ◽  
Relaxant Effect ◽  
Isobolographic Analysis ◽  
Scavenging Effect ◽  
Synergistic Interactions ◽  
Pure Compounds ◽  
Intermediate Effect

Due to their ubiquitous distribution, flavonoids from different classes are commonly present together in foods. However, little is known about the interactions between them. The flavonol quercetin and the flavan-3-ol (+)-catechin are among the most abundant flavonoids in the diet. In the present study, we have analysed the interactions between these two flavonoids on vascular function using two pure compounds and mixtures of these flavonoids in 1:0·1, 1:1 or 1:10 proportions. Quercetin induced a more potent concentration-dependent relaxant effect than catechin in the isolated rat aorta, and the isobolographic analysis of the mixtures showed no synergistic or antagonistic effects between them, i.e. their effects were additive. Quercetin was more potent in mesenteric than in pulmonary arteries. Catechin had weak effects in these vessels and did not modify the effects of quercetin. Endothelial dysfunction induced by increased oxidative stress by the superoxide dismutase inhibitor diethyldithiocarbamate was prevented by quercetin, whereas catechin showed a weak effect and the 1:1 mixture an intermediate effect compared with the pure compounds. Quercetin but not catechin showed a pro-oxidant and NO-scavenging effect, which was not prevented by catechin. In conclusion, catechin was less potent than quercetin as a vasodilator, pro-oxidant or to prevent endothelial dysfunction, and there were no synergistic interactions between quercetin and catechin.

scholarly journals Effects of aging and exercise training on spinotrapezius muscle microvascular Po2 dynamics and vasomotor control

2011 ◽  
Vol 110 (3) ◽  
pp. 695-704 ◽  
Author(s):  
Danielle J. McCullough ◽  
Robert T. Davis ◽  
James M. Dominguez ◽  
John N. Stabley ◽  
Christian S. Bruells ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Exercise Training ◽  
Sodium Nitroprusside ◽  
Vascular Function ◽  
Treadmill Running ◽  
Aged Rats ◽  
Phosphorescence Quenching

With advancing age, there is a reduction in exercise tolerance, resulting, in part, from a perturbed ability to match O2 delivery to uptake within skeletal muscle. In the spinotrapezius muscle (which is not recruited during incline treadmill running) of aged rats, we tested the hypotheses that exercise training will 1) improve the matching of O2 delivery to O2 uptake, evidenced through improved microvascular Po2 (PmO2), at rest and throughout the contractions transient; and 2) enhance endothelium-dependent vasodilation in first-order arterioles. Young (Y, ∼6 mo) and aged (O, >24 mo) Fischer 344 rats were assigned to control sedentary (YSED; n = 16, and OSED; n = 15) or exercise-trained (YET; n = 14, and OET; n = 13) groups. Spinotrapezius blood flow (via radiolabeled microspheres) was measured at rest and during exercise. Phosphorescence quenching was used to quantify PmO2 in vivo at rest and across the rest-to-twitch contraction (1 Hz, 5 min) transition in the spinotrapezius muscle. In a follow-up study, vasomotor responses to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) stimuli were investigated in vitro. Blood flow to the spinotrapezius did not increase above resting values during exercise in either young or aged groups. Exercise training increased the precontraction baseline PmO2 (OET 37.5 ± 3.9 vs. OSED 24.7 ± 3.6 Torr, P < 0.05); the end-contracting PmO2 and the time-delay before PmO2 fell in the aged group but did not affect these values in the young. Exercise training improved maximal vasodilation in aged rats to acetylcholine (OET 62 ± 16 vs. OSED 27 ± 16%) and to sodium nitroprusside in both young and aged rats. Endurance training of aged rats enhances the PmO2 in a nonrecruited skeletal muscle and is associated with improved vascular smooth muscle function. These data support the notion that improvements in vascular function with exercise training are not isolated to the recruited muscle.

Gender influences coronary L-type Ca2+current and adaptation to exercise training in miniature swine

2001 ◽  
Vol 91 (6) ◽  
pp. 2503-2510 ◽  
Author(s):  
D. K. Bowles
Keyword(s):  
Smooth Muscle ◽  
Exercise Training ◽  
Endurance Training ◽  
Coronary Arteries ◽  
Current Density ◽  
Adaptive Response ◽  
Heart Weight ◽  
Internal Diameter ◽  
Resistance Arteries ◽  
Miniature Swine

Endurance exercise training increases smooth muscle L-type Ca2+current density in both resistance and proximal coronary arteries of female miniature swine. The purpose of the present study was to determine 1) whether gender differences exist in coronary smooth muscle (CSM) L-type Ca2+ current density and 2) whether endurance training in males would demonstrate a similar adaptive response as females. Proximal, conduit (∼1.0 mm), and resistance [∼200 μm (internal diameter)] coronary arteries were obtained from sedentary and treadmill-trained swine of both sexes. CSM were isolated by enzymatic digestion (collagenase plus elastase), and voltage-gated Ca2+-channel current ( I Ca) was determined by using whole cell voltage clamp during superfusion with 75 mM tetraethylammonium chloride and 10 mM BaCl2. Current-voltage relationships were obtained at test potentials from −60 to 70 mV from a holding potential of −80 mV, and I Ca was normalized to cell capacitance (pA/pF). Endurance treadmill training resulted in similar increases in heart weight-to-body weight ratio, endurance time, and skeletal muscle citrate synthase activity in male and female swine. I Ca density was significantly greater in males compared with females in both conduit (−7.57 ± 0.58 vs. −4.14 ± 0.47 pA/pF) and resistance arteries (−11.25 ± 0.74 vs. −6.49 ± 0.87 pA/pF, respectively). In addition, voltage-dependent activation of I Ca in resistance arteries was shifted to more negative membrane potentials in males. Exercise training significantly increased I Ca density in both conduit and resistance arteries in females (−7.01 ± 0.47 and −9.73 ± 1.13 pA/pF, respectively) but had no effect in males (−8.61 ± 0.50 and −12.04 ± 1.07 pA/pF, respectively). Thus gender plays a significant role in determining both the magnitude and voltage dependence of I Ca in CSM and the adaptive response of I Ca to endurance training.

Protoporphyrin IX generation from δ-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation

2006 ◽  
Vol 291 (3) ◽  
pp. L337-L344 ◽  
Author(s):  
Christopher J. Mingone ◽  
Sachin A. Gupte ◽  
Joseph L. Chow ◽  
Mansoor Ahmad ◽  
Nader G. Abraham ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Vascular Function ◽  
Soluble Guanylate Cyclase ◽  
Aminolevulinic Acid ◽  
Pulmonary Arteries ◽  
Protoporphyrin Ix ◽  
Physiological Mechanism ◽  
No Donor ◽  
Vasp Phosphorylation ◽  
Guanylate Cyclase Activation

Protoporphyrin IX is an activator of soluble guanylate cyclase (sGC), but its role as an endogenous regulator of vascular function through cGMP has not been previously reported. In this study we examined whether the heme precursor δ-aminolevulinic acid (ALA) could regulate vascular force through promoting protoporphyrin IX-elicited activation of sGC. Exposure of endothelium-denuded bovine pulmonary arteries (BPA) in organoid culture to increasing concentrations of the heme precursor ALA caused a concentration-dependent increase in BPA epifluorescence, consistent with increased tissue protoporphyrin IX levels, associated with decreased force generation to increasing concentrations of serotonin. The force-depressing actions of 0.1 mM ALA were associated with increased cGMP-associated vasodilator-stimulated phosphoprotein (VASP) phosphorylation and increased sGC activity in homogenates of BPA cultured with ALA. Increasing iron availability with 0.1 mM FeSO4 inhibited the decrease in contraction to serotonin and increase in sGC activity caused by ALA, associated with decreased protoporphyrin IX and increased heme. Chelating endogenous iron with 0.1 mM deferoxamine increased the detection of protoporphyrin IX and force depressing activity of 10 μM ALA. The inhibition of sGC activation with the heme oxidant 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) attenuated the force depressing actions of an NO donor without altering the actions of ALA. Thus control of endogenous formation of protoporphyrin IX from ALA by the availability of iron is potentially a novel physiological mechanism of controlling vascular function through regulating the activity of sGC.

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