Aortic stiffness in vivo in hypertensive rat via echo-tracking: analysis of the pulsatile distension waveform

2011 ◽  
Vol 301 (2) ◽  
pp. H382-H390 ◽  
Author(s):  
Christine Vayssettes-Courchay ◽  
Christophe Ragonnet ◽  
Marc Isabelle ◽  
Tony J. Verbeuren
Keyword(s):  
Nitric Oxide ◽  
Aortic Stiffness ◽  
Vascular Wall ◽  
Stiffness Index ◽  
Large Artery ◽  
Arterial Stiffening ◽  
Wall Properties ◽  
Wistar Kyoto ◽  
Echo Tracking

Large-artery stiffening is a major risk factor in aging and hypertension. Elevated blood pressure (BP) and vascular wall properties participate in arterial stiffening; we aimed to evaluate their respective role by combining echo-tracking and the spontaneously hypertensive rats (SHR) treated with low doses of a nitric oxide synthase inhibitor, shown to have arterial stiffening. Normotensive [Wistar-Kyoto (WKY)], SHR, and SHR treated for 2 wk with NG-nitro-l-arginine methyl ester (SHRLN) were anesthetized; BP and distension (pulsatile displacement) of the aortic walls with the ArtLab echo-tracking device were measured. Stiffness index increased in SHRLN vs. SHR; compliance, distensibility, and the slopes and area of the distension-pressure loop curve decreased. The pulsatile distension and pressure waveforms were strongly altered in SHRLN. Maximal values were decreased and increased, respectively, and the waveform kinetics also differed. Thus the area under the curve adjusted to heart rate (AUC/ms) was calculated. Acute BP reductions were induced by diltiazem in SHR and SHRLN, to levels similar to those of WKY. In SHR, compliance, distensibility, stiffness index, and the ascending slope of the distension-pressure loop reached the values of WKY, whereas they were only partially improved in SHRLN. Aortic distension (maximal value and AUC/ms) and the area of the distension-pressure loop were improved in SHR, but not in SHRLN. These data confirm the aortic stiffening induced by nitric oxide reduction in SHR. They show that the ArtLab system analyzes aortic stiffness in rats, and that the aortic pulsatile distension waveform is a parameter strongly dependent on the vascular wall properties.

scholarly journals Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall

2008 ◽  
Vol 295 (2) ◽  
pp. H499-H508 ◽  
Author(s):  
Wael F. Alzawahra ◽  
M. A. Hassan Talukder ◽  
Xiaoping Liu ◽  
Alexandre Samouilov ◽  
Jay L. Zweier
Keyword(s):  
Nitric Oxide ◽  
Heme Proteins ◽  
Soluble Guanylyl Cyclase ◽  
Vascular Wall ◽  
Rat Aorta ◽  
No Production ◽  
Paramagnetic Resonance ◽  
Physiological Importance

Nitric oxide (NO) has been shown to be the endothelium-derived relaxing factor (EDRF), and its impairment contributes to a variety of cardiovascular disorders. Recently, it has been recognized that nitrite can be an important source of NO; however, questions remain regarding the activity and mechanisms of nitrite bioactivation in vessels and its physiological importance. Therefore, we investigated the effects of nitrite on in vivo hemodynamics in rats and in vitro vasorelaxation in isolated rat aorta under aerobic conditions. Studies were performed to determine the mechanisms by which nitrite is converted to NO. In anesthetized rats, nitrite dose dependently decreased both systolic and diastolic blood pressure with a threshold dose of 10 μM. Similarly, nitrite (10 μM-2 mM) caused vasorelaxation of aortic rings, and NO was shown to be the intermediate factor responsible for this activity. With the use of electrochemical as well as electron paramagnetic resonance (EPR) spectroscopy techniques NO generation was measured from isolated aortic vessels following nitrite treatment. Reduction of nitrite to NO was blocked by heating the vessel, suggesting that an enzymatic process is involved. Organ chamber experiments demonstrated that aortic relaxation induced by nitrite could be blocked by both hemoglobin and soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). In addition, both electrochemical and EPR spin-trapping measurements showed that ODQ inhibits nitrite-mediated NO production. These findings thus suggest that nitrite can be a precursor of EDRF and that sGC or other heme proteins inhibited by ODQ catalyze the reduction of nitrite to NO.

Estimating oxygen transport resistance of the microvascular wall

2000 ◽  
Vol 279 (2) ◽  
pp. H657-H671 ◽  
Author(s):  
Arjun Vadapalli ◽  
Roland N. Pittman ◽  
Aleksander S. Popel
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Diffusion Model ◽  
Oxygen Transport ◽  
Vascular Wall ◽  
Nitric Oxide Production ◽  
Endothelial Surface

The problem of diffusion of O2 across the endothelial surface in precapillary vessels and its utilization in the vascular wall remains unresolved. To establish a relationship between precapillary release of O2 and vascular wall consumption, we estimated the intravascular flux of O2 on the basis of published in vivo measurements. To interpret the data, we utilized a diffusion model of the vascular wall and computed possible physiological ranges for O2 consumption. We found that many flux values were not consistent with the diffusion model. We estimated the mitochondrial-based maximum O2 consumption of the vascular wall (Mmt) and a possible contribution to O2 consumption of nitric oxide production by endothelial cells (MNO). Many values of O2 consumption predicted from the diffusion model exceeded Mmt + MNO. In contrast, reported values of O2consumption for endothelial and smooth muscle cell suspensions and vascular strips in vitro do not exceed Mmt. We conjecture that most of the reported values of intravascular O2 flux are overestimated, and the likely source is in the experimental estimates of convective O2 transport at upstream and downstream points of unbranched vascular segments.

scholarly journals Cerebral microvascular dilation during hypotension and decreased oxygen tension: a role for nNOS

2007 ◽  
Vol 293 (4) ◽  
pp. H2193-H2201 ◽  
Author(s):  
Holly D. Bauser-Heaton ◽  
H. Glenn Bohlen
Keyword(s):  
Nitric Oxide ◽  
Brain Tissue ◽  
Oxygen Tension ◽  
Vascular Wall ◽  
Vessel Diameter ◽  
Selective Blockade ◽  
Vascular Regulation ◽  
Cerebral Arterioles ◽  
Oxide Synthase

Endothelial (eNOS) and neuronal nitric oxide synthase (nNOS) are implicated as important contributors to cerebral vascular regulation through nitric oxide (NO). However, direct in vivo measurements of NO in the brain have not been used to dissect their relative roles, particularly as related to oxygenation of brain tissue. We found that, in vivo, rat cerebral arterioles had increased NO concentration ([NO]) and diameter at reduced periarteriolar oxygen tension (Po2) when either bath oxygen tension or arterial pressure was decreased. Using these protocols with highly selective blockade of nNOS, we tested the hypothesis that brain tissue nNOS could donate NO to the arterioles at rest and during periods of reduced perivascular oxygen tension, such as during hypotension or reduced local availability of oxygen. The decline in periarteriolar Po2 by bath manipulation increased [NO] and vessel diameter comparable with responses at similarly decreased Po2 during hypotension. To determine whether the nNOS provided much of the vascular wall NO, nNOS was locally suppressed with the highly selective inhibitor N-(4S)-(4-amino-5-[aminoethyl]aminopentyl)- N′-nitroguanidine. After blockade, resting [NO], Po2, and diameters decreased, and the increase in [NO] during reduced Po2 or hypotension was completely absent. However, flow-mediated dilation during occlusion of a collateral arteriole did remain intact after nNOS blockade and the vessel wall [NO] increased to ∼80% of normal. Therefore, nNOS predominantly increased NO during decreased periarteriolar oxygen tension, such as that during hypotension, but eNOS was the dominant source of NO for flow shear mechanisms.

scholarly journals Chronic NO Restriction in Hypertensive Rats Increases Abdominal but Not Thoracic Aortic Intrinsic Stiffness via an Augmentation in Profibrotic Materials

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
George Lindesay ◽  
Yvonnick Bézie ◽  
Christophe Ragonnet ◽  
Véronique Duchatelle ◽  
Marc Isabelle ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Dynamic Properties ◽  
Stiffness Index ◽  
Operating Pressure ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Spontaneously Hypertensive Rat Model

The spontaneously hypertensive rat model with reduced NO synthesis (SHRLN) shares features with aging and hypertension in humans, among other a severe aortic stiffening. The present in vivo study aimed to compare thoracic (TA) and abdominal (AA) aortic stiffness in the SHRLN (treated 5 weeks with L-NAME), SHR, and normotensive Wistar Kyoto (WKY). Dynamic properties of TA and AA were measured in the same rats, using echotracking recording of aortic diameter coupled with blood pressure (BP). Measurements were performed first at operating BP and then after BP reduction in hypertensive rats, thus in isobaric conditions. Histological staining and immunohistochemistry were used for structural analysis at both sites. At operating pressure, BP and pulse pressure (PP) were higher in SHRLN compared with SHR. Stiffness index was also increased and distensibility decreased in both TA and AA in SHRLN. At WKY-matched blood pressure, isobaric AA parameters remained specifically altered in SHRLN, whereas TA recovered to values identical to WKYs. Collagen, fibronectin, α5-selectin, and FAK were increased in SHRLN compared with SHR or WKY. Nevertheless, only the strong accumulations of fibronectin and collagen at the AA site in SHRLN were associated with intrinsic stiffening. In conclusion, we confirm that NO restriction associated with hypertension induces a severe pathological phenotype and shows that L-NAME induced stiffening is more pronounced in AA than in TA as a result of greater fibrosis.

Thrombin Does Not Alter Vascular Hyporeactivity in Models of Endotoxin-Induced Septic Shock in Rats

1995 ◽  
Vol 88 (2) ◽  
pp. 149-157 ◽  
Author(s):  
Viviane Martin ◽  
Marie-Louise Wiesel ◽  
Anne Albert ◽  
Alain Beretz
Keyword(s):  
Nitric Oxide ◽  
Disseminated Intravascular Coagulation ◽  
Vascular Tone ◽  
Endotoxic Shock ◽  
Vascular Wall ◽  
Anticoagulant Treatment ◽  
Intravascular Coagulation ◽  
Vascular Hyporeactivity

1. Hypotension and vascular hyporesponsiveness to vasoconstrictors are observed during endotoxic shock, and are associated with increased production of nitric oxide in the vascular wall. Disseminated intravascular coagulation is another feature of septicaemia. We hypothesized that thrombin generated during disseminated intravascular coagulation might modulate the changes in vascular tone induced by endotoxin. 2. Incubation of rat aortic rings for 4 h with α-thrombin (0.003–3.0 NIH units/ml) did not change their reactivity to noradrenaline. Incubation for 4 h with lipopolysaccharide increased the EC50 for noradrenaline, whereas co-incubation of thrombin (0.5 NIH units/ml) with lipopolysaccharide did not alter this hyporeactivity to noradrenaline. 3. In vivo in rats, lipopolysaccharide caused early (1 h) and late (4–6 h) hyporeactivity to noradrenaline. In rats infused with lipopolysaccharide and heparin (1 U min−1 kg−1, 0.4 ml/h) or hirudin (2.2 mg ml−1 kg−1, 0.8 ml/h), vasopressor responses to noradrenaline were not different from those after infusion of lipopolysaccharide alone. Aortic rings taken from rats receiving both anticoagulant treatment and lipopolysaccharide had the same sensitivity to noradrenaline as those obtained from rats receiving lipopolysaccharide alone. 4. Our results suggest that, in vivo, disseminated intravascular coagulation does not modify the early and late effects of lipopolysaccharide on arterial pressure and that, in vitro, thrombin neither induces hyporeactivity to noradrenaline nor modifies lipopolysaccharide-induced hyporeactivity. We propose that thrombin generated during disseminated intravascular coagulation in rats does not play a major role in the alterations of vascular tone observed during endotoxic shock.

Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)–deficient mice

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 136-142 ◽  
Author(s):  
Steffen Massberg ◽  
Sabine Grüner ◽  
Ildiko Konrad ◽  
Maisa I. Garcia Arguinzonis ◽  
Martin Eigenthaler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinases ◽  
Platelet Adhesion ◽  
Vascular Wall ◽  
Guanosine Monophosphate ◽  
Wild Type ◽  
Dependent Protein ◽  
Deficient Mice ◽  
Null Mutants

Abstract Platelet adhesion and activation at the vascular wall are the initial steps leading to arterial thrombosis and vascular occlusion. Prostacyclin and nitric oxide inhibit platelet adhesion, acting via cyclic adenosine monophosphate (cAMP)– and cyclic guanosine monophosphate (cGMP)–dependent protein kinases. A major downstream target for both cAMP- and cGMP-dependent protein kinases is the vasodilator-stimulated phosphoprotein (VASP). To test the significance of VASP for the regulation of platelet adhesion in vivo, we studied platelet–vessel wall interactions using VASP-deficient (VASP–/–) mice. Under physiologic conditions, platelet adhesion to endothelial cells was significantly enhanced in VASP null mutants when compared with wild-type mice (P < .05). Platelet recruitment in VASP null mice involved P-selectin and the fibrinogen receptor glycoprotein IIb-IIIa (GPIIb-IIIa). Under pathophysiologic conditions, the loss of VASP increased platelet adhesion to the postischemic intestinal microvasculature, to the atherosclerotic endothelium of ApoE-deficient mice, and to the subendothelial matrix following endothelial denudation (P < .05 vs wild type). Importantly, platelet adhesion in VASP null mutants was unresponsive to nitric oxide. These data show for the first time in vivo that VASP is involved in down-regulation of platelet adhesion to the vascular wall under both physiologic and pathophysiologic conditions.

Abstract 73: Pre- and Post-Translational Regulation of Lysyl Oxidase/β1-Intergrin in Aortic Vascular Smooth Cell of Hypertension

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Ben Ma ◽  
Ning Zhou ◽  
Shaunrick Stoll ◽  
Hongyu Qiu
Keyword(s):  
Translational Regulation ◽  
Aortic Stiffness ◽  
Amine Oxidase ◽  
Lysyl Oxidase ◽  
Aortic Pressure ◽  
Doppler Imaging ◽  
Stiffness Index ◽  
Causative Role ◽  
Gene And Protein Expression ◽  
Wistar Kyoto

Background: An increase in aortic stiffness is a fundamental component of hypertension . We previous showed that aortic vascular smooth muscle cells (VSMCs) play an causative role in aortic stiffening not only due to the increased intrinsic stiffness in VSMC itself but also due to its interaction with extracellular matrix (ECM). However, the molecular mechanism involved is unclear. Here, we test the hypothesis that the aortic VSMCs mediates pre- and post-translational regulation of Lysyl Oxidase (Lox)/β1intergrain pathway which may be one of the mechanisms of VSMCs-ECM remodeling in hypertension. Methods and Results: 4 months old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Aortic pressure and stiffness were measured with an invasive catheter and Doppler imaging echocardiography, respectively. Compared to WKY, SHR showed a significant higher aortic pressure (mean arterial pressure (MAP) 138.7±11.8 vs 102.7±7 mmHg, ( p <0.01) and a greater aorta stiffness reflected by 2.5-fold higher arterial stiffness index (ASI) in SHR vs WKY ( p <0.01). VSMCs were isolated from thoracic aorta, then cultured and measured at passages 2 to 4. Real time PCR and western blot were used to detect the gene and protein expression. Compared to WKY, VSMCs from SHR showed a significant increase in mRNA Lox, a copper-dependent amine oxidase mediating the crosslinking of collagens and elastin (2.7 folds vs WKY, p <0.01). The abundance of LOX protein was significant increased not only at pro-enzyme lox level, but also at the regulatory pro-peptide lox and matured active enzyme Lox in SHR VSMCs by 3.5 folds and 1.4 folds respectively ( p <0.01), indicating an increased post-translational regulation of LOX in SHR VSMCs. In addition, the glycosylated β1 integrin, a transmembrane receptor that facilitate cell-ECM adhesion, was found to be significant increase in SHR VSMCs vs WKY. Conclusion: The regulation of pre- and post-translational regulation of Lox/β1intergrain pathway in aortic VSMCs presents a novel mechanism of cell-ECM interaction, which may contribute to the increased aortic stiffness in SHR.

scholarly journals OR17-06 Transglutaminase 2 Inhibition Reduces Aortic Stiffness in Western Diet-Fed Female Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bhavana Chinnakotla ◽  
Camila Margarita Manrique Acevedo ◽  
Padilla Jaume ◽  
Makenzie L Woodford ◽  
Annayya R Aroor ◽  
...  
Keyword(s):  
Aortic Stiffness ◽  
Weight Control ◽  
Ex Vivo ◽  
Transglutaminase 2 ◽  
Competitive Inhibitor ◽  
Tolerance Test ◽  
Western Diet ◽  
Arterial Stiffening ◽  
Female Mice

Abstract Widespread consumption of diets high in fat, sugars and salt (Western diet, WD) is associated arterial stiffening, which is a major independent risk factor for cardiovascular disease (CVD). Notably, while WD feeding increases the risk of CVD in both males and females, the latter are more prone to develop arterial stiffening. However, the mechanisms underlying WD-induced arterial stiffening are poorly understood, particularly in females, and there are currently no specific treatments targeted at vascular stiffening.Tissue transglutaminase 2 (TG2) is an enzyme that mediates the cross-linking and stabilization of extracellular matrix proteins such as collagen, and promotes the polymerization of actin stress fibers of the cytoskeleton. It is ubiquitously expressed and abundantly present in the vasculature. Mounting evidence implicates TG2 activation in the pathogenesis of arterial stiffening and vascular fibrosis. Herein we propose that TG2 activation is central to WD-induced arterial stiffening and sought to determine the efficacy of cystamine (a non-specific competitive inhibitor of TG2) for reducing arterial stiffening in the setting of WD consumption. Accordingly, we fed 20 female mice (4 weeks old) a WD (4.65 kcal/g of food, fat 46% kcals, high-fructose corn syrup 17.5%, sucrose 17.5%, protein 17.6%, salt 1.6%) for 43 weeks. Ten of these mice received cystamine (40 mg/Kg/d in the drinking water) during their last 8 weeks on the WD. Another group of female mice (n=10) fed regular chow was used as reference controls. Aortic stiffness was measured in vivo via ultrasound-based pulse wave velocity and ex vivo by aortic explant atomic force microscopy. Vasomotor responses were assessed in isolated aortic rings via wire myography.Cystamine did not influence glucose homeostasis (intraperitoneal glucose tolerance test) or blood pressure (tail-cuff) (control 77.208±2.229 mm Hg versus WD 77.208±6.077 versus WD+Cystamine 76.297±7.894), but it was associated with increased body weight (control 26.860±2.215 grams versus WD 25.320±2.889 versus WD+Cystamine 33.220±4.848, p&lt;0.05). Notably, cystamine reduced aortic stiffness in WD-fed mice both in vivo and ex vivo such that differences between chow-fed and WD-fed mice were normalized (control 5.294±1.713 versus WD 11.735±5.962 p≤0.05, control 5.294±1.713 versus WD+Cystamine 3.940±0.378 KPa, p&lt;0.05). In addition, WD-induced impairments in endothelium-independent vasorelaxation (i.e. responses to sodium nitroprusside) were restored with cystamine. Collectively, our data show that cystamine reduces aortic stiffness and improves endothelium-independent vasorelaxation in female mice chronically exposed to WD, and that these effects occur despite an increase in weight gain. These findings implicate TG2 as a promising therapeutic target for reducing arterial stiffening in the context of chronic over-nutrition in females.

scholarly journals Noninvasive assessment of vascular structure and function in conscious rats based on in vivo imaging of the albino iris

2011 ◽  
Vol 300 (6) ◽  
pp. R1333-R1343 ◽  
Author(s):  
Harald M. Stauss ◽  
Kevin R. Rarick ◽  
Katie M. Leick ◽  
Jason W. Burkle ◽  
Diane L. Rotella ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Disease ◽  
In Vivo Imaging ◽  
Lumen Diameter ◽  
Albino Rats ◽  
Noninvasive Technique ◽  
Spontaneously Hypertensive ◽  
Conscious Rats ◽  
Wistar Kyoto

Experimental techniques allowing longitudinal studies of vascular disease progression or treatment effects are not readily available for most animal models. Thus, most existing studies are destined to either study individual time points or use large cohorts of animals. Here we describe a noninvasive technique for studying vascular disease that is based on in vivo imaging of the long posterior ciliary artery (LPCA) in the iris of albino rats. Using a slit-lamp biomicroscope, images of the LPCA were taken weekly in conscious normotensive Wistar Kyoto rats (WKY, n = 10) and spontaneously hypertensive rats (SHR, n = 10) for 10 wk. Using imaging software, we found that lumen diameter was significantly smaller and the wall-to-lumen (W/L) ratio larger in SHR than in WKY. Wall thickness was not different. Blood pressure correlated with the W/L ratio. Histology of the abdominal aorta also revealed a smaller lumen diameter and greater W/L ratio in SHR compared with WKY. Corneal application of the muscarinic receptor agonist pilocarpine elicited a dose-dependent vasodilation of the LPCA that could be antagonized by inhibition of nitric oxide synthase, suggesting that the pilocarpine response is mainly mediated by endothelium-derived nitric oxide. Consistent with endothelial dysfunction in SHR, pilocarpine-induced vasodilation was greater in WKY rats than in SHR. These findings indicate that in vivo imaging of the LPCA allows assessment of several structural and functional vascular parameters in conscious rats and that the LPCA responds to disease insults and pharmacologic treatments in a fashion that will make it a useful model for further studies.

scholarly journals Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide

2009 ◽  
Vol 297 (6) ◽  
pp. H2227-H2233 ◽  
Author(s):  
Xiaosun Zhou ◽  
H. Glenn Bohlen ◽  
Joseph L. Unthank ◽  
Steven J. Miller
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Spontaneously Hypertensive Rat ◽  
Oxidant Stress ◽  
Mesenteric Arteries ◽  
No Production ◽  
Aged Rats ◽  
Wistar Kyoto Rats ◽  
Wistar Kyoto

Previous work in our laboratory showed increased basal periarterial nitric oxide (NO) and H2O2 concentrations in the spontaneously hypertensive rat, characterized by oxidant stress, as well as impaired flow-mediated NO production that was corrected by a reduction of periarterial H2O2. Aging is also associated with an increase in vascular reactive oxygen species and results in abnormal vascular function. The current study was designed to assess the role of H2O2 in regulating NO production during vascular aging. In vivo, real-time NO and H2O2 concentrations were measured by microelectrodes in mesenteric arteries of retired breeder (aged; 8–12 mo) and young (2 to 3 mo) Wistar-Kyoto rats under conditions of altered flow. The results in aged rats revealed elevated basal NO (1,611 ± 286 vs. 793 ± 112 nM, P < 0.05) and H2O2 concentrations (16 ± 2 vs. 9 ± 1 μM, P < 0.05) and a flow-mediated increase in H2O2 but not NO production. Pretreatment of aged rats with the antioxidant apocynin lowered both basal H2O2 (8 ± 1 μM) and NO (760 ± 102 nM) to young levels and restored flow-mediated NO production. Similar results were obtained with the NAD(P)H oxidase inhibitor gp91ds-tat. In addition, acute incubation with topical polyethylene-glycolated catalase lowered the baseline NO concentration and restored flow-mediated NO production. Taken together, the data indicate that elevated baseline and suppressed flow-mediated NO production in aged Wistar-Kyoto rats are mediated by NAD(P)H oxidase-derived H2O2.

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