Determinants of renal afferent arteriolar actions of bradykinin: evidence that multiple pathways mediate responses attributed to EDHF

2003 ◽  
Vol 285 (3) ◽  
pp. F540-F549 ◽  
Author(s):  
Xuemei Wang ◽  
Greg Trottier ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Afferent Arteriole ◽  
Ang Ii ◽  
Epoxyeicosatrienoic Acid ◽  
Nitric Oxide Synthase Inhibitor ◽  
Afferent Arterioles ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Arteriolar Vasodilation

The determinants of bradykinin (BK)-induced afferent arteriolar vasodilation were investigated in the in vitro perfused hydronephrotic rat kidney. BK elicited a concentration-dependent vasodilation of afferent arterioles that had been preconstricted with ANG II (0.1 nmol/l), but this dilation was transient in character. Pretreatment with the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (100 μmol/l) and the cyclooxygenase inhibitor ibuprofen (10 μmol/l) did not prevent this dilation when tone was established by ANG II but fully blocked the response when tone was established by elevated extracellular KCl, which suggests roles for both NO and endothelium-derived hyperpolarizing factor (EDHF). We had previously shown that the EDHF-like response of the afferent arteriole evoked by ACh was fully abolished by a combination of charybdotoxin (ChTX;10 nmol/l) and apamin (AP; 1 μmol/l). However, in the current study, treatment with ChTX plus AP only reduced the EDHF-like component of the BK response from 98 ± 5 to 53 ± 6% dilation. Tetraethylammonium (TEA; 1 mmol/l), which had no effect on the EDHF-induced vasodilation associated with ACh, reduced the EDHF-like response to BK to 88 ± 3% dilation. However, the combination of TEA plus ChTX plus AP abolished the response (0.3 ± 1% dilation). Similarly, 17-octadecynoic acid (17-ODYA) did not prevent the dilation when it was administered alone (77 ± 9% dilation) but fully abolished the EDHF-like response when added in combination with ChTX plus AP (-0.5 ± 4% dilation). These findings suggest that BK acts via multiple EDHFs: one that is similar to that evoked by ACh in that it is blocked by ChTX plus AP, and a second that is blocked by either TEA or 17-ODYA. Our finding that a component of the BK response is sensitive to TEA and 17-ODYA is consistent with previous suggestions that the EDHF released by BK is an epoxyeicosatrienoic acid.

Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2

2005 ◽  
Vol 288 (1) ◽  
pp. F65-F75 ◽  
Author(s):  
Xuemei Wang ◽  
Morley D. Hollenberg ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Combined Treatment ◽  
Afferent Arteriole ◽  
Vasodilatory Response ◽  
Signaling Mechanisms ◽  
Afferent Arterioles ◽  
Arteriolar Vasodilation ◽  
Dependent Mechanism ◽  
Stimulation Of

We previously demonstrated that stimulation of proteinase-activated receptor-2 (PAR-2) by SLIGRL-NH2 elicits afferent arteriolar vasodilation, in part, by elaborating nitric oxide (NO), suggesting an endothelium-dependent mechanism (Trottier G, Hollenberg M, Wang X, Gui Y, Loutzenhiser K, and Loutzenhiser R. Am J Physiol Renal Physiol 282: F891–F897, 2002). In the present study, we characterized the NO-independent component of this response, using the in vitro perfused hydronephrotic rat kidney. SLIGRL-NH2 (10 μmol/l) dilated afferent arterioles preconstricted with ANG II, and the initial transient component of this response was resistant to NO synthase (NOS) and cyclooxygenase inhibition. This NO-independent response was not prevented by treatment with 10 nmol/l charybdotoxin and 1 μmol/l apamin, a manipulation that prevents the endothelium-derived hyperpolarizing factor (EDHF)-like response of the afferent arteriole to acetylcholine, nor was it blocked by the addition of 1 mmol/l tetraethylammonium (TEA) or 50 μmol/l 17-octadecynoic acid, treatments that block the EDHF-like response to bradykinin. To determine whether the PAR-2 response additionally involves the electrogenic Na+-K+-ATPase, responses were evaluated in the presence of 3 mmol/l ouabain. In this setting, SLIGRL-NH2 induced a biphasic dilation in control and a transient response after NOS inhibition. The latter was not prevented by charybdotoxin plus apamin or by TEA alone but was abolished by combined treatment with charybdotoxin, apamin, and TEA. This treatment did not prevent the NO-dependent dilation evoked in the absence of NOS inhibition. Our findings indicate a remarkable redundancy in the signaling cascade mediating PAR-2 -induced afferent arteriolar vasodilation, suggesting an importance in settings such as inflamation or ischemia, in which vascular mechanisms might be impaired and the PAR system is thought to be activated.

PAR-2 elicits afferent arteriolar vasodilation by NO-dependent and NO-independent actions

2002 ◽  
Vol 282 (5) ◽  
pp. F891-F897 ◽  
Author(s):  
Greg Trottier ◽  
Morley Hollenberg ◽  
Xuemei Wang ◽  
Yu Gui ◽  
Kathy Loutzenhiser ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Peptide Sequence ◽  
Afferent Arteriole ◽  
Proteinase Activated Receptors ◽  
Normal Rat ◽  
Afferent Arterioles ◽  
Arteriolar Vasodilation ◽  
G Protein Coupled ◽  
Arteriolar Diameter

Proteinase-activated receptors (PARs) are a novel class of G protein-coupled receptors that respond to signals through endogenous proteinases. PAR activation involves enzymatic cleavage of the extracellular NH2-terminal domain and unmasking of a new NH2 terminus, which serves as an anchored ligand to activate the receptor. At least four PAR subtypes have been identified. In the present study, we used the in vitro perfused hydronephrotic rat kidney to examine the effects of activating PAR-2 on the afferent arteriole. The synthetic peptide SLIGRL-NH2, which corresponds to the exposed ligand sequence and selectively activates PAR-2, did not alter basal afferent arteriolar diameter but caused a concentration-dependent vasodilation (3–30 μM) of arterioles preconstricted by angiotensin II (0.1 nM). A modified peptide sequence (LSIGRL-NH2, inactive at PAR-2) had no effect. This vasodilation was characterized by an initial transient component followed by a smaller sustained response. A similar pattern of vasodilation was seen when SLIGRL-NH2 was administered to isolated perfused normal rat kidney. The sustained component of the PAR-2-induced afferent arteriolar vasodilation was eliminated by nitric oxide (NO) synthase inhibition (100 μM nitro-l-arginine methyl ester). In contrast, the transient vasodilation persisted under these conditions. This transient response was not observed when afferent arterioles were preconstricted with elevated KCl, suggesting involvement of an endothelium-derived hyperpolarizing factor. Finally, RT-PCR revealed the presence of PAR-2 mRNA in isolated afferent arterioles. These findings indicate that PAR-2 is expressed in the afferent arteriole and that its activation elicits afferent arteriolar vasodilation by NO-dependent and NO-independent mechanisms.

Glomerular and tubular interactions between renal adrenergic activity and nitric oxide

1995 ◽  
Vol 268 (6) ◽  
pp. F1004-F1008 ◽  
Author(s):  
F. B. Gabbai ◽  
S. C. Thomson ◽  
O. Peterson ◽  
L. Wead ◽  
K. Malvey ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Glomerular Filtration ◽  
Renal Nerves ◽  
Ang Ii ◽  
Nitric Oxide Synthase Inhibitor ◽  
Adrenergic Activity ◽  
Single Nephron ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5–9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

Abstract 18060: TRAIL Promotes Angiogenesis and Ischemia-Induced Neovascularisation via NOX4, H2O2 and Nitric Oxide-Dependent Mechanisms

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Belinda A Di Bartolo ◽  
Sian P Cartland ◽  
Leonel Prado-Lourenco ◽  
Nor Saadah M Azahri ◽  
Thuan Thai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiogenic Factor ◽  
Tubule Formation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Therapeutic Implications ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
First Time

Background: Angiogenesis and neovascularization are essential processes that follow ischemia insults. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) not only induces endothelial cell (EC) death and inhibits angiogenesis, but also promotes EC migration, invasion and proliferation in vitro . These seemingly opposite effects make its role in angiogenesis in vivo unclear. Using TRAIL -/- and wild-type mice, we sought to determine the role of TRAIL in angiogenesis and neovascularisation. We also sought mechanisms in vitro . Methods and Results: Reduced vascularisation assessed by real-time in vivo 3D Vevo ultrasound imaging and CD31 staining was observed in TRAIL -/- mice 28 d after hindlimb ischemia. Moreover, reduced capillary formation and increased apoptosis was evident in TRAIL -/- muscles even at 3 d after ischemic surgery. We have previously shown that fibroblast growth factor-2 (FGF-2), a potent angiogenic factor, regulates TRAIL gene expression in vascular smooth muscle cells. Indeed, FGF-2 also regulates TRAIL expression in ECs, and FGF-2-inducible proliferation, migration and tubule formation was inhibited with siRNA targeting TRAIL. Notably, both FGF-2 and TRAIL significantly increased NOX4 expression. TRAIL-inducible angiogenic activity in ECs was inhibited with siRNAs targeting NOX4, and consistent with these, NOX4 mRNA was reduced in 3 d ischemic hindlimbs of TRAIL -/- mice. TRAIL stimulated intracellular H 2 O 2 levels in ECs, and TRAIL-inducible proliferation, migration and tubule formation was inhibited with not only PEG-catalase, a H 2 O 2 scavenger, but also blocked with L-NAME, a nitric oxide synthase inhibitor. Conclusions: This is the first demonstration showing that TRAIL promotes angiogenesis in vivo . We show for the first time that the TRAIL stimulates NOX4 expression to mediate nitric oxide-dependent angiogenic effects. This has significant therapeutic implications such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with CVD and diabetes.

Modulation of vascular tone in renal microcirculation by erythrocytes: role of EDRF

1993 ◽  
Vol 264 (1) ◽  
pp. H190-H195 ◽  
Author(s):  
J. D. Imig ◽  
D. Gebremedhin ◽  
D. R. Harder ◽  
R. J. Roman
Keyword(s):  
Vascular Tone ◽  
Physiological Salt Solution ◽  
Nitric Oxide Synthase Inhibitor ◽  
Renal Microcirculation ◽  
Vasoconstrictor Response ◽  
A Cell ◽  
Afferent Arterioles ◽  
Synthase Inhibitor

The effect of erythrocytes (red blood cells, RBC) on vascular tone in the renal microcirculation was examined using the juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. The basal diameters of the arcuate, interlobular, proximal, and distal afferent arterioles averaged 444 +/- 24, 74 +/- 3, 29 +/- 1, and 19 +/- 1 micron, respectively, when perfused with a cell-free solution at a pressure of 80 mmHg. The diameters of the arcuate and interlobular arteries increased by 14 +/- 4 and 13 +/- 4%, respectively, whereas the diameter of the proximal and distal portions of the afferent arterioles decreased by 7 +/- 2% when perfusion pressure was elevated from 80 to 160 mmHg. The addition of RBC to the perfusate reduced the basal diameters of interlobular and afferent arterioles by 11 +/- 4 and 15 +/- 3%, respectively. The maximal vasoconstrictor response was seen after the addition of only 1% RBC to the perfusate. Removal of platelets did not block the vasoconstrictor response to addition of RBC to the perfusate. The role of endothelium-derived relaxing factor (EDRF) in the vasoconstrictor response to RBC was studied by addition of nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NNA, 100 microM) to the perfusate. L-NNA reduced the basal diameters of interlobular and afferent arterioles by 7 +/- 3 and 9 +/- 3%, respectively, and abolished the vasoconstrictor response to RBC. L-NNA had no effect on the pressure-diameter relationships of the preglomerular vasculature when added to perfusates already containing RBC.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent arteriolar adenosine A2a receptors are coupled to KATP in in vitro perfused hydronephrotic rat kidney

1999 ◽  
Vol 277 (6) ◽  
pp. F926-F933 ◽  
Author(s):  
Lilong Tang ◽  
Michael Parker ◽  
Qing Fei ◽  
Rodger Loutzenhiser
Keyword(s):  
Rat Kidney ◽  
Afferent Arteriole ◽  
Adenosine A2a Receptors ◽  
A2a Receptors ◽  
High Affinity ◽  
Vasodilatory Response ◽  
Renal Microvasculature ◽  
Adenosine A2a ◽  
Arteriolar Vasodilation

Adenosine is known to exert dual actions on the afferent arteriole, eliciting vasoconstriction, by activating A1 receptors, and vasodilation at higher concentrations, by activating lower-affinity A2 receptors. We could demonstrate both of these known adenosine responses in the in vitro perfused hydronephrotic rat kidney. Thus, 1.0 μM adenosine elicited a transient vasoconstriction blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and 10–30 μM adenosine reversed KCl-induced vasoconstriction. However, when we examined the effects of adenosine on pressure-induced afferent arteriolar vasoconstriction, we observed a third action. In this setting, a high-affinity adenosine vasodilatory response was observed at concentrations of 10–300 nM. This response was blocked by both 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM-241385) and glibenclamide and was mimicked by 2-phenylaminoadenosine (CV-1808) (IC50 of 100 nM), implicating adenosine A2a receptors coupled to ATP-sensitive K channels (KATP). Like adenosine, 5′- N-ethylcarboxamidoadenosine (NECA) elicited both glibenclamide-sensitive and glibenclamide-insensitive vasodilatory responses. The order of potency for the glibenclamide-sensitive component was NECA > adenosine = CV-1808. Our findings suggest that, in addition to the previously described adenosine A1 and low-affinity A2b receptors, the renal microvasculature is also capable of expressing high-affinity adenosine A2areceptors. This renal adenosine receptor elicits afferent arteriolar vasodilation at submicromolar adenosine levels by activating KATP.

In vivo production of nitric oxide correlates with NMDA-induced cerebral hyperemia in newborn sheep

1995 ◽  
Vol 269 (1) ◽  
pp. H215-H221 ◽  
Author(s):  
F. J. Northington ◽  
J. R. Tobin ◽  
R. C. Koehler ◽  
R. J. Traystman
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Production ◽  
Nitric Oxide Synthase Inhibitor ◽  
Oxide Production ◽  
Adenosine Receptor Agonist ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Hydrogen Clearance

Stimulation of N-methyl-D-aspartate (NMDA) receptors in brain increases nitric oxide production in vitro. We tested the hypothesis that nitric oxide participates in the increase in local cerebral blood flow (CBF) caused by infusion of NMDA in anesthetized newborn sheep. We used the combined hydrogen clearance and microdialysis technique for simultaneous measurement of local CBF, infusion of drugs, and measurement of interstitial levels of L-[14C]citrulline in the parietal cortex. Release of L-[14C]citrulline into the dialysate during continuous infusion of L-[14C]arginine was used as a marker of nitric oxide production in vivo. Citrulline recovery and CBF were measured hourly during a 4-h infusion of cerebrospinal fluid containing either 1) no additional drugs, 2) 1 mM NMDA, 3) 1 mM NG-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), 4) 1 mM NMDA + 1 mM L-NAME, 5) 0.1 mM 2-chloroadenosine (adenosine receptor agonist), or 6) 0.1 mM 2-chloroadenosine + 1 mM L-NAME. At 240 min of perfusion, CBF (ml.min-1.100 g-1; means +/- SE) was as follows: control 52 +/- 3, NMDA 116 +/- 11, L-NAME 32 +/- 5, NMDA+L-NAME 40 +/- 4,2-chloroadenosine 201 +/- 63, and 2-chloroadenosine+L-NAME 129 +/- 18. Citrulline recovery (fmol/min) at 240 min of perfusion was as follows: control 38 +/- 12, NMDA 149 +/- 21, L-NAME 9 +/- 1, NMDA+L-NAME 39 +/- 5, 2-chloroadenosine 13 +/- 5, and 2-chloroadenosine+L-NAME 17 +/- 1.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of CYP epoxygenases in A2AAR-mediated relaxation using A2AAR-null and wild-type mice

2008 ◽  
Vol 295 (5) ◽  
pp. H2068-H2078 ◽  
Author(s):  
Mohammed A. Nayeem ◽  
Samuel M. Poloyac ◽  
John R. Falck ◽  
Darryl C. Zeldin ◽  
Catherine Ledent ◽  
...  
Keyword(s):  
Epoxyeicosatrienoic Acid ◽  
Wild Type ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cgs 21680 ◽  
Sch 58261 ◽  
Specific Antagonist ◽  
Synthase Inhibitor ◽  
Mouse Aorta ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We hypothesized that A2A adenosine receptor (A2AAR) activation causes vasorelaxation through cytochrome P-450 (CYP) epoxygenases and endothelium-derived hyperpolarizing factors, whereas lack of A2AAR activation promotes vasoconstriction through Cyp4a in the mouse aorta. Adenosine 5′- N-ethylcarboxamide (NECA; 10−6 M), an adenosine analog, caused relaxation in wild-type A2AAR (A2AAR+/+; +33.99 ± 4.70%, P < 0.05) versus contraction in A2AAR knockout (A2AAR−/−; −27.52 ± 4.11%) mouse aortae. An A2AAR-specific antagonist (SCH-58261; 1μM) changed the NECA (10−6 M) relaxation response to contraction (−35.82 ± 4.69%, P < 0.05) in A2AAR+/+ aortae, whereas no effect was noted in A2AAR−/− aortae. Significant contraction was seen in the absence of the endothelium in A2AAR+/+ (−2.58 ± 2.25%) aortae compared with endothelium-intact aortae. An endothelial nitric oxide synthase inhibitor ( N-nitro-l-arginine methyl ester; 100 μM) and a cyclooxygenase inhibitor (indomethacin; 10 μM) failed to block NECA-induced relaxation in A2AAR+/+ aortae. A selective inhibitor of CYP epoxygenases (methylsulfonyl-propargyloxyphenylhexanamide; 10 μM) changed NECA-mediated relaxation (−22.74 ± 5.11% at 10−6 M) and CGS-21680-mediated relaxation (−18.54 ± 6.06% at 10−6 M) to contraction in A2AAR+/+ aortae, whereas no response was noted in A2AAR−/− aortae. Furthermore, an epoxyeicosatrienoic acid (EET) antagonist [14,15-epoxyeicosa-5( Z)-enoic acid; 10 μM] was able to block NECA-induced relaxation in A2AAR+/+ aortae, whereas ω-hydroxylase inhibitors (10 μM dibromo-dodecenyl-methylsulfimide and 10 μM HET-0016) changed contraction into relaxation in A2AAR−/− aorta. Cyp2c29 protein was upregulated in A2AAR+/+ aortae, whereas Cyp4a was upregulated in A2AAR−/− aortae. Higher levels of dihydroxyeicosatrienoic acids (DHETs; 14,15-DHET, 11,12-DHET, and 8,9-DHET, P < 0.05) were found in A2AAR+/+ versus A2AAR−/− aortae. EET levels were not significantly different between A2AAR+/+ and A2AAR−/− aortae. It is concluded that CYP epoxygenases play an important role in A2AAR-mediated relaxation, and the deletion of the A2AAR leads to contraction through Cyp4a.

Nebivolol-induced vasodilation of renal afferent arterioles involves β3-adrenergic receptor and nitric oxide synthase activation

2012 ◽  
Vol 303 (5) ◽  
pp. F775-F782 ◽  
Author(s):  
Ming-Guo Feng ◽  
Minolfa C. Prieto ◽  
L. Gabriel Navar
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Soluble Guanylate Cyclase ◽  
Adrenergic Blocker ◽  
Afferent Arterioles ◽  
Renal Microvasculature ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Arteriolar Vasodilation

Nebivolol is a β1-adrenergic blocker that also elicits renal vasodilation and increases the glomerular filtration rate (GFR). However, its direct actions on the renal microvasculature and vasodilator mechanism have not been established. We used the in vitro blood-perfused juxtamedullary nephron technique to determine the vasodilator effects of nebivolol and to test the hypothesis that nebivolol induces vasodilation of renal afferent arterioles via an nitric oxide synthase (NOS)/nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway and the afferent arteriolar vasodilation effect may be mediated through the release of NO by activation of NOS via a β3-adrenoceptor-dependent mechanism. Juxtamedullary nephrons were superfused with nebivolol either alone or combined with the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or the NOS inhibitor Nω-nitro-l-arginine (l-NNA) or the β-blockers metoprolol (β1), butoxamine (β2), and SR59230A (β3). Nebivolol (100 μmol/l) markedly increased afferent and efferent arteriolar diameters by 18.9 ± 3.0 and 15.8 ± 1.8%. Pretreatment with l-NNA (1,000 μmol/l) or ODQ (10 μmol/l) decreased afferent vasodilator diameters and prevented the vasodilator effects of nebivolol (2.0 ± 0.2 and 2.4 ± 0.6%). Metoprolol did not elicit significant changes in afferent vasodilator diameters and did not prevent the effects of nebivolol to vasodilate afferent arterioles. However, treatment with SR59230A, but not butoxamine, markedly attenuated the vasodilation responses to nebivolol. Using a monoclonal antibody to β3-receptors revealed predominant immunostaining on vascular and glomerular endothelial cells. These data indicate that nebivolol vasodilates both afferent and efferent arterioles and that the afferent vasodilator effect is via a mechanism that is independent of β1-receptors but is predominantly mediated via a NOS/NO/sGC/cGMP-dependent mechanisms initiated by activation of endothelial β3-receptors.

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