scholarly journals Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maria Giulia Battelli ◽  
Letizia Polito ◽  
Massimo Bortolotti ◽  
Andrea Bolognesi
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Second Messengers ◽  
Endothelial Activation ◽  
Reactive Species ◽  
Xanthine Oxidoreductase ◽  
Leukocyte Activation ◽  
Superoxide Ion ◽  
Cancer Pathology ◽  
Induce Mutagenesis

Xanthine oxidoreductase (XOR) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is widely distributed among species. In addition to this housekeeping function, mammalian XOR is a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various pathways. This review intends to address the physiological and pathological roles of XOR-derived oxidant molecules. The cytocidal action of XOR products has been claimed in relation to tissue damage, in particular damage induced by hypoxia and ischemia. Attempts to exploit this activity to eliminate unwanted cells via the construction of conjugates have also been reported. Moreover, different aspects of XOR activity related to phlogosis, endothelial activation, leukocyte activation, and vascular tone regulation, have been taken into consideration. Finally, the positive and negative outcomes concerning cancer pathology have been analyzed because XOR products may induce mutagenesis, cell proliferation, and tumor progression, but they are also associated with apoptosis and cell differentiation. In conclusion, XOR activity generates free radicals and other oxidant reactive species that may result in either harmful or beneficial outcomes.

scholarly journals Inorganic nitrate attenuates cardiac dysfunction: role for xanthine oxidoreductase and nitric oxide

2021 ◽  
Author(s):  
Lorna C. Gee ◽  
Gianmichele Massimo ◽  
Clement Lau ◽  
Christopher Primus ◽  
Daniel Fernandes ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Dysfunction ◽  
Xanthine Oxidoreductase ◽  
Inorganic Nitrate

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

2007 ◽  
Vol 293 (5) ◽  
pp. L1261-L1270 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Mark R. Girton ◽  
Matthew J. Metropoulus ◽  
Mandar S. Joshi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Vascular Tone ◽  
Age Groups ◽  
Soluble Guanylyl Cyclase ◽  
No Production ◽  
Sprague Dawley ◽  
No Donor ◽  
Early Postnatal Development ◽  
Old Rats

Nitric oxide (NO) is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7- and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine augmented the K+-induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-day-old rats. Vasodilation to 0.1 μM of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 μM of the cGMP analog 8-(4-chlorophenylthio)guanosine-3′,5′-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels.

Abstract 530: Decreased NSF S-Nitrosylation in the Aorta and an Age-Dependent Endothelial Activation in Mice with Fabry Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Justin J Kang ◽  
Liming Shu ◽  
Karl C Desch ◽  
Peter F Bodary ◽  
James A Shayman
Keyword(s):  
Nitric Oxide ◽  
Fabry Disease ◽  
Endothelial Activation ◽  
Lysosomal Storage ◽  
Agarose Beads ◽  
Endothelial Inflammation ◽  
Enos Uncoupling ◽  
Age Dependent ◽  
The Many ◽  
Main Component

Fabry disease is an X-linked lysosomal storage disorder caused by loss of activity of the enzyme, α-galactosidase A (GLA). The loss of GLA function leads to an age-dependent accumulation of globotriaosylceramide (Gb3) in endothelial cells. Endothelial Gb3 accumulation is associated with endothelial nitric oxide synthase (eNOS) uncoupling and decreased nitric oxide (NO) bioavailability. We hypothesized that GLA deficiency promotes endothelial inflammation. von Willebrand factor (VWF) is the main component of Weibel Palade bodies (WPB) and is secreted upon endothelial inflammation. We observed significantly elevated plasma VWF in GLA null mice (FA) compared to age-matched Wild-Type mice (WT) (p=0.046 at 2 months and p<0.001 at 5 and 17 months), indicating increased endothelial inflammation in FA. Out of the many proteins that regulate WPB exocytosis, N-ethylmaleimide sensitive factor (NSF) is a critical mediator of the exocytic machinery and a major target of NO. NO can reversibly modify NSF cysteine residues via a process called S-nitrosylation (SNO), leading to decreased WPB exocytosis. To evaluate whether GLA deficiency promotes a decrease in SNO-NSF, nitrosylated cysteines of aortic homogenates from male WT and FA were first labeled with biotin through a biotin switch assay. Next, biotinylated proteins were isolated with streptavidin-agarose beads. We observed an approximately 60% decrease in the level of SNO-NSF in the aorta of FA compared to that of WT by Western blot (WT vs. Fabry: 1.0±0.03 vs. 0.4±0.11, p=0.002, n=4-5/group) whereas total protein expression of NSF and GAPDH were not different between groups. The level of thioredoxin-1 (TRX-1) was significantly elevated in FA compared to WT (WT vs. Fabry: 1.0±0.05 vs. 1.4±0.14, p=0.01, n=6-9/group), suggesting high levels of reactive oxygen species and protein denitrosylase activity in Fabry disease. In conclusion, these results provide evidence of endothelial activation in Fabry disease. GLA deficiency resulted in decreased SNO-NSF and increased TRX-1 in parallel with the robust elevation of VWF. Future study is required for further understanding of the mechanistic links between these observations, and to determine whether this is a reversible phenomenon in the setting of Fabry disease.

Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone

2004 ◽  
Vol 286 (1) ◽  
pp. H230-H239 ◽  
Author(s):  
Yuan-Lin Dong ◽  
Sujatha Vegiraju ◽  
Madhu Chauhan ◽  
Pandu R. R. Gangula ◽  
Gary D. V. Hankins ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Human Placenta ◽  
Vascular Tone ◽  
Umbilical Artery ◽  
Force Measurement ◽  
Isometric Force ◽  
Calcitonin Gene Related Peptide ◽  
Immunofluorescent Staining ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP), one of the most potent endogenous vasodilators known, has been implicated in vascular adaptations and placental functions during pregnancy. The present study was designed to examine the existence of CGRP-A receptor components, the calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 1 (RAMP1), in the human placenta and the vasoactivity of CGRP in the fetoplacental circulation. Immunofluorescent staining of the human placenta in term labor using polyclonal anti-CRLR and RAMP1 antibodies revealed that labeling specifically concentrated in the vascular endothelium and the underlying smooth muscle cells in the umbilical artery/vein, chorionic artery/vein, and stem villous vessels as well as in the trophoblast layer of the placental villi. In vitro isometric force measurement showed that CGRP dose dependently relaxes the umbilical artery/vein, chorionic artery/vein, and stem villous vessels. Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8–37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor ( Nω-nitro-l-arginine methyl ester). We propose that CGRP may play a role in the control of human fetoplacental vascular tone, and the vascular dilations in response to CGRP may involve activation of KATP channels, cAMP, and a nitric oxide pathway.

Tonic regulation of vascular tone by nitric oxide and chloride ions in rat isolated small coronary arteries

2000 ◽  
Vol 279 (6) ◽  
pp. H2604-H2611 ◽  
Author(s):  
Jonathan E. Graves ◽  
Iain A. Greenwood ◽  
William A. Large
Keyword(s):  
Nitric Oxide ◽  
Coronary Arteries ◽  
Vascular Tone ◽  
Physiological Saline ◽  
Chloride Ions ◽  
Bathing Solution ◽  
Contractile Mechanism ◽  
Mechanical Removal ◽  
Voltage Dependent ◽  
Physiological Saline Solution

We have investigated the involvement of Cl− in regulating vascular tone in rat isolated coronary arteries mounted on a small vessel myograph. Mechanical removal of the endothelium or inhibition of nitric oxide (NO) synthase with N ω-nitro-l-arginine methyl ester (l-NAME, 10−4 M) led to contraction of rat coronary arteries, and these contractions were sensitive to nicardipine (10−6 M). This suggests that release of NO tonically inhibits a contractile mechanism that involves voltage-dependent Ca2+ channels. In arteries contracted withl-NAME, switching the bathing solution to physiological saline solution with a reduced Cl− concentration potentiated the contraction. DIDS (5 × 10−6–3 × 10−4 M) caused relaxation of l-NAME-induced tension (IC50 = 55 ± 10 μM), providing evidence for a role of Cl−. SITS (10−5–5 × 10−4 M) did not affectl-NAME-induced tension, suggesting that DIDS is not acting by inhibition of anion exchange. Mechanical removal of the endothelium led to contraction of arteries, which was sensitive to DIDS (IC50 = 50 ± 8 μM) and was not affected by SITS. This study suggests that, in rat coronary arteries, NO tonically suppresses a contractile mechanism that involves a Cl−conductance.

scholarly journals Control of coronary vascular tone by nitric oxide.

1990 ◽  
Vol 66 (6) ◽  
pp. 1561-1575 ◽  
Author(s):  
M Kelm ◽  
J Schrader
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Coronary Vascular Tone

scholarly journals EvidenceIn VivoShowing Increase of Baseline Nitric Oxide Generation and Impairment of Endothelium-Dependent Vasodilation in Normotensive Patients on Chronic Hemodialysis

2000 ◽  
Vol 11 (9) ◽  
pp. 1726-1734 ◽  
Author(s):  
JENS PASSAUER ◽  
ECKHART BÜSSEMAKER ◽  
URSULA RANGE ◽  
MARIA PLUG ◽  
PETER GROSS
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Forearm Blood Flow ◽  
Matched Control ◽  
Venous Occlusion ◽  
Chronic Hemodialysis ◽  
Invasive Technique ◽  
Vascular Effects ◽  
Control Subjects ◽  
Pharmacologic Agents

Abstract.Cardiovascular mortality is excessive in hemodialyzed patients. Observations in atherosclerosis suggest that endothelial dysfunction and impaired nitric oxide (NO) may be involved. However, the relation of endothelial NO to its vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive patients who were on hemodialysis (HD;n= 11) and in matched control subjects (n= 11). Pharmacologic agents were infused into the brachial artery to test the chain of events from NO generation to smooth muscle cell relaxation, measuring forearm blood flow by venous occlusion plethysmography. Glyceroltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establish the reaction of the vessel wall to defined doses of NO, caused a reduced response in HD patients (control subjects: 183 ± 20 [SEM], 246 ± 26, and 338 ± 29%; HD patients: 161 ± 7, 206 ± 12, and 262 ± 24%; baseline = 100% for each group,P= 0.032 by ANOVA). All subsequent data were corrected for this decreased response to defined doses of NO in HD patients. L-arginine (10 mg/min), given to exclude substrate deficiency of NO synthase (NOS), caused no significant changes (control subjects: 108 ± 4%; HD patients: 103 ± 4%;P= NS). Acetylcholine (ACH 1:55 nmol/min; ACH 2:110; ACH 3:220), infused to stimulate endothelial NOS, had a significantly reduced effect in HD patients (control subjects: 246 ± 32, 340 ± 40, and 465 ± 52%; HD patients: 251 ± 55, 244 ± 36, and 318 ± 50%;P= 0.002).N-monomethyl-L-arginine (LMA 1:1 μmol/min; LMA 2:2; LMA 3:4), given to block baseline NO generation, showed an enhanced response in HD patients (control subjects: 90 ± 2, 83 ± 2, and 74 ± 4%; HD patients: 84 ± 3, 73 ± 3, and 64 ± 4%;P= 0.037). Vascular response to three doses of norepinephrine (60, 120, and 240 pmol/min) was comparable in both groups, which indicated similar endothelium-independent vasoconstriction. In summary, in normotensive HD patients, (1) vasodilation to defined doses of exogenous NO was reduced, (2) there was no evidence of substrate deficiency of NOS, and (3) stimulation of NOS was impaired; however, (4) baseline NO generation was increased. It is concluded that in HD patients, the NO system has a reduced capacity to regulate vascular tone and this impairment is most significant under conditions of NOS stimulation.

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