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  • Intratracheal injection of nitric oxide, generated from air by pulsed electrical discharge, for the treatment of pulmonary hypertension in awake ambulatory lambs
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-23
    Binglan Yu; Francesco Zadek; Anna Fischbach; Steffen B. Wiegand; Lorenzo Berra; Donald B. Bloch; Warren M. Zapol

    Objectives To test the feasibility, safety, and efficacy of intratracheal delivery of nitric oxide (NO) generated from air by pulsed electrical discharge via a Scoop catheter. Study design We studied healthy 3- to 4-month-old lambs weighing 34 ± 4 kg (mean ± SD, n = 6). A transtracheal Scoop catheter was inserted through a cuffed tracheostomy tube. U46619 was infused to increase mean pulmonary arterial pressure (mPAP) from 16 ± 1 to 32 ± 3 mmHg (mean ± SD). Electrically generated NO was delivered via the Scoop catheter to awake lambs. A sampling line, to monitor NO and nitrogen dioxide (NO2) levels, was placed in the distal trachea of the lambs. The effect of varying doses of electrically generated NO, produced continuously, on pulmonary hypertension was assessed. Results In awake lambs with acute pulmonary hypertension, NO was continuously delivered via the Scoop catheter at 400 ml/min. NO induced pulmonary vasodilation. NO2 levels, measured in the trachea, were below 0.5 ppm at intratracheal NO doses of 10–80 ppm. No changes were detected in the levels of methemoglobin in blood samples before and after 5 min of NO breathing. Conclusions Continuously delivering electrically generated NO through a Scoop catheter produces vasodilation of the pulmonary vasculature of awake lambs with pulmonary hypertension. Transtracheal NO delivery may provide a long-term treatment for patients with chronic pulmonary hypertension as an outpatient without requiring a mask or tracheal intubation.

  • Poor glycemic control impairs the cardioprotective effects of red blood cells on myocardial ischemia/reperfusion injury
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-22
    Johanna M. Muessig; Luise Moellhoff; Johanna Noelle; Sema Kaya; Leonie Hidalgo Pareja; Maryna Masyuk; Michael Roden; Malte Kelm; Christian Jung
  • 更新日期:2020-01-21
  • Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-16
    Yang Liu; Kevin D. Croft; Jonathan M. Hodgson; Trevor Mori; Natalie C. Ward

    Within the body, NO is produced by nitric oxide synthases via converting l-arginine to citrulline. Additionally, NO is also produced via the NOS-independent nitrate-nitrite-NO pathway. Unlike the classical pathway, the nitrate-nitrite-NO pathway is oxygen independent and viewed as a back-up function to ensure NO generation during ischaemia/hypoxia. Dietary nitrate and nitrite have emerged as substrates for endogenous NO generation and other bioactive nitrogen oxides with promising protective effects on cardiovascular and metabolic function. In brief, inorganic nitrate and nitrite can decrease blood pressure, protect against ischaemia-reperfusion injury, enhance endothelial function, inhibit platelet aggregation, modulate mitochondrial function and improve features of the metabolic syndrome. However, many questions regarding the specific mechanisms of these protective effects on cardiovascular and metabolic diseases remain unclear. In this review, we focus on nitrate/nitrite bioactivation, as well as the potential mechanisms for nitrate/nitrite-mediated effects on cardiovascular and metabolic diseases. Understanding how dietary nitrate and nitrite induce beneficial effect on cardiovascular and metabolic diseases could open up novel therapeutic opportunities in clinical practice.

  • Real-time redox monitoring of a nitrosyl ruthenium complex acting as NO-donor agent in a single A549 cancer cell with multiplex Fourier-transform infrared microscopy
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-14
    Fernando Postalli Rodrigues; Lucyano J.A. Macedo; Leandro N.C. Máximo; Fernanda C.P.F. Sales; Roberto Santana da Silva; Frank N. Crespilho

    Multiplex Fourier-transform infrared microscopy (μFT-IR) helped to monitor trans-[Ru(NO) (NH3)4 (isn)]3+ (I), uptake by A549 lung carcinoma cell, as well as the generation of its product, nitric oxide (NO), inside the cell. Chronoamperometry with NO-sensor and μFT-IR showed that exogenous NADH and the A549 cell induced the NO release redox mechanism. Chemical imaging confirmed that (I) was taken up by the cell, and that its localization coincided with its consumption in the cellular environment within 15 min of exposure. The Ru–NO absorption band in the IR spectrum shifted from 1,932 cm−1, when NO was coordinated to Ru such as {RuII–NO+}3+, to 1,876 cm−1, due the formation of reduced specie {RuII–NO0}2+, a precursor of NO release. Futhermore, the μFT-IR spectral profile demonstrated that, as a result of the No action on the target, NO interacted with nucleic acids, which provided a biochemical response that is detectable in living cells.

  • Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-12
    Jeffrey A. Kline; Michael A. Puskarich; Jonathan Pike; John Zagorski; Nathan J. Alves
  • Nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) attenuates remobilization-induced joint inflammation
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-08
    Akinori Kaneguchi; Junya Ozawa; Kengo Minamimoto; Kaoru Yamaoka

    Shortly after joint remobilization, inflammation is induced in the joint and aggravates joint contracture via subsequent fibrosis. However, the mechanisms involved in remobilization-induced inflammation are not yet fully understood. We hypothesized that joint immobilization followed by remobilization induces hypoxia/reoxygenation, initiating inflammatory reactions through nitric oxide (NO) production via NO synthase 2 (NOS2). This study aimed to investigate whether: 1) administration of the NOS inhibitor L-NG-nitroarginine methyl ester (l-NAME) can attenuate remobilization-induced joint inflammation; and 2) hypoxia/reoxygenation is induced by joint immobilization and followed by remobilization. Unilateral knee joints of rats were immobilized using external fixators for three weeks. After removal of the fixation device, knees were allowed to move freely for one day (remobilization) with or without l-NAME administration. Without L-NAME administration, inflammatory reactions including joint swelling and inflammatory cell infiltration, edema, and upregulation of inflammatory mediator genes in the joint capsule were detected following upregulation of the NOS2 gene after remobilization. These remobilization-induced inflammatory reactions were partially attenuated by administration of L-NAME. Therefore, NOS2/NO elevation has potential as a novel treatment for remobilization-induced joint inflammation. Gene expression of the hypoxia marker hypoxia inducible factor-1α was upregulated after one day of remobilization, rather than after immobilization. These results suggest that upregulation of NOS2 by remobilization might be not due to hypoxia/reoxygenation.

  • Cellular microdomains for nitric oxide signaling in endothelium and red blood cells
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-03
    Francesca Leo; Beate Hutzler; Claire A. Ruddiman; Brant E. Isakson; Miriam M. Cortese-Krott
  • Maternal disease and gasotransmitters
    Nitric Oxide (IF 3.371) Pub Date : 2020-01-03
    Aishwarya Rengarajan; Amanda K. Mauro; Derek S. Boeldt

    The three known gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide are involved in key processes throughout pregnancy. Gasotransmitters are known to impact on smooth muscle tone, regulation of immune responses, and oxidative state of cells and their component molecules. Failure of the systems that tightly regulate gasotransmitter production and downstream effects are thought to contribute to common maternal diseases such as preeclampsia and preterm birth. Normal pregnancy-related changes in uterine blood flow depend heavily on gasotransmitter signaling. In preeclampsia, endothelial dysfunction is a major contributor to aberrant gasotransmitter signaling, resulting in hypertension after 20 weeks gestation. Maintenance of pregnancy to term also requires gasotransmitter-mediated uterine quiescence. As the appropriate signals for parturition occur, regulation of gasotransmitter signaling must work in concert with those endocrine signals in order for appropriate labor and delivery timing. Like preeclampsia, preterm birth may have origins in abnormal gasotransmitter signaling. We review the evidence for the involvement of gasotransmitters in preeclampsia and preterm birth, as well as mechanistic and molecular signaling targets.

  • Therapies that enhance pulmonary vascular NO-signaling in the neonate
    Nitric Oxide (IF 3.371) Pub Date : 2019-12-20
    Julie Dillard; Marta Perez; Bernadette Chen

    There are several pulmonary hypertensive diseases that affect the neonatal population, including persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). While the indication for inhaled nitric oxide (iNO) use is for late-preterm and term neonates with PPHN, there is a suboptimal response to this pulmonary vasodilator in ∼40% of patients. Additionally, there are no FDA-approved treatments for BPD-associated PH or for preterm infants with PH. Therefore, investigating mechanisms that alter the nitric oxide-signaling pathway has been at the forefront of pulmonary vascular biology research. In this review, we will discuss the various mechanistic pathways that have been targets in neonatal PH, including NO precursors, soluble guanylate cyclase modulators, phosphodiesterase inhibitors and antioxidants. We will review their role in enhancing NO-signaling at the bench, in animal models, as well as highlight their role in the treatment of neonates with PH.

  • DDAH-1 via HIF-1 target genes improves cerebral ischemic tolerance after hypoxic preconditioning and middle cerebral artery occlusion-reperfusion
    Nitric Oxide (IF 3.371) Pub Date : 2019-12-20
    Yichen Zhao; Yuchen Zhou; Xiaoye Ma; Xiaohui Liu; Yanxin Zhao; Xueyuan Liu

    Dimethylarginine dimethylamino hydrolase-1 (DDAH-1) as an indirect regulator of nitric oxide (NO) metabolism, its role in hypoxic preconditioning (HPC) and ischemic tolerance (IT) of ischemic stroke has still been unknown and needs to be elucidated. Herein, DDAH-1 knock-out (KO) and wild-type (WT) rats underwent HPC and middle cerebral artery occlusion/reperfusion (MCAO/R) model. After 24 h, neurological severity scores, TTC staining and TUNEL assay were used to evaluate neurological damages. To explore the mechanism, the expression of hypoxia inducible factor (HIF-1α) and its target genes were assessed by Western blot and RT-qPCR. NO and ADMA contents were also tested. In addition, supplementation of l-arginine to DDAH-1 KO rats was used to explore the role of DDAH-1 in regulating NO. After HPC the ischemic outcome improved in both KO and WT rats, while KO rats showed attenuated IT exhibiting less expression of HIF-1α and its target genes, lower NO but higher ADMA content. The supplement of l-arginine to KO rats partly alleviated neurological damages accompanied with higher expression of HIF-1α. To sum up, DDAH-1 could regulate the level of NO and enhance IT following HPC and MCAO model via activating the expression of HIF-1α and its target genes.

  • The role of gasotransmitters in neonatal physiology
    Nitric Oxide (IF 3.371) Pub Date : 2019-12-20
    Taiming Liu; George T. Mukosera; Arlin B. Blood

    The gasotransmitters, nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), are endogenously-produced volatile molecules that perform signaling functions throughout the body. In biological tissues, these small, lipid-permeable molecules exist in free gaseous form for only seconds or less, and thus they are ideal for paracrine signaling that can be controlled rapidly by changes in their rates of production or consumption. In addition, tissue concentrations of the gasotransmitters are influenced by fluctuations in the level of O2 and reactive oxygen species (ROS). The normal transition from fetus to newborn involves a several-fold increase in tissue O2 tensions and ROS, and requires rapid morphological and functional adaptations to the extrauterine environment. This review summarizes the role of gasotransmitters as it pertains to newborn physiology. Particular focus is given to the vasculature, ventilatory, and gastrointestinal systems, each of which uniquely illustrate the function of gasotransmitters in the birth transition and newborn periods. Moreover, given the relative lack of studies on the role that gasotransmitters play in the newborn, particularly that of H2S and CO, important gaps in knowledge are highlighted throughout the review.

  • Inhaled nitric oxide use in neonates: Balancing what is evidence-based and what is physiologically sound
    Nitric Oxide (IF 3.371) Pub Date : 2019-12-19
    Laurie G. Sherlock; Clyde J. Wright; John P. Kinsella; Cassidy Delaney

    Inhaled nitric oxide is a powerful therapeutic used in neonatology. Its use is evidenced-based for term and near-term infants with persistent pulmonary hypertension; however, it is frequently used off-label both in term and preterm babies. This article reviews the off-label uses of iNO in infants. Rationale is discussed for a selective application of iNO based on physiologically guided principles, and new research avenues are considered.

  • Saliva panel of protein candidates: A comprehensive study for assessing high altitude acclimatization
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-25
    Shikha Jain, Subhojit Paul, Ram Niwas Meena, Anamika Gangwar, Usha Panjwani, Yasmin Ahmad, Kalpana Bhargava

    Altitude acclimatization describes the processes whereby lowland humans respond to decreased partial pressure of oxygen. It refers to the changes seen as beneficial and involves a series of physiological adjustments that compensate for reduced ambient PO2, as opposed to changes that are pathological. Although numerous reports document the physiological effects of exposures to hypobaric hypoxia of varying durations but an interesting aspect overlooked by many researchers is that of acclimatization related studies. As proteome, a dynamic entity responds immediately to external stimuli, protein markers and their trends can be studied to assess acclimatization status of an individual. Compared to blood, the use of saliva is advantageous because sample collection and processing are easy, minimally invasive, low cost and better tolerated by individuals. In this study, we employed iTRAQ based LC-MS/MS for comparing saliva samples from humans exposed to hypobaric hypoxia from 7 to 120 days with normoxic controls followed by analysis using Ingenuity Pathway Analysis software and validation by immunoassays. Nearly 67 proteins were found to be differentially expressed in the exposed groups as compared to normoxia indicating modulated canonical pathways as lipid metabolism; acute phase response signalling and proteins as carbonic anhydrase 6, alpha-enolase, albumin, and prolactin inducible protein. Collectively, this study provides the proof of concept for the non-invasive assessment of high altitude acclimatization.

  • Nitric oxide signaling inhibits microglia proliferation by activation of protein kinase-G
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-21
    Matthew J.E. Maksoud, Vasiliki Tellios, Yun-Yan Xiang, Wei-Yang Lu

    Microglia population is primarily determined by a finely-regulated proliferation process during early development of the central nervous system (CNS). Nitric oxide (NO) is known to inhibit proliferation of numerous types of cells. However, how NO signaling regulates microglia proliferation remains elusive. Using wildtype (WT) and inducible nitric oxide synthase knockout (iNOS−/-) mice, this study investigated the role and underlying mechanisms of iNOS/NO signaling in microglia proliferation. Here we reported that iNOS−/- mice displayed significantly more BrdU-labeled proliferating microglia in the cortex than that in WT mice at postnatal day 10. Compared to microglia isolated from WT mouse cortex, significantly more iNOS−/- microglia displayed specific cell-cycle markers Ki67 and phospho-histone H3 (pH3) in their nuclei. In addition, treating WT microglia with the NOS inhibitor LNAME drastically increased the percentage of cells expressing Ki67 and pH3, whereas treating iNOS−/- microglia with NOC18, a slow-release NO-donor, significantly decreased the percentage of microglia expressing the two cell-cycle markers. Moreover, inhibition of protein kinase-G (PKG) in WT microglia increased the proportion of microglia expressing Ki67 and pH3, whereas activation of PKG signaling using 8Br-cGMP in iNOS−/- microglia significantly decreased the fraction of microglia displaying Ki67 and pH3. Interestingly, in the presence of a PKG inhibitor, NOC18 increased the quantity of iNOS−/- microglia expressing Ki67 and pH3. Together, these results indicate that basal activity of iNOS/NO signaling impedes microglial cell-cycle progression and attenuates proliferation through activation of the cGMP-PKG pathway. However, NO increases microglia cell-cycle progression in the absence of cGMP-PKG signaling.

  • Role of hippocampal nitrergic neurotransmission in behavioral and cardiovascular dysfunctions evoked by chronic social stress
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-21
    Jeferson Almeida, Leandro A. Oliveira, Ricardo Benini, Carlos C. Crestani

    Increased nitric oxide (NO) levels have been identified in the hippocampus of animals subjected to social isolation. However, a role of this change in behavioral and physiological changes evoked by isolation has never been evaluated. Thus, this study investigated the involvement of nitrergic neurotransmission acting via the neuronal isoform of nitric oxide synthase (nNOS) within the dorsal hippocampus in behavioral and cardiovascular changes in isolated reared rats. For this, male rats were isolated from weaning at 21 days postnatal for 40 days. We identified that social isolation increased hippocampal NO formation and nNOS expression. Besides, anxiogenic- and depressive-like effect identified in isolated animals were not affected by intra-hippocampal microinjection of either the NO scavenger carboxy-PTIO or the selective nNOS inhibitor Nω-Propyl-l-arginine (NPLA). Isolation also increased basal arterial pressure, impaired the baroreflex function and decreased the tachycardia to restraint stress. The effects in restraint-evoked tachycardia were inhibited by hippocampal treatment with either carboxy-PTIO or NPLA. Intra-hippocampal administration of either carboxy-PTIO or NPLA also enhanced the pressor response to restraint in isolated, but not in control animals. Taken together, these findings indicate that increased NO release within the dorsal hippocampus is involved in impairment of cardiovascular responses to a novel stressor, but not in behavioral effects and baroreflex changes, evoked by social isolation. Furthermore, exposure to this stressor evokes the emergence of an inhibitory role of hippocampal nNOS activation in cardiovascular changes to a novel stressor, which might constitute a prominent adaptive response.

  • Delivering nitric oxide into human skin from encapsulated S-nitrosoglutathione under UV light: An in vitro and ex vivo study
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-21
    Milena T. Pelegrino, Richard B. Weller, André Paganotti, Amedea B. Seabra
  • Exogenous nitric oxide alleviates sulfur deficiency-induced oxidative damage in tomato seedlings
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-07
    Manzer H. Siddiqui, Saud Alamri, Qasi D. Alsubaie, Hayssam M. Ali, M. Nasir Khan, Abdullah Al-Ghamdi, Abdullah A. Ibrahim, Abdullah Alsadon

    Despite numerous reports on the role of nitric oxide (NO) in regulating plants growth and mitigating different environmental stresses, its participation in sulfur (S) -metabolism remains largely unknown. Therefore, we studied the role of NO in S acquisition and S-assimilation in tomato seedlings under low S-stress conditions by supplying NO to the leaves of S-sufficient and S-deficient seedlings. S-starved plants exhibited a substantial decreased in plant growth attributes, photosynthetic pigment chlorophyll (Chl) and other photosynthetic parameters, and activity of enzymes involved in Chl biosynthesis (δ-aminolevulinic acid dehydratase), and photosynthetic processes (carbonic anhydrase and RuBisco). Also, S-deficiency enhanced reactive oxygen species (ROS) (superoxide and hydrogen peroxide) and lipid peroxidation (malondialdehyde) levels in tomato seedlings. Contrarily, foliar supplementation of NO to S-deficient seedlings resulted in considerably reduced ROS formation in leaves and roots, which alleviated low S-stress-induced lipid peroxidation. However, exogenous NO enhanced proline accumulation by increasing proline metabolizing enzyme (Δ1-pyrroline-5-carboxylate synthetase) activity and also increased NO, hydrogen sulfide (a gasotransmitter small signaling molecule) and S uptake, and content of S-containing compounds (cysteine and reduced glutathione). Under S-limited conditions, NO improved S utilization efficiency of plants by upregulating the activity of S-assimilating enzymes (ATP sulfurylase, adenosine 5-phosphosulfate reductase, sulfide reductase and O-acetylserine (thiol) lyase). Under S-deprived conditions, improved S-assimilation of seedlings receiving NO resulted in improved redox homeostasis and ascorbate content through increased NO and S uptake. Application of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy l-3-oxide (an NO scavenger) invalidated the effect of NO and again caused low S-stress-induced oxidative damage, confirming the beneficial role of NO in seedlings under S-deprived conditions. Thus, exogenous NO enhanced the tolerance of tomato seedlings to limit S-triggered oxidative stress and improved photosynthetic performance and S assimilation.

  • Sickle cell disease subjects and mouse models have elevated nitrite and cGMP levels in blood compartments
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-02
    Luis E.F. Almeida, Sayuri Kamimura, Celia M. de Souza Batista, Nicholas Spornick, Margaret Y. Nettleton, Elizabeth Walek, Meghann L. Smith, Julia Finkel, Deepika Darbari, Paul Wakim, Zenaide M.N. Quezado

    The hypothesis of decreased nitric oxide (NO) bioavailability in sickle cell disease (SCD) proposes that multiple factors leading to decreased NO production and increased consumption contributes to vaso-occlusion, pulmonary hypertension, and pain. The anion nitrite is central to NO physiology as it is an end product of NO metabolism and serves as a reservoir for NO formation. However, there is little data on nitrite levels in SCD patients and its relationship to pain phenotype. We measured nitrite in SCD subjects and examined its relationship to SCD pain. In SCD subjects, median whole blood, red blood cell and plasma nitrite levels were higher than in controls, and were not associated with pain burden. Similarly, Townes and BERK homozygous SCD mice had elevated blood nitrite. Additionally, in red blood cells and plasma from SCD subjects and in blood and kidney from Townes homozygous mice, levels of cyclic guanosine monophosphate (cGMP) were higher compared to controls. In vitro, hemoglobin concentration, rather than sickle hemoglobin, was responsible for nitrite metabolism rate. In vivo, inhibition of NO synthases and xanthine oxidoreductase decreased nitrite levels in homozygotes but not in control mice. Long-term nitrite treatment in SCD mice further elevated blood nitrite and cGMP, worsened anemia, decreased platelets, and did not change pain response. These data suggest that SCD in humans and animals is associated with increased nitrite/NO availability, which is unrelated to pain phenotype. These findings might explain why multiple clinical trials aimed at increasing NO availability in SCD patients failed to improve pain outcomes.

  • Effects of age, sex and diet on salivary nitrate and nitrite in infants
    Nitric Oxide (IF 3.371) Pub Date : 2019-11-02
    Niklas Timby, Magnus Domellöf, Olle Hernell, Bo Lönnerdal, Carina Nihlen, Ingegerd Johanssson, Eddie Weitzberg

    The inorganic anions nitrate and nitrite are oxidation products from endogenous nitric oxide (NO) generation and constituents in our diet. A nitrate-nitrite-NO pathway exists in which nitrate can be serially reduced to bioactive NO. The first step of this pathway occurs in the oral cavity where oral bacteria convert salivary nitrate to nitrite, whereafter nitrite is reduced to NO systemically by several enzymatic and non-enzymatic pathways. Data are scarce regarding salivary levels and oral conversion capacity of these anions in infants. We measured salivary nitrate and nitrate in infants at 4 and 12 months of age and related values to age, sex, dietary pattern and oral microbiome. Saliva was collected from a total of 188 infants at 4 and 12 months of age. Salivary nitrate, nitrite and nitrite/nitrate ratio as a measure of oral nitrate-reducing capacity were analyzed by HPLC and related to age, sex, type of diet (breast milk or formula) and oral microbiome. There was no difference in salivary nitrate, nitrite or nitrite/nitrate ratio between boys and girls at any age. At 4 months levels of these parameters were lower than what has been described in adults but they had all increased significantly at 12 months of age. At 4 months of age salivary nitrite/nitrate ratio was lower in breast-fed compared to formula-fed infants, but these differences disappeared at 12 months. Several bacterial species were associated with oral nitrate reducing capacity including Prevotella, Veillonella, Alloprevotella and Leptotrichia. We conclude that in infants there is an increase in salivary nitrate and nitrite as well as in oral nitrate-reductase capacity during the first year of life. Differences observed at 4 months of age between breast-fed and formula-fed infants disappear at one year of age.

  • Influence of hemoglobin and albumin on the NO donation effect of tetranitrosyl iron complex with thiosulfate
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-31
    Olesya Pokidova, Tatiana Rudneva, Bogdan Tretyakov, Raisa Kotelnikova, Alexander Kotelnikov, Sergey Aldoshin

    The effects of deoxyhemoglobin (Hb) and albumin on the NO-donor activity of the anionic tetranitrosyl iron complex with thiosulfate ligands (1) were studied for the first time. It was shown that Hb significantly stabilizes complex 1; in its presence, NO generation from the complex proceeds at a noticeably slower rate. A similar effect is observed when complex 1 is bound to albumin, in which case complex 1 decomposes 27 times slower than in the absence of albumin in the solution. The observed effects provide a prolonged action of complex 1 as NO-donor, which may enhance its potential pharmacological efficacy.

  • A randomized pilot study of nitrate supplementation with beetroot juice in acute respiratory failure
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-25
    D. Clark Files, Timothy Heinrich, Katherine L. Shields, Nathan J. Love, Carly Brailer, Rita N. Bakhru, Lina Purcell, Lori Flores, Kevin Gibbs, Gary D. Miller, Peter E. Morris, Michael J. Berry

    Nitrate rich beetroot juice (BRJ) can enhance nitric oxide signaling, leading to improved physical function in healthy and diseased populations, but its safety and biologic efficacy have not been evaluated in a critically ill population. We randomized 22 previously functional acute respiratory failure patients to either BRJ or placebo daily until day 14 or discharge. We measured blood nitrate and nitrite levels and quantified strength and physical function at intensive care unit (ICU) and hospital discharge. 54% of participants were male, aged 68.5 years with an APACHE III score of 62. BRJ increased plasma nitrate (mean 219.2 μM increase, p = 0.002) and nitrite levels (mean 0.144 μM increase, p = 0.02). We identified no adverse events. The unadjusted and adjusted effect sizes of the intervention on the short physical performance battery were small (d = 0.12 and d = 0.17, respectively). In this pilot trial, administration of BRJ was feasible and safe, increased blood nitrate and nitrate levels, but had a small effect on physical function. Future studies could evaluate the clinical efficacy of BRJ as a therapy to improve physical function in survivors of critical illness.

  • Modulation of endothelium-derived nitric oxide production and activity by taurine and taurine-conjugated bile acids
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-24
    Daniele M. Guizoni, Jean F. Vettorazzi, Everardo M. Carneiro, Ana Paula Davel

    Taurine is a semiessential amino acid found at high concentrations in mammalian plasma and cells, where it regulates cellular functions such as ion flux, controls cell volume and serves as a substrate for conjugated bile acids (BAs). Exogenous administration of both taurine and taurine-conjugated BAs have also been implicated in the modulation of cardiovascular functions. This brief review summarizes the role of taurine and taurine-conjugated BAs in vascular relaxation through the modulation of endothelium-derived nitric oxide (NO). The effects of taurine on vascular health are controversial. However, in the presence of cardiometabolic risk factors, it has been proposed that taurine can increase vascular NO levels by increasing eNOS expression, eNOS phosphorylation on Ser1177, NO bioavailability, the level of antioxidative defense, and the l-arginine/NOS inhibitor asymmetric dimethylarginine (ADMA) ratio. The taurine-conjugated BA-mediated activation of Farnesoid X receptor (FXR), G protein-coupled BA receptor (TGR5) and/or muscarinic 3 receptor (M3) was also reported to increase vascular NO production. FXR activation increases eNOS expression and may reduce ADMA formation, while TGR5 increases mobilization of Ca2+ and phosphorylation of eNOS and AKT in endothelial cells. Furthermore, taurine and taurine-conjugated BAs might regulate NO synthesis and activity by enhancing H2S generation. Several studies have demonstrated the beneficial effects of both taurine and taurine-conjugated BAs in reversing the endothelial dysfunction associated with diabetes, atherosclerosis, hypertension, obesity, malnutrition, and smoking. In addition, taurine-conjugated BAs have emerged as a potential treatment for portal hypertension. Despite these favorable findings, there is a need to further explore the mechanisms and signaling pathways underlying the endothelial effects of taurine and taurine-conjugated BAs. Here, we summarize the main findings regarding the effects of taurine and taurine-conjugated BAs on the endothelial dysfunction associated with altered NO metabolism in cardiovascular diseases.

  • Nitrate uptake and metabolism in human skeletal muscle cell cultures
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-08
    Sirada Srihirun, Ji Won Park, Rujia Teng, Waritta Sawaengdee, Barbora Piknova, Alan N. Schechter

    Several studies show that dietary nitrate enhances exercise performance, presumably by increasing muscle blood flow and improving oxygen utilization. These effects are likely mediated by nitrate metabolites, including nitrite and nitric oxide (NO). However, the mechanisms of nitrate production, storage, and metabolism to nitrite and NO in skeletal muscle cells are still unclear. We hypothesized that exogenous nitrate can be taken up and metabolized to nitrite/NO inside the skeletal muscle. We found rapid uptake of exogeneous nitrate in both myoblasts and myotubes, increasing nitrite levels in myotubes, but not myoblasts. During differentiation we found increased expression of molybdenum containing proteins, such as xanthine oxidoreductase (XOR) and the mitochondrial amidoxime-reducing component (MARC); nitrate and nitrite reductases. Sialin, a known nitrate transporter, was detected in myoblasts; nitrate uptake decreased after sialin knockdown. Inhibition of chloride channel 1 (CLC1) also led to significantly decreased uptake of nitrate. Addition of exogenous nitrite, which resulted in higher intracellular nitrite levels, increased intracellular cGMP levels in myotubes. In summary, our results demonstrate for the first time the presence of the nitrate/nitrite/NO pathway in skeletal muscle cells, namely the existence of strong uptake of exogenous nitrate into cells and conversion of intracellular nitrate to nitrite and NO. Our results further support our previously formulated hypothesis about the importance of the nitrate to nitrite to NO intrinsic reduction pathways in skeletal muscles, which likely contributes to improved exercise tolerance after nitrate ingestion.

  • Treatment with nitrite prevents reactive oxygen species generation in the corpora cavernosa and restores intracavernosal pressure in hypertensive rats
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-11
    Natália A. Gonzaga, Gabriel T. do Vale, Carla B.P. da Silva, Lucas C. Pinheiro, Letícia N. Leite, Fernando S. Carneiro, José E. Tanus-Santos, Carlos R. Tirapelli

    Hypertension is a risk factor for erectile dysfunction (ED) and both conditions are associated with oxidative stress. Given that nitrite is described to display antioxidant effects, we hypothesized that treatment with nitrite would exert antioxidant effects attenuating both reactive oxygen species (ROS) generation in the corpora cavernosa (CC) and ED induced by hypertension. Two kidney, one clip (2K1C) hypertension was induced in male Wistar rats. Treatment with sodium nitrite (15 mg/kg/day, p.o., gavage) was initiated two weeks after surgery to induce hypertension and maintained for four weeks. Nitrite abrogated both the decrease in intracavernosal pressure and endothelial dysfunction of the CC induced by hypertension. Treatment with nitrite decreased hypertension-induced ROS generation in the CC assessed in situ using the fluorescent dye dihidroethidium (DHE) and with the lucigenin assay. Western immunoblotting analysis revealed that nitrite prevented the increase in Nox1 expression in the CC from 2K1C rats. Decreased concentrations of hydrogen peroxide (H2O2) were found in the CC from hypertensive rats and treatment with nitrite prevented this response. Treatment with nitrite increased the fluorescence of DAF-2DA in the CC from sham-operated rats and restored nitric oxide (NO) levels in the CC from 2K1C rats. In summary, we found novel evidence that nitrite reversed the decrease in intracavernosal pressure induced by 2K1C hypertension. This response was partially attributed to the antioxidant effect of nitrite that blunted ROS generation and endothelial dysfunction in the CC. In addition, nitrite-derived NO may have promoted direct protective actions against hypertension-induced CC dysfunction.

  • Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude – A randomised controlled trial (Xtreme Alps)
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-08
    Andrew F. Cumpstey, Philip J. Hennis, Edward T. Gilbert-Kawai, Bernadette O. Fernandez, Daniel Grant, William Jenner, Matthieu Poudevigne, Helen Moyses, Denny ZH. Levett, Alexandra Cobb, Paula Meale, Kay Mitchell, Helmut Pöhnl, Monty G. Mythen, Michael PW. Grocott, Daniel S. Martin, Martin Feelisch

    Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate ‘placebo’. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 μM) and at day 5 (D5) of high altitude (22.9 vs 84.3 μM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 μM SL, 0.31 vs. 0.41 μM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

  • Sapropterin reduces coronary artery malformation in offspring of pregestational diabetes mice
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-07
    Anish Engineer, Yong Jin Lim, Xiangru Lu, Mella Y. Kim, Kambiz Norozi, Qingping Feng
  • Central angiotensin II-Protein inhibitor of neuronal nitric oxide synthase (PIN) axis contribute to neurogenic hypertension
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-22
    Neeru M. Sharma, Andrea S. Haibara, Kenichi Katsurada, Xuefei Liu, Kaushik P. Patel

    Activation of renin-angiotensin- system, nitric oxide (NO•) bioavailability and subsequent sympathoexcitation plays a pivotal role in the pathogenesis of many cardiovascular diseases, including hypertension. Previously we have shown increased protein expression of PIN (a protein inhibitor of nNOS: neuronal nitric oxide synthase, known to dissociate nNOS dimers into monomers) with concomitantly reduced levels of catalytically active dimers of nNOS in the PVN of rats with heart failure. To elucidate the molecular mechanism by which Angiotensin II (Ang II) increases PIN expression, we used Sprague-Dawley rats (250–300 g) subjected to intracerebroventricular infusion of Ang II (20 ng/min, 0.5 μl/h) or saline as vehicle (Veh) for 14 days through osmotic mini-pumps and NG108-15 hybrid neuronal cell line treated with Ang II as an in vitro model. Ang II infusion significantly increased baseline renal sympathetic nerve activity and mean arterial pressure. Ang II infusion increased the expression of PIN (1.24 ± 0.04* Ang II vs. 0.65 ± 0.07 Veh) with a concomitant 50% decrease in dimeric nNOS and PIN-Ub conjugates (0.73 ± 0.04* Ang II vs. 1.00 ± 0.03 Veh) in the PVN. Substrate-dependent ligase assay in cells transfected with pCMV-(HA-Ub)8 vector revealed a reduction of HA-Ub-PIN conjugates after Ang II and a proteasome inhibitor, Lactacystin (LC), treatment (4.5 ± 0.7* LC Ang II vs. 9.2 ± 2.5 LC). TUBE (Tandem Ubiquitin-Binding Entities) assay showed decrease PIN-Ub conjugates in Ang II-treated cells (0.82 ± 0.12* LC Ang II vs. 1.21 ± 0.06 LC) while AT1R blocker, Losartan (Los) treatment diminished the Ang II-mediated stabilization of PIN (1.21 ± 0.07 LC Los vs. 1.16 ± 0.04* LC Ang II Los). Taken together, our studies suggest that increased central levels of Ang II contribute to the enhanced expression of PIN leading to reduced expression of the dimeric form of nNOS, thus diminishing the inhibitory action of NO• on pre-autonomic neurons in the PVN resulting in increased sympathetic outflow.

  • Systemic vasoprotection by inhaled carbon monoxide is mediated through prolonged alterations in monocyte/macrophage function
    Nitric Oxide (IF 3.371) Pub Date : 2019-10-05
    Andrew Leake, Karim Salem, Michael C. Madigan, Ghee Rye Lee, Ankur Shukla, Guiying Hong, Brian S. Zuckerbraun, Edith Tzeng

    Carbon monoxide (CO) is anti-inflammatory and protective in models of disease. Its actions in vitro are short-lived but are sustained in vivo. We hypothesize that systemic CO can mediate prolonged phenotype changes in vivo, with a focus on macrophages (Mϕs). Mϕs isolated from CO treated rats responded to lipopolysaccharide (LPS) with increased IL6, IL10 and iNOS expression but decreased TNF. Conditioned media (CM) collected from peritoneal Mϕs isolated from CO treated rats stimulated endothelial cell (EC) proliferation versus CM from Mϕs from air treated rats. This effect was mediated by Mϕ released VEGF and HMGB1. Inhaled CO reduced LPS induced Mϕ M1 inflammatory phenotype for up to 5 days. Mitochondrial oxygen consumption in LPS treated Mϕs from CO treated mice was preserved compared to LPS treated Mϕs from control mice. Finally, transient reduction of inflammatory cells at the time of inhaled CO treatment eliminated the vasoprotective effect of CO in a rodent carotid injury model. Thus, inhaled CO induces a prolonged mixed phenotype change in Mϕs, and potentially other inflammatory cells, that contribute to vasoprotection. These findings demonstrate the ability of inhaled CO to modify Mϕs in a sustained manner to mediate its therapeutic actions, supporting the translational potential of inhaled CO.

  • Nitric oxide stimulates a PKC-Src-Akt signaling axis which increases human immunodeficiency virus type 1 replication in human T lymphocytes
    Nitric Oxide (IF 3.371) Pub Date : 2019-09-17
    Marli F. Curcio, Wagner L. Batista, Eloísa D. Castro, Scheilla T. Strumillo, Fernando T. Ogata, Wagner Alkmim, Milena K.C. Brunialti, Reinaldo Salomão, Gilberto Turcato, Ricardo S. Diaz, Hugo P. Monteiro, Luiz Mário R. Janini
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上海纽约大学William Glover