Browsing by Subject "Nitric oxide"

Now showing 1 - 10 of 27
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    A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach
    (BMC, 2022-08-12) Singh, Jaipal; Lee, Young; Kellum, John A.; Cellular and Integrative Physiology, School of Medicine
    The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia-reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia-reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA "bed to bench" suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.
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    Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis
    (American Thoracic Society, 2017-07) Shapiro, Adam J.; Josephson, Maureen; Rosenfeld, Margaret; Yilmaz, Ozge; Davis, Stephanie D.; Polineni, Deepika; Guadagno, Elena; Leigh, Margaret W.; Lavergne, Valery; Pediatrics, School of Medicine
    RATIONALE: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. OBJECTIVES: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. DATA SOURCES: Ten databases were searched for reference sources from database inception through July 29, 2016. DATA EXTRACTION: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. SYNTHESIS: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7-99.2) and specificity was 96.0% (87.9-98.7), with a positive likelihood ratio of 24.3 (7.6-76.9), a negative likelihood ratio of 0.03 (0.01-0.08), and a diagnostic odds ratio of 956.8 (141.2-6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7-98.9) and specificity of 96.4% (85.1-99.2), with a positive likelihood ratio of 26.5 (5.9-119.1), a negative likelihood ratio of 0.04 (0.01-0.12), and a diagnostic odds ratio of 699.3 (67.4-7256.0). Certainty of the evidence was graded as moderate. CONCLUSIONS: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.
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    Airway Thiol-NO Adducts as Determinants of Exhaled NO
    (MDPI, 2021-09-26) Pophal, Megan; Grimmett, Zachary W.; Chu, Clara; Margevicius, Seunghee; Raffay, Thomas; Ross, Kristie; Jafri, Anjum; Giddings, Olivia; Stamler, Jonathan S.; Gaston, Benjamin; Reynolds, James D.; Pediatrics, School of Medicine
    Thiol-NO adducts such as S-nitrosoglutathione (GSNO) are endogenous bronchodilators in human airways. Decreased airway S-nitrosothiol concentrations are associated with asthma. Nitric oxide (NO), a breakdown product of GSNO, is measured in exhaled breath as a biomarker in asthma; an elevated fraction of expired NO (FENO) is associated with asthmatic airway inflammation. We hypothesized that FENO could reflect airway S-nitrosothiol concentrations. To test this hypothesis, we first studied the relationship between mixed expired NO and airway S-nitrosothiols in patients endotracheally intubated for respiratory failure. The inverse (Lineweaver-Burke type) relationship suggested that expired NO could reflect the rate of pulmonary S-nitrosothiol breakdown. We thus studied NO evolution from the lungs of mice (GSNO reductase -/-) unable reductively to catabolize GSNO. More NO was produced from GSNO in the -/- compared to wild type lungs. Finally, we formally tested the hypothesis that airway GSNO increases FENO using an inhalational challenge model in normal human subjects. FENO increased in all subjects tested, with a median t1/2 of 32.0 min. Taken together, these data demonstrate that FENO reports, at least in part, GSNO breakdown in the lungs. Unlike GSNO, NO is not present in the lungs in physiologically relevant concentrations. However, FENO following a GSNO challenge could be a non-invasive test for airway GSNO catabolism.
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    Beetroot supplementation in women enjoying exercise together (BEE SWEET): Rationale, design and methods
    (Elsevier, 2020-03-21) Baranauskas, Marissa N.; Altherr, Cody A.; Gruber, Allison H.; Coggan, Andrew R.; Raglin, John S.; Gupta, Samir K.; Carter, Stephen J.; Kinesiology, School of Health and Human Sciences
    Background: Postmenopausal women exhibit higher rates of disability and cardiovascular disease (CVD) with aging compared to men. Whereas habitual exercise training is a known strategy to enhance physiologic function in men and premenopausal women, exercise-related adaptations are often modest in postmenopausal women. We propose dietary nitrate (beetroot juice) administered prior to exercise training may be a feasible approach to improve mobility and cardio-metabolic health outcomes in postmenopausal women. Methods: Our randomized, placebo-controlled study aims to determine preliminary effects sizes for changes in functional mobility and endothelium-dependent vasodilation across three study arms: exercise only (EX), exercise + placebo (EX + PL), and exercise + beetroot (EX + BR). Thirty-six postmenopausal women are recruited in small cohorts wherein group exercise is implemented to facilitate social support and adherence to an 8-week training progression. Participants are randomized to one of three study arms (n = 12 per group) following baseline assessments. Post-intervention assessments are used to determine pre-post changes in outcome measures including distance covered during a 6 min walk test, walking economy, muscle speed and power, and endothelial-dependent vasodilation as determined by flow-mediated dilation. Measures of feasibility include recruitment, retention, adherence to exercise prescription, perceived exercise session difficulty, and adverse event rates. Discussion: Evidence-based, translational strategies are needed to optimize exercise training-related adaptations in postmenopausal women. Findings will inform larger randomized clinical trials to determine if pre-exercise consumption of beetroot juice is an efficacious strategy to promote mobility and attenuate CVD disease risk.
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    Contribution of Perivascular Adipose Tissue to Coronary Vascular Dysfunction
    (2011-03-10) Payne, Gregory Allen; Tune, Johnathan D.; Bohlen, H. Glenn; Considine, Robert V.; Sturek, Michael Stephen
    The epidemic of obesity and associated cardiovascular complications continues to grow at an alarming rate. Currently, obesity is thought to initiate a state of chronic inflammation, which if unresolved potentially causes cardiovascular dysfunction and disease. Although poorly understood, release of inflammatory mediators and other cytokines from adipose tissue (adipocytokines) has been proposed to be the molecular link between obesity and coronary artery disease. Furthermore, the anatomic location of adipose has been increasingly recognized as a potential contributor to vascular disease. Importantly, the development of coronary atherosclerosis, a key component of heart disease, is typically found in segments of coronary arteries surrounded by perivascular adipose tissue. Accordingly, the goal of this project was to determine how perivascular adipose tissue affects coronary artery function and elucidate the critical mechanisms involved. Initial studies assessing arterial function were conducted with and without perivascular adipose tissue. Preliminary results demonstrated that factors released by perivascular adipose tissue effectively impaired coronary endothelial function both in vitro and in vivo. This observation was determined to be caused by direct inhibition of nitric oxide synthase (NOS), a critical enzyme for the production nitric oxide. Attenuation of endothelium-dependent vasodilation was independent of changes in superoxide production, smooth muscle response, or peroxide-mediated vasodilation. Additional studies revealed that perivascular adipose-induced impairment of NOS was due to increased inhibitory regulation by the β isoform of protein kinase C (PKC-β). Specifically, perivascular adipose-derived factors caused site specific phosphorylation of nitric oxide synthase at Thr-495. Additional experiments investigated how perivascular adipose-derived factors contributed to coronary artery disease in an animal model of obesity. Results from these studies indicated that perivascular adipose-derived leptin markedly exacerbated underlying endothelial dysfunction, and significantly contributed to coronary endothelial dysfunction through a PKC-β dependent mechanism. Findings from this project confirm epicardial perivascular adipose tissue as a local source of harmful adipocytokines. In addition, perivascular adipose-derived leptin was demonstrated to be a critical mediator of coronary vascular dysfunction in obesity. Together, the results strongly suggest that perivascular adipose tissue is a key contributor to coronary artery disease in obesity.
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    Dietary Nitrate Enhances the Contractile Properties of Human Skeletal Muscle
    (Wolters Kluwer, 2018-10) Coggan, Andrew R.; Peterson, Linda R.; Cellular and Integrative Physiology, School of Medicine
    Dietary nitrate, a source of nitric oxide (NO), improves the contractile properties of human muscle. We present the hypothesis that this is due to nitrosylation of the ryanodine receptor and increased NO signaling via the soluble guanyl cyclase-cyclic guanosine monophosphate-protein kinase G pathway, which together increase the free intracellular Ca concentration along with the Ca sensitivity of the myofilaments themselves.
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    Dietary nitrate-induced increases in human muscle power: high versus low responders
    (Wiley, 2018-01) Coggan, Andrew R.; Broadstreet, Seth R.; Mikhalkova, Deana; Bole, Indra; Leibowitz, Joshua L.; Kadkhodayan, Ana; Park, Soo; Thomas, Deepak P.; Thies, Dakkota; Peterson, Linda R.; Kinesiology, School of Physical Education and Tourism Management
    Maximal neuromuscular power is an important determinant of athletic performance and also quality of life, independence, and perhaps even mortality in patient populations. We have shown that dietary nitrate (NO3- ), a source of nitric oxide (NO), improves muscle power in some, but not all, subjects. The present investigation was designed to identify factors contributing to this interindividual variability. Healthy men (n = 13) and women (n = 7) 22-79 year of age and weighing 52.1-114.9 kg were studied using a randomized, double-blind, placebo-controlled, crossover design. Subjects were tested 2 h after ingesting beetroot juice (BRJ) either containing or devoid of 12.3 ± 0.8 mmol of NO3- . Plasma NO3- and nitrite (NO2- ) were measured as indicators of NO bioavailability and maximal knee extensor speed (Vmax ), power (Pmax ), and fatigability were determined via isokinetic dynamometry. On average, dietary NO3- increased (P < 0.05) Pmax by 4.4 ± 8.1%. Individual changes, however, ranged from -9.6 to +26.8%. This interindividual variability was not significantly correlated with age, body mass (inverse of NO3- dose per kg), body mass index (surrogate for body composition) or placebo trial Vmax or fatigue index (in vivo indicators of muscle fiber type distribution). In contrast, the relative increase in Pmax was significantly correlated (r = 0.60; P < 0.01) with the relative increase in plasma NO2- concentration. In multivariable analysis female sex also tended (P = 0.08) to be associated with a greater increase in Pmax. We conclude that the magnitude of the dietary NO3- -induced increase in muscle power is dependent upon the magnitude of the resulting increase in plasma NO2- and possibly female sex.
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    DIFFERENTIAL EFFECTS OF VARYING DOSES OF DIETARY NITRATE ON MUSCLE FUNCTION AND BLOOD PRESSURE IN OLDER SUBJECTS
    (Oxford University Press, 2019-11) Coggan, Andrew R.; Gallardo, Edgar; Gray, Derrick A.; Hoffman, Richard; Moorthi, Ranjani; Kinesiology, School of Physical Education and Tourism Management
    We have recently demonstrated that dietary nitrate, a source of nitric oxide via the enterosalivary pathway, can improve muscle contractile function in healthy older men and women. Nitrate ingestion has also been shown to reduce blood pressure in older individuals. However, the optimal dose for eliciting these beneficial effects is unknown. We therefore performed a randomized, double-blind, crossover study to determine the effects of ingesting 3.3 mL/kg of beetroot juice (BRJ) containing 0, 212, or 425 µmol/kg of nitrate in six healthy older (age 69±3 y) subjects. Maximal knee extensor speed (Vmax) and power (Pmax) were measured 2 h after BRJ ingestion using isokinetic dynamometry; blood pressure was monitored periodically throughout each study. Mean arterial pressure (in mmHg) was lower (P<0.05) after the high (80±4) vs. the low (84±3) or placebo (88±2) doses. Vmax (in rad/s), however, was higher (P<0.05) after the low dose (11.7±0.8), but not the high dose (10.8±1.0), compared to the placebo (10.5±1.0). Pmax (in W/kg) also tended to be higher (P=0.11) in the low (3.9±0.5) compared to the placebo (3.7±0.5) or high (3.7±0.5) trials. Five out of six subjects achieved a higher Vmax and Pmax after the low vs. the high dose. We conclude that dietary nitrate has differential effects on muscle function and blood pressure in older individuals. A high dose of nitrate intake further lowers blood pressure but does not enhance muscle contractility as much as a lower dose. Supported by Indiana University Purdue University Indianapolis and by the NIA (R21 AG053606).
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    Disrupted NOS2 metabolism drives myoblast response to wasting-associated cytokines
    (Elsevier, 2021) Arneson-Wissink, Paige C.; Doles, Jason D.; Anatomy, Cell Biology and Physiology, School of Medicine
    Skeletal muscle wasting drives negative clinical outcomes and is associated with a spectrum of pathologies including cancer. Cancer cachexia is a multi-factorial syndrome that encompasses skeletal muscle wasting and remains understudied, despite being a frequent and serious co-morbidity. Deviation from the homeostatic balance between breakdown and regeneration leads to muscle wasting disorders, such as cancer cachexia. Muscle stem cells (MuSCs) are the cellular compartment responsible for muscle regeneration, which makes MuSCs an intriguing target in the context of wasting muscle. Molecular studies investigating MuSCs and skeletal muscle wasting largely focus on transcriptional changes, but our group and others propose that metabolic changes are another layer of cellular regulation underlying MuSC dysfunction in cancer cachexia. In the present study, we combined gene expression and non-targeted metabolomic profiling of myoblasts exposed to wasting conditions (cancer cell conditioned media, CC-CM) to derive a more complete picture of the myoblast response to wasting factors. After mapping these features to annotated pathways, we found that more than half of the mapped pathways were amino acid-related, linking global amino acid metabolic disruption to conditioned media-induced myoblast defects. Notably, arginine metabolism was a highly enriched pathway in combined metabolomic and transcriptomic data. Arginine catabolism generates nitric oxide (NO), an important signaling molecule known to have negative effects on mature muscle. We hypothesize that tumor-derived disruptions in Nitric Oxide Synthase (NOS)2-regulated arginine catabolism impair differentiation of MuSCs. The work presented here further investigates the effect of NOS2 overactivity on myoblast proliferation and differentiation. We show that NOS2 inhibition is sufficient to rescue wasting phenotypes associated with inflammatory cytokines. Ultimately, this work provides new insights into MuSC biology and opens up potential therapeutic avenues for addressing disrupted MuSC dynamics in cancer cachexia.
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    Dose–Response Effect of Dietary Nitrate on Muscle Contractility and Blood Pressure in Older Subjects: A Pilot Study
    (Oxford University Press, 2021) Gallardo, Edgar J.; Gray, Derrick A.; Hoffman, Richard L.; Yates, Brandon A.; Moorthi, Ranjani N.; Coggan, Andrew R; Kinesiology, School of Health and Human Sciences
    We have recently demonstrated that dietary nitrate, a source of nitric oxide (NO) via the nitrate → nitrite → NO enterosalivary pathway, can improve muscle contractility in healthy older men and women. Nitrate ingestion has also been shown to reduce blood pressure in some, but not all, studies of older individuals. However, the optimal dose for eliciting these beneficial effects is unknown. A pilot randomized, double-blind, placebo-controlled crossover study was therefore performed to determine the effects of ingesting 3.3 mL/kg of concentrated beetroot juice containing 0, 200, or 400 µmol/kg of nitrate in 9 healthy older subjects (mean age 70 ± 1 years). Maximal knee extensor power (Pmax) and speed (Vmax) were measured ~2.5 hours after nitrate ingestion using isokinetic dynamometry. Blood pressure was monitored periodically throughout each study. Pmax (in W/kg) was higher (p < .05) after the lower dose (3.9 ± 0.4) compared to the placebo (3.7 ± 0.4) or higher dose (3.7 ± 0.4). Vmax (in rad/s) also tended to be higher (p = .08) after the lower dose (11.9 ± 0.7) compared to the placebo (10.8 ± 0.8) or higher dose (11.2 ± 0.8). Eight out of 9 subjects achieved a higher Pmax and Vmax after the lower versus the higher dose. These dose-related changes in muscle contractility generally paralleled changes in breath NO levels. No significant changes were found in systolic, diastolic, or mean arterial blood pressure. A lower dose of nitrate increases muscle speed and power in healthy older individuals, but these improvements are lost at a higher dose. Blood pressure, on the other hand, is not reduced even with a higher dose.