Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training

2003 ◽  
Vol 284 (3) ◽  
pp. L452-L457 ◽  
Author(s):  
T. Vassilakopoulos ◽  
G. Deckman ◽  
M. Kebbewar ◽  
G. Rallis ◽  
R. Harfouche ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Exercise Training ◽  
Protein Expression ◽  
Experimental Period ◽  
Whole Body ◽  
Control Group ◽  
No Production ◽  
Inos Protein Expression ◽  
Nnos Expression ◽  
Ventilatory Muscles

In this study, we evaluated the differential influence of chronic treadmill training (30 m/min, 15% incline, 1 h/day, 5 days/wk) on nitric oxide (NO) production and NO synthase (NOS) isoform expression as well as 3-nitrotyrosine formation (footprint of peroxynitrite) both in limb (gastrocnemius) and ventilatory (diaphragm) muscles. A group of exercise-trained rats and a control group (no training) were examined after a 4-wk experimental period. Exercise training elicited an approximate fourfold rise in gastrocnemius NOS activity and augmented protein expression of the endothelial (eNOS) and neuronal (nNOS) isoforms of NOS to ∼480% and 240%, respectively. Qualitatively similar but quantitatively smaller elevations in NOS activity and eNOS and nNOS expression were observed in the diaphragm. No detectable inducible NOS (iNOS) protein expression was found in any of the muscle samples. Training increased the intensity of 3-nitrotyrosine only in the gastrocnemius muscle. We conclude that whole body exercise training enhances both limb and ventilatory muscle NO production and that constitutive and not iNOS isoforms are responsible for increased protein tyrosine nitration in trained limb muscles.

scholarly journals l-Arginine Availability Regulates Inducible Nitric Oxide Synthase-Dependent Host Defense against Helicobacter pylori

2007 ◽  
Vol 75 (9) ◽  
pp. 4305-4315 ◽  
Author(s):  
Rupesh Chaturvedi ◽  
Mohammad Asim ◽  
Nuruddeen D. Lewis ◽  
Holly M. Scott Algood ◽  
Timothy L. Cover ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Helicobacter Pylori ◽  
Protein Expression ◽  
Translation Initiation Factor ◽  
No Production ◽  
Dependent Manner ◽  
Inos Protein ◽  
Inos Protein Expression ◽  
H Pylori ◽  
Inducible Nitric Oxide

ABSTRACT Helicobacter pylori infection of the stomach causes an active immune response that includes stimulation of inducible nitric oxide (NO) synthase (iNOS) expression. Although NO can kill H. pylori, the bacterium persists indefinitely, suggesting that NO production is inadequate. We determined if the NO derived from iNOS in macrophages was dependent on the availability of its substrate, l-arginine (l-Arg). Production of NO by H. pylori-stimulated RAW 264.7 cells was dependent on the l-Arg concentration in the culture medium, and the 50% effective dose for l-Arg was 220 μM, which is above reported plasma l-Arg levels. While iNOS mRNA induction was l-Arg independent, iNOS protein increased in an l-Arg-dependent manner that did not involve changes in iNOS protein degradation. l-Lysine, an inhibitor of l-Arg uptake, attenuated H. pylori-stimulated iNOS protein expression, translation, NO levels, and killing of H. pylori. While l-Arg starvation suppressed global protein translation, at concentrations of l-Arg at which iNOS protein was only minimally expressed in response to H. pylori, global translation was fully restored and eukaryotic translation initiation factor α was dephosphorylated. H. pylori lacking the gene rocF, which codes for a bacterial arginase, induced higher levels of NO production by increasing iNOS protein levels. When murine gastric macrophages were activated with H. pylori, supraphysiologic levels of l-Arg were required to permit iNOS protein expression and NO production. These findings indicate that l-Arg is rate limiting for iNOS translation and suggest that the levels of l-Arg that occur in vivo do not permit sufficient NO generation by the host to kill H. pylori.

Time course of nitric oxide production after endotoxin challenge in mice

2004 ◽  
Vol 287 (5) ◽  
pp. E912-E918 ◽  
Author(s):  
Valeria B. Braulio ◽  
Gabrie A. M. Ten Have ◽  
Yvonne L. J. Vissers ◽  
Nicolaas E. P. Deutz
Keyword(s):  
Nitric Oxide ◽  
Time Course ◽  
De Novo ◽  
Whole Body ◽  
Constant Infusion ◽  
Saline Control ◽  
Control Group ◽  
No Production ◽  
Arterial Blood ◽  
Second Peak

Nitric oxide (NO) regulates numerous processes during endotoxemia and inflammation. However, the sequential changes in whole body (Wb) nitric oxide (NO) production during endotoxemia in vivo remain to be clarified. Male Swiss mice were injected intraperitoneally with saline (control group) or lipopolysaccharide (LPS group). After 0, 2, 4, 6, 9, 12, and 24 h, animals received a primed constant infusion of l-[guanidino-15N2-2H2]arginine, l-[ureido-15N]citrulline, l-[5-15N]glutamine, and l-[ ring-2H5]phenylalanine in the jugular vein. Arterial blood was collected for plasma arginine (Arg), citrulline (Cit), glutamine (Gln), and phenylalanine (Phe) concentrations and tracer-to-tracee ratios. NO production was calculated as plasma Arg-to-Cit flux, Wb de novo Arg synthesis as plasma Cit-to-Arg flux, and Wb protein breakdown as plasma Phe flux. LPS reduced plasma Arg and Cit and increased Gln and Phe concentrations. Two peaks of NO production were observed at 4 and 12 h after LPS. Although LPS did not affect total Arg production, de novo Arg production decreased after 12 h. The second peak of NO production coincided with increased Wb Cit, Gln, and Phe production. In conclusion, the curve of NO production in both early and late phases of endotoxemia is not related to plasma Arg kinetics. However, because Wb Cit, Gln, and Phe fluxes increased concomitantly with the second peak of NO production, NO production is probably related to the catabolic phase of endotoxemia.

Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease

2010 ◽  
Vol 298 (3) ◽  
pp. R815-R823 ◽  
Author(s):  
L. G. Bongartz ◽  
B. Braam ◽  
M. C. Verhaar ◽  
M. J. Cramer ◽  
R. Goldschmeding ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Whole Body ◽  
Control Group ◽  
High Dose ◽  
No Production

Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor Nω-nitro-l-arginine (l-NNA; 20 mg/l water; SNX+l-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, l-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX+l-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose l-NNA (l-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX+l-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In l-NNA-High, LVSD was not as severe as in SNX+l-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in l-NNA-High after l-NNA was stopped, but both were persistently low in SNX+l-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX+l-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.

scholarly journals Downregulation of Neuronal Nitric Oxide Synthase in the Rat Remnant Kidney

1999 ◽  
Vol 10 (4) ◽  
pp. 704-713
Author(s):  
AGNES ROCZNIAK ◽  
JAMES N. FRYER ◽  
DAVID Z. LEVINE ◽  
KEVIN D. BURNS
Keyword(s):  
Nitric Oxide ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Nitric Oxide Synthase ◽  
Protein Expression ◽  
Collecting Duct ◽  
Neuronal Nitric Oxide Synthase ◽  
No Production ◽  
Oxide Synthase ◽  
Nnos Expression

Abstract. Chronic renal failure is associated with disturbances in nitric oxide (NO) production. This study was conducted to determine the effect of 5/6 nephrectomy (5/6 Nx) on expression of intrarenal neuronal nitric oxide synthase (nNOS) in the rat. In normal rat kidney, nNOS protein was detected in the macula densa and in the cytoplasm and nuclei of cells of the inner medullary collecting duct by both immunofluorescence and electron microscopy. Western blot analysis revealed that 2 wk after 5/6 Nx, there were significant decreases in nNOS protein expression in renal cortex (sham: 95.42 ± 15.60 versus 5/6 Nx: 47.55 ± 12.78 arbitrary units, P < 0.05, n = 4) and inner medulla (sham: 147.70 ± 26.96 versus 5/6 Nx: 36.95 ± 17.24 arbitrary units, P < 0.005, n = 8). Losartan treatment was used to determine the role of angiotensin II (AngII) AT1 receptors in the inhibition of nNOS expression in 5/6 Nx. Losartan had no effect on the decreased expression of nNOS in the inner medulla, but partially increased nNOS protein expression in the cortex of 5/6 Nx rats. In contrast, in sham rats losartan significantly inhibited nNOS protein expression in the cortex (0.66 ± 0.04-fold of sham values, P < 0.05, n = 6) and inner medulla (0.74 ± 0.12-fold of sham values, P < 0.05, n = 6). nNOS mRNA was significantly decreased in cortex and inner medulla from 5/6 Nx rats, and the effects of losartan on nNOS mRNA paralleled those observed on nNOS protein expression. These data indicate that 5/6 Nx downregulates intrarenal nNOS mRNA and protein expression. In normal rats, AngII AT1 receptors exert a tonic stimulatory effect on expression of intrarenal nNOS. These findings suggest that the reduction in intrarenal nNOS expression in 5/6 Nx may play a role in contributing to hypertension and altered tubular transport responses in chronic renal failure.

scholarly journals Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide–Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia

2008 ◽  
Vol 54 (2) ◽  
pp. 292-300 ◽  
Author(s):  
Renke Maas ◽  
Edzard Schwedhelm ◽  
Lydia Kahl ◽  
Huige Li ◽  
Ralf Benndorf ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Function ◽  
Urinary Excretion ◽  
Indirect Evidence ◽  
No Oxidation ◽  
Whole Body ◽  
Gas Chromatography Mass Spectrometry ◽  
Synthesis Rate ◽  
No Production

Abstract Background: Endothelial function is impaired in hypercholesterolemia and atherosclerosis. Based on mostly indirect evidence, this impairment is attributed to reduced synthesis or impaired biological activity of endothelium-derived nitric oxide (NO). It was the aim of this study to directly estimate and compare whole-body NO production in normo- and hypercholesterolemia by applying a nonradioactive stable isotope dilution technique in vivo. Methods: We enrolled 12 normocholesterolemic and 24 hypercholesterolemic volunteers who were all clinically healthy. To assess whole-body NO synthesis, we intravenously administered l-[guanidino-(15N2)]-arginine and determined the urinary excretion of 15N-labeled nitrate, the specific end product of NO oxidation in humans, by use of gas chromatography-mass spectrometry. In addition, we measured flow-mediated vasodilation (FMD) of the brachial artery, expression of endothelial NOS (eNOS) in platelets, plasma concentration of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA), and urinary excretion of 8-isoprostaglandin F2α (8-iso-PGF2α). Results: After infusion of l-[guanidino-(15N2)]-arginine, cumulative excretion of 15N-labeled-nitrate during 48 h was 40% [95% CI 15%–66%] lower in hypercholesterolemic than normocholesterolemic volunteers [mean 9.2 (SE 0.8) μmol vs 15.4 (2.3) μmol/l, P = 0.003]. FMD was on average 36% [4%–67%] lower in hypercholesterolemic than normocholesterolemic volunteers [6.3 (4.0)% vs 9.4 (4.6)%, P = 0.027]. Normalized expression of NOS protein in platelets was also significantly lower in hypercholesterolemic volunteers, whereas there were no significant differences in plasma ADMA concentration or urinary excretion of 8-iso-PGF2α between the 2 groups. Conclusions: This study provides direct evidence for a decreased whole body NO synthesis rate in healthy people with hypercholesterolemia.

Renal and pressor effects of aminoguanidine in cirrhotic rats with ascites.

1996 ◽  
Vol 7 (12) ◽  
pp. 2694-2699
Author(s):  
M C Ortíz ◽  
L A Fortepiani ◽  
C Martínez ◽  
N M Atucha ◽  
J García-Estañ
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Liver Cirrhosis ◽  
Experimental Model ◽  
Systemic Blood Pressure ◽  
Arterial Hypotension ◽  
Control Group ◽  
No Production ◽  
Water Excretion ◽  
Excretory Function

Recent work indicates that nitric oxide (NO) plays an important role in the systemic and renal alterations of liver cirrhosis. This study used aminoguanidine (AG), a preferential inhibitor of inducible nitric oxide synthase (iNOS), to evaluate the role of this NOS isoform in the systemic and renal alterations of an experimental model of liver cirrhosis with ascites (carbon tetrachloride/ phenobarbital). Experiments have been performed in anesthetized cirrhotic rats and their respective control rats prepared for clearance studies. Administration of AG (10 to 100 mg/kg, iv) elevated dose-dependent mean arterial pressure (MAP, in mm Hg) in the cirrhotic rats from a basal level of 79.3 +/- 3.6 to 115.0 +/- 4.7, whereas in the control animals, MAP increased only with the highest dose of the inhibitor (from 121.8 +/- 3.6 to 133.3 +/- 1.4). In the cirrhotic group, AG also significantly increased sodium and water excretion, whereas these effects were very modest in the control group. Plasma concentration of nitrates+nitrites, measured as an index of NO production, were significantly increased in the cirrhotic animals in the basal period and decreased with AG to levels not significantly different from the control animals. Similar experiments performed with the nonspecific NOS inhibitor N omega-nitro-L-arginine (NNA) also demonstrated an increased pressor sensitivity of the cirrhotic rats, but the arterial hypotension was completely corrected. These results, in an experimental model of liver cirrhosis with ascites, show that AG exerts a beneficial effect as a result of inhibition of NO production, increasing blood pressure and improving the reduced excretory function. Because NNA, but not AG, completely normalized the arterial hypotension, it is suggested that the constitutive NOS isoform is also contributing in an important degree. It is concluded that the activation of both inducible and constitutive NOS isoforms plays an important role in the lower systemic blood pressure and associated abnormalities that characterize liver cirrhosis.

Exercise Training Adaptations in Metabolic Syndrome Individuals on Chronic Statin Treatment

2019 ◽  
Vol 105 (4) ◽  
pp. e1695-e1704 ◽  
Author(s):  
Felix Morales-Palomo ◽  
Miguel Ramirez-Jimenez ◽  
Juan F Ortega ◽  
Alfonso Moreno-Cabañas ◽  
Ricardo Mora-Rodriguez
Keyword(s):  
Metabolic Syndrome ◽  
Exercise Training ◽  
Fat Oxidation ◽  
Time Effect ◽  
Whole Body ◽  
Atherogenic Dyslipidemia ◽  
Control Group ◽  
Training Adaptations ◽  
Statin Group ◽  
Statin Use

Abstract Background Statins reduce atherogenic dyslipidemia and cardiovascular disease (CVD) risk in metabolic syndrome (MetS) individuals. Exercise training could also contribute to reduce CVD by improving cardiorespiratory fitness and fat oxidation. However, statin use could interfere with training adaptations. Methods A total of 106 MetS individuals were divided into statin users (statin group, n = 46) and statin-naïve (control group, n = 60). Groups were matched by age, weight, and MetS components. Subjects completed 16 weeks of high intensity interval training (HIIT). Before and after HIIT, muscle biopsies were collected to assess mitochondrial content (citrate synthase [CS] activity) and the activity of the rate limiting β-oxidation enzyme (3-hydroxyacyl-CoA-dehydrogenase [HAD]). Fasting plasma glucose, insulin, TG, HDL-c, and LDL-c concentrations were measured. Exercise maximal fat oxidation (FOMAX) and oxygen uptake (VO2PEAK) were determined. Results Training improved MetS similarly in both groups (MetS z-score -0.26 ± 0.38 vs. -0.22 ± 0.31; P &lt; 0.001 for time and P = 0.60 for time x group). Before training, the statin group had reduced muscle HAD activity and whole body FOMAX compared to the control group. However, 16 weeks of HIIT increased HAD and FOMAX in both groups (P &lt; 0.03, time-effect). The statin group did not prevent the increases in CS with HIIT observed in the control group (38% vs 64%, respectively; P &lt; 0.001, time-effect). Conversely, with training VO2PEAK improved less in the statin than in the control group (12% vs. 19%, respectively; P = 0.013, time × group effect). Conclusion Chronic statin use in MetS does not interfere with exercise training improvements in MetS components, FOMAX, or mitochondrial muscle enzymes (ie, CS and HAD). However, the statin group attenuated the improvements in VO2PEAK with training. Clinical Trial Information ClinicalTrials.gov identifier no. NCT03019796, January 13, 2017.

scholarly journals Timing-Dependent Protection of Swimming Exercise against d-Galactose-Induced Aging-Like Impairments in Spatial Learning/Memory in Rats

2019 ◽  
Vol 9 (9) ◽  
pp. 236 ◽  
Author(s):  
Xue Li ◽  
Lu Wang ◽  
Shuling Zhang ◽  
Xiang Hu ◽  
Huijun Yang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Exercise Training ◽  
Protein Expression ◽  
Morris Water Maze ◽  
Spatial Learning ◽  
Water Maze ◽  
Training Group ◽  
Swimming Exercise ◽  
Control Group ◽  
Creb Protein

This study was designed to investigate beneficial effects of swimming exercise training on learning/memory, synaptic plasticity and CREB (cAMP response element binding protein) expression in hippocampus in a rat model of d-galactose-induced aging (DGA). Eighty adult male rats were randomly divided into four groups: Saline Control (group C), DGA (group A), Swimming exercise before DGA (group S1), and Swimming during DGA (group S2). These four groups of animals were further divided into Morris water maze training group (M subgroup) and sedentary control group (N subgroup). Spatial learning/memory was tested using Morris water maze training. The number and density of synaptophysin (Syp) and metabotropic glutamate receptor 1 (mGluR1) in hippocampal dentate gyrus area, CREB mRNA and protein expression and DNA methylation levels were determined respectively with immunohistochemistry, western blot, real-time PCR, and MassArray methylation detection platform. We found that compared with group C, DGA rats showed aging-like poor health and weight loss as well as hippocampal neurodegenerative characteristics. Exercise training led to a time-dependent decrease in average escape latency and improved spatial memory. Exercise training group (S2M) had significantly increased swim distance as compared with controls. These functional improvements in S2M group were associated with higher Syp and mGluR1 values in hippocampus (p < 0.01) as well as higher levels of hippocampal CREB protein/mRNA expression and gene methylation. In conclusion, swimming exercise training selectively during drug-induced aging process protected hippocampal neurons against DGA-elicited degenerative changes and in turn maintained neuronal synaptic plasticity and learning/memory function, possibly through upregulation of hippocampal CREB protein/mRNA and reduction of DGA-induced methylation of CREB.

Endothelial nitric oxide production during in vitro simulation of external limb compression

2002 ◽  
Vol 282 (6) ◽  
pp. H2066-H2075 ◽  
Author(s):  
Guohao Dai ◽  
Olga Tsukurov ◽  
Michael Chen ◽  
Jonathan P. Gertler ◽  
Roger D. Kamm
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Umbilical Vein ◽  
Control Group ◽  
No Production ◽  
Vein Thrombosis ◽  
Enos Mrna ◽  
Umbilical Vein Endothelial Cells ◽  
Endothelial Nitric Oxide

External pneumatic compression (EPC) is effective in preventing deep vein thrombosis (DVT) and is thought to alter endothelial thromboresistant properties. We investigated the effect of EPC on changes in nitric oxide (NO), a critical mediator in the regulation of vasomotor and platelet function. An in vitro cell culture system was developed to simulate flow and vessel collapse conditions under EPC. Human umbilical vein endothelial cells were cultured and subjected to tube compression (C), pulsatile flow (F), or a combination of the two (FC). NO production and endothelial nitric oxide synthase (eNOS) mRNA expression were measured. The data demonstrate that in the F and FC groups, there is a rapid release of NO followed by a sustained increase. NO production levels in the F and FC groups were almost identical, whereas the C group produced the same low amount of NO as the control group. Conditions F and FC also upregulate eNOS mRNA expression by a factor of 2.08 ± 0.25 and 2.11 ± 0.21, respectively, at 6 h. Experiments with different modes of EPC show that NO production and eNOS mRNA expression respond to different time cycles of compression. These results implicate enhanced NO release as a potentially important factor in the prevention of DVT.

Aerobic exercise training-induced irisin secretion is associated with the reduction of arterial stiffness via nitric oxide production in adults with obesity

2020 ◽  
Vol 45 (7) ◽  
pp. 715-722 ◽  
Author(s):  
Kenichiro Inoue ◽  
Shumpei Fujie ◽  
Natsuki Hasegawa ◽  
Naoki Horii ◽  
Masataka Uchida ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Exercise Training ◽  
Arterial Stiffness ◽  
Aerobic Exercise ◽  
Animal Study ◽  
Human Study ◽  
Aerobic Exercise Training ◽  
No Production ◽  
Circulating Levels

This study aimed to clarify whether muscle-derived irisin secretion induced by aerobic exercise training is involved in reduction of arterial stiffness via arterial nitric oxide (NO) productivity in obesity. In animal study, 16 Otsuka Long-Evans Tokushima Fatty (OLETF) rats with obesity were randomly divided into 2 groups: sedentary control (OLETF-CON) and 8-week aerobic treadmill training (OLETF-EX) groups. In human study, 15 subjects with obesity completed 8-week aerobic exercise training for 45 min at 60%–70% peak oxygen uptake intensity for 3 days/week. As a result of animal study, carotid-femoral pulse wave velocity (cfPWV) was decreased, and arterial phosphorylation levels of AMP-activated protein kinase (AMPK), protein kinase B (Akt), and endothelial NO synthase (eNOS), circulating levels of nitrite/nitrate (NOx) and irisin, and muscle messenger RNA expression of fibronectin type III domain containing 5 (Fndc5) were increased in the OLETF-EX group compared with OLETF-CON group. In a human study, regular aerobic exercise reduced cfPWV and elevated circulating levels of NOx and irisin. Furthermore, change in circulating irisin levels by regular exercise was positively correlated with circulating NOx levels and was negatively correlated with cfPWV. Thus, aerobic exercise training-induced increase in irisin secretion may be related to reduction of arterial stiffness achieved by NO production via activated arterial AMPK–Akt–eNOS signaling pathway in obesity. Novelty Aerobic exercise training promoted irisin secretion with upregulation of muscle Fndc5 gene expression in rats with obesity. Irisin affected the activation of arterial AMPK–Akt–eNOS signaling by aerobic exercise training. Increased serum irisin level by aerobic exercise training was associated with reduction of arterial stiffness in obese adults.

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