Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for L-arginine

1995 ◽  
Vol 268 (1) ◽  
pp. G183-G188 ◽  
Author(s):  
J. Stadler ◽  
D. Barton ◽  
H. Beil-Moeller ◽  
S. Diekmann ◽  
C. Hierholzer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Hepatic Dysfunction ◽  
Urea Synthesis ◽  
No Donors ◽  
Gapdh Activity ◽  
Urea Production ◽  
Dependent Inhibition ◽  
High Concentrations ◽  
Glucose Output ◽  
Exact Correlation

Inflammatory stimulation of the liver is known to induce nitric oxide (NO) biosynthesis. NO can interfere with the activity of a number of enzymes important to cellular metabolism. This study was carried out to investigate the influence of NO on rat hepatocyte glucose output and urea production. Induction of NO synthesis by incubation with a combination of cytokines and lipopolysaccharide led to a 48.8 +/- 2.4% inhibition of glucose output and to a 45.0 +/- 6.4% suppression of urea production. Inhibition of NO synthesis with NG-monomethyl-L-arginine was able to totally prevent these effects. High concentrations of L-arginine overcame the inhibition of urea production caused by endogenous NO synthesis. Exposure of HC to NO donors resulted in a concentration-dependent inhibition of glucose output, without having any effect on urea production. Hepatocellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was also found to be inhibited by endogenously produced NO (33.5 +/- 5.2%), as well as by exogenously applied NO. However, an exact correlation between GAPDH activity and glucose output could not be established. These data indicate that NO biosynthesis may contribute to the development of hepatic dysfunction in chronic sepsis.

NO inhibits Na+-K+-2Cl−cotransport via a cytochrome P-450-dependent pathway in renal epithelial cells (MMDD1)

2003 ◽  
Vol 284 (6) ◽  
pp. F1235-F1244 ◽  
Author(s):  
Hao He ◽  
Tiina Podymow ◽  
Joseph Zimpelmann ◽  
Kevin D. Burns
Keyword(s):  
Nitric Oxide ◽  
Cytosolic Calcium ◽  
Inhibitory Effect ◽  
Epoxyeicosatrienoic Acid ◽  
No Donors ◽  
Dependent Inhibition ◽  
A Cell ◽  
Oxide Synthase ◽  
Cytochrome P 450 ◽  
Dependent Pathway

Nitric oxide (NO) exerts direct effects on nephron transport. We determined the effect of NO on Na+-K+-2Cl− cotransport in a cell line (MMDD1) with properties of macula densa. Na+-K+-2Cl− cotransport was measured as bumetanide-sensitive 86Rb+ uptake in the presence of ouabain. MMDD1 cells expressed mRNA for the neuronal isoform of nitric oxide synthase, as well as NKCC1 and NKCC2(B) isoforms of the Na+-K+-2Cl−cotransporter. Preincubation of cells with the NO donors sodium nitroprusside (SNP) or S-nitroso- N-acetylpenicillamine (SNAP) caused concentration-dependent inhibition of Na+-K+-2Cl− cotransport. Both apical and basolateral Na+-K+-2Cl−cotransport was inhibited by NO donors. SNP or SNAP had no significant effect on cellular levels of cGMP, cAMP, cytosolic calcium, or phosphorylation of ERK1 and ERK2. In contrast, the inhibitors of cytochrome P-450, 1-aminobenzotriazole (ABT; 10−3 M) or ketoconazole (1.5 × 10−5 M), completely reversed the inhibitory effect of SNAP on apical or basolateral Na+-K+-2Cl−cotransport [apical: control 1.18 ± 0.15 vs. SNAP (10−4 M) 0.41 ± 0.05 pmol · mg−1 · 5 min−1; P < 0.001; SNAP (10−4M) + ABT 1.32 ± 0.10 pmol · mg−1 · 5 min−1; P = not significant vs. control; n = 5]. The cytochrome P-450 epoxyeicosatrienoic acid (EET) metabolite 14,15-EET (5 × 10−7 M) inhibited both apical and basolateral cotransport, whereas 8,9-EET and 11,12-EET had no significant effect. Although 20-hydroxyeicosatetraenoic acid inhibited apical cotransport, the inhibitor of ω-hydroxylase activity HET0016 did not reverse SNAP-mediated inhibition of apical cotransport. These data indicate that NO inhibits apical and basolateral Na+-K+-2Cl− cotransport in MMDD1 cells. The results suggest that the inhibitory pathway is independent of cGMP and might involve stimulation of a cytochrome P-450-dependent pathway.

Growth inhibition and chemosensitization of exogenous nitric oxide released from NONOates in glioma cells in vitro

2009 ◽  
Vol 110 (1) ◽  
pp. 128-136 ◽  
Author(s):  
Astrid Weyerbrock ◽  
Brunhilde Baumer ◽  
Anna Papazoglou
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Vascular Permeability ◽  
Glioma Cells ◽  
Glioblastoma Cells ◽  
No Donors ◽  
Exogenous Nitric Oxide ◽  
High Concentrations ◽  
Spermine Nonoate

Object Exogenous nitric oxide (NO) from NO donors has cytotoxic, chemosensitizing, and radiosensitizing effects, and increases vascular permeability and blood flow in tumors. Yet little is known about whether these cytotoxic and chemosensitizing effects can be observed in glioma cells at doses that alter tumor physiological characteristics in vivo and whether these effects are tumor selective. Methods The effect of NO released from proline NONOate, diethylamine NONOate, spermine NONOate, and sodium nitrite on cell proliferation, apoptosis, and chemosensitivity to carboplatin of cultured glioma cells was studied in C6, U87 glioma cells, human glioblastoma cells, and human astrocytes and fibroblasts. Results Although proline NONOate failed to induce cell death, the other NO donors induced growth arrest when present in high concentrations (10−2 M) in all cell lines. Chemosensitization was observed after concomitant incubation with spermine NONOate and carboplatin in C6 and human glioblastoma cells. There is strong evidence that cell death occurs primarily by necrosis and to a lesser degree by apoptosis. The NO doses, which altered tumor physiology in vivo, were not cytotoxic, indicating that NO alters vascular permeability and cell viability in vivo by different mechanisms. Conclusions The authors found that NO-generating agents at high concentrations are potent growth inhibitors and might also be useful as chemosensitizers in glioma cells. These data corroborate the theory that the use of NOgenerating agents may play a role in the multimodal treatment of malignant gliomas but that the NO release must be targeted more specifically to tumor cells to improve selectivity and efficacy.

Activity of nitric oxide-generating compounds against encephalomyocarditis virus.

1996 ◽  
Vol 40 (4) ◽  
pp. 1057-1059 ◽  
Author(s):  
E Guillemard ◽  
M Geniteau-Legendre ◽  
R Kergot ◽  
G Lemaire ◽  
J F Petit ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Virus Replication ◽  
Encephalomyocarditis Virus ◽  
Virus Growth ◽  
No Donors ◽  
Low Level ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Nitric oxide (NO) generated by two NO donors (sodium nitroprusside or S-nitroso-L-glutathione) was shown to exert a dose-dependent inhibition of encephalomyocarditis virus growth in L-929 cells. This activity was not due to the cytotoxic or direct virucidal effects of NO donors. L-929 cells were shown to produce NO endogenously, but this low level of production did not counter encephalomyocarditis virus replication.

Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury

1997 ◽  
Vol 273 (3) ◽  
pp. L504-L512 ◽  
Author(s):  
Y. C. Huang ◽  
P. W. Fisher ◽  
E. Nozik-Grayck ◽  
C. A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Average Rate ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
No Production ◽  
Protective Effects ◽  
Lung Weight ◽  
Edema Formation ◽  
No Donors

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

DNA Methylation Changes Induced in Rice by Exposure to High Concentrations of the Nitric Oxide Modulator, Sodium Nitroprusside

2015 ◽  
Vol 33 (5) ◽  
pp. 1428-1440 ◽  
Author(s):  
Xiufang Ou ◽  
Tingting Zhuang ◽  
Wenchao Yin ◽  
Yiling Miao ◽  
Bo Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Methylation ◽  
Sodium Nitroprusside ◽  
High Concentrations

scholarly journals The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice.

1996 ◽  
Vol 183 (4) ◽  
pp. 1447-1459 ◽  
Author(s):  
F P Huang ◽  
G J Feng ◽  
G Lindop ◽  
D I Stott ◽  
F Y Liew
Keyword(s):  
Nitric Oxide ◽  
Autoimmune Disease ◽  
Cultured Cells ◽  
Daily Injection ◽  
Interleukin 12 ◽  
No Production ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
Peritoneal Cells ◽  
High Concentrations

MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum from these mice contained significantly higher concentrations of nitrite/nitrate than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice. Spleen and peritoneal cells from MRL/lpr mice also produced significantly more nitric oxide (NO) than those from the control mice when cultured with interferon (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that peritoneal cells from MRL/lpr mice also produced markedly higher concentrations of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with same stimuli. It is striking that cells from MRL/lpr mice produced high concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced NO synthesis induced by IFN-gamma/LPS was substantially inhibited by anti-IL-12 antibody. In addition, IL-12-induced NO production can also be markedly inhibited by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis factor alpha antibody. The effect of IL-12 on NO production was dependent on the presence of natural killer and possibly T cells. Serum from MRL/lpr mice contained significantly higher concentrations of IL-12 compared with those of MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to increased serum levels of IFN-gamma and NO metabolites, and accelerated glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared with controls injected with phosphate-buffered saline alone. These data, together with previous finding that NO synthase inhibitors can ameliorate autoimmune disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12 and their greater responsiveness to IL-12, leading to the production of high concentrations of NO, are important factors in this spontaneous model of autoimmune disease.

Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells

2004 ◽  
Vol 287 (1) ◽  
pp. L60-L68 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Tamara L. Young ◽  
Leif D. Nelin
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
No Synthase ◽  
No Production ◽  
Urea Production ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Regular Medium ◽  
Necrosis Factor

Nitric oxide (NO) is produced by NO synthase (NOS) from l-arginine (l-Arg). Alternatively, l-Arg can be metabolized by arginase to produce l-ornithine and urea. Arginase (AR) exists in two isoforms, ARI and ARII. We hypothesized that inhibiting AR with l-valine (l-Val) would increase NO production in bovine pulmonary arterial endothelial cells (bPAEC). bPAEC were grown to confluence in either regular medium (EGM; control) or EGM with lipopolysaccharide and tumor necrosis factor-α (L/T) added. Treatment of bPAEC with L/T resulted in greater ARI protein expression and ARII mRNA expression than in control bPAEC. Addition of l-Val to the medium led to a concentration-dependent decrease in urea production and a concentration-dependent increase in NO production in both control and L/T-treated bPAEC. In a second set of experiments, control and L/T bPAEC were grown in EGM, EGM with 30 mM l-Val, EGM with 10 mM l-Arg, or EGM with both 10 mM l-Arg and 30 mM l-Val. In both control and L/T bPAEC, treatment with l-Val decreased urea production and increased NO production. Treatment with l-Arg increased both urea and NO production. The addition of the combination l-Arg and l-Val decreased urea production compared with the addition of l-Arg alone and increased NO production compared with l-Val alone. These data suggest that competition for intracellular l-Arg by AR may be involved in the regulation of NOS activity in control bPAEC and in response to L/T treatment.

Inhibition of endotoxemia-induced nitric oxide synthase expression by cyclosporin A enhances hepatocyte injury in rats: amelioration by NO donors

2002 ◽  
Vol 2 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Hassan Farghali ◽  
Nikolina Canová ◽  
Norbert Gaier ◽  
Dagmar Lincová ◽  
Eva Kmonı́čková ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cyclosporin A ◽  
No Donors ◽  
Hepatocyte Injury ◽  
Oxide Synthase

scholarly journals Differential mechanisms of inhibition of glyceraldehyde-3-phosphate dehydrogenase by S-nitrosothiols and NO in cellular and cell-free conditions

2010 ◽  
Vol 299 (4) ◽  
pp. H1212-H1219 ◽  
Author(s):  
Katarzyna A. Broniowska ◽  
Neil Hogg
Keyword(s):  
Nitric Oxide ◽  
Signaling Mechanism ◽  
Aortic Endothelial Cells ◽  
Signaling Specificity ◽  
Physiological Conditions ◽  
Irreversible Inhibition ◽  
Bovine Aortic Endothelial Cells ◽  
Mechanism Of Inhibition ◽  
Dependent Inhibition ◽  
Inhibition Pattern

S-nitrosothiols are nitric oxide (NO)-derived molecules found in biological systems. They have been variously discussed as both NO reservoirs and as major actors in NO-dependent, but cGMP-independent, signal transduction. Although S-nitrosation of specific cysteine residues has been suggested to represent a novel redox-based signaling mechanism, the exact mechanisms of S-nitrosothiol formation under (patho)physiological conditions and the determinants of signaling specificity have not yet been established. Here we examined the sensitivity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to inhibition by S-nitrosocysteine (CysNO) and NO both intracellularly and in isolation. Bovine aortic endothelial cells (BAECs) and purified GAPDH preparations were treated with CysNO or NO, and enzymatic activity was monitored. Intracellular GAPDH was irreversibly inhibited upon CysNO administration, whereas treatment with NO resulted in a DTT-reversible inhibition of the enzyme. Purified GAPDH was inhibited by both CysNO and NO, but the inhibition pattern was diametrically opposite to that observed in the cells; CysNO-dependent inhibition was reversed with DTT, whereas NO-dependent inhibition was not. In the presence of GSH, NO inhibited purified GAPDH in a DTT-reversible way. Our data suggest that in response to CysNO treatment, cellular GAPDH undergoes S-nitrosation, which results in an irreversible inhibition of the enzyme under turnover conditions. In contrast, NO inhibits the enzyme via oxidative mechanisms that do not involve S-nitrosation and are reversible. In summary, our data show that GAPDH is a target for CysNO- and NO-dependent inhibition; however, these two agents inhibit the enzyme via different mechanisms both inside the cell and in isolation. Additionally, the differences observed between the cellular system and purified protein strongly imply that the intracellular environment dictates the mechanism of inhibition.

scholarly journals In vitro anticancer activity of hydrogen sulfide and nitric oxide alongside nickel nanoparticle and novel mutations in their genes in CRC patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zjwan Housein ◽  
Tayeb Sabir Kareem ◽  
Abbas Salihi
Keyword(s):  
Nitric Oxide ◽  
Cell Proliferation ◽  
Hydrogen Sulfide ◽  
Direct Sequencing ◽  
Scorpion Venom ◽  
Enos Gene ◽  
Cytotoxic Activities ◽  
No Donors ◽  
The Impact

AbstractThis study was carried out to assess the impact of nickel nanoparticles (NiNPs) as well as scorpion venom on colorectal cancer (CRC) cells in the presence and/or absence of 5-fluorouracil (5-FU), hydrogen sulfide (H2S), and nitric oxide (NO) donors and to determine alterations in endothelial NO synthase (eNOS) and cystathionine γ-lyase (CSE) enzyme-producing genes in CRC patients. The IC50 of both H2S and NO donors, along with NiNPs, were determined. The CRC cells were treated for 24hrs, and the cytotoxic activities were assessed using the MTT test. Moreover, the apoptosis was determined after 24hrs and 48hrs using TUNEL assay. Furthermore, the mutations in the eNOS gene (intron 4, -786T>C and 894 G>T) and CSE gene (1364GT) were determined using direct sequencing. The IC50 values for sodium disulfide (Na2S) and sodium nitroprusside (SNP) at 24hrs treatment were found to be 5 mM and 10−6 M, respectively, while the IC50 value for 5-FU was reached after 5-days of treatment in CRC cell line. Both black and yellow scorpion venoms showed no inhibition of cell proliferation after 24hrs treatment. Furthermore, Na2S showed a significant decrease in cell proliferation and an increase in apoptosis. Moreover, a co-treatment of SNP and 5-FU resulted in inhibition of the cytotoxic effect of 5-FU, while a combination treatment of NiNPs with Na2S, SNP, and 5-FU caused highly significant cytotoxicity. Direct sequencing reveals new mutations, mainly intronic variation in eNOS gene that has not previously been described in the database. These findings indicate that H2S promotes the anticancer efficiency of 5-FU in the presence of NiNPs while NO has antiapoptotic activity in CRC cell lines.

Sign in / Sign up

Export Citation Format

Share Document