Inhibitory effect of nitric oxide-donating aspirin against prostatic cancer angiogenesis in tumor-bearing mice

Nitric oxide (NO) is known to increase the affinity of the intracellular iron-regulatory protein (IRP) for iron-response elements (IREs) in transferrin receptor and ferritin mRNAs, suggesting that it may act as a regulator of cellular iron metabolism. In this study, exogenous NO produced by adding the NO-generator S-nitroso-N-acetyl penicillamine gave a dose-dependent upregulation of transferrin receptor expression by K562 erythroleukemia cells and increased levels of transferrin receptor mRNA. NO did not affect the affinity of transferrin binding by the transferrin receptor. NO alone did not alter intracellular ferritin levels, but it did abrogate the inhibitory effect of the iron chelator desferrioxamine and potentiated the stimulatory effect of additional iron. NO also caused some increase in ferritin mRNA levels, which might mask any IRP-/IRE-mediated inhibitory effect of NO on ferritin translation. Although NO did not affect net iron uptake, it increased release of iron from K562 cells pulsed previously with 59Fe, and subcellular fractionation showed that it also increased the proportion of intracellular iron bound to ferritin. These findings provide direct evidence that NO can affect cellular iron metabolism and suggest that NO produced in vivo by activated bone marrow macrophages might affect erythropoiesis.

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Pharmacologic responses of the mouse urinary bladder

Open Medicine ◽

10.2478/s11536-008-0082-2 ◽

2009 ◽

Vol 4 (2) ◽

pp. 192-197 ◽

Cited By ~ 1

Author(s):

A. Canda ◽

Christopher Chapple ◽

Russ Chess-Williams

Keyword(s):

Nitric Oxide ◽

Urinary Bladder ◽

Electrical Field Stimulation ◽

Inhibitory Effect ◽

Minor Role ◽

Detrusor Muscle ◽

Field Stimulation ◽

Muscarinic Agonists ◽

Electrical Field ◽

M3 Receptor

AbstractThe aim of the study was to determine pathways involved in contraction and relaxation of the mouse urinary bladder. Mouse bladder strips were set up in gassed Krebs-bicarbonate solution and responses to various drugs and electrical field stimulation were obtained. Isoprenaline (b-receptor agonist) caused a 63% inhibition of carbachol precontracted detrusor (EC50=2nM). Carbachol caused contraction (EC50=0.3µM), responses were antagonised more potently by 4-DAMP (M3-antagonist) than methoctramine (M2-antagonist). Electrical field stimulation caused contraction, which was inhibited by atropine (60%) and less by guanethidine and α,β-methylene-ATP. The neurogenic responses were not potentiated by inhibition of nitric oxide synthase. Presence of an intact urothelium significantly depressed responses to carbachol (p=0.02) and addition of indomethacin and L-NNA to remove prostaglandin and nitric oxide production respectively did not prevent the inhibitory effect of the urothelium. In conclusion, b-receptor agonists cause relaxation and muscarinic agonists cause contraction via the M3-receptor. Acetylcholine is the main neurotransmitter causing contraction while nitric oxide has a minor role. The mouse and human urothelium are similar in releasing a factor that inhibits contraction of the detrusor muscle which is unidentified but is not nitric oxide or a prostaglandin. Therefore, the mouse may be used as a model to study the lower urinary tract.

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Inhibitory effect of the alkyl side chain of caffeic acid analogues on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2008.07.006 ◽

2008 ◽

Vol 16 (16) ◽

pp. 7795-7803 ◽

Cited By ~ 52

Author(s):

Koji Uwai ◽

Yuu Osanai ◽

Takuma Imaizumi ◽

Syu-ichi Kanno ◽

Mitsuhiro Takeshita ◽

...

Keyword(s):

Nitric Oxide ◽

Caffeic Acid ◽

Inhibitory Effect ◽

Side Chain ◽

Nitric Oxide Production ◽

Alkyl Side Chain ◽

Oxide Production ◽

Raw264.7 Macrophages

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Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats

AJP Renal Physiology ◽

10.1152/ajprenal.00065.2003 ◽

2003 ◽

Vol 285 (2) ◽

pp. F295-F302 ◽

Cited By ~ 24

Author(s):

Mong-Heng Wang ◽

Jishi Wang ◽

Hsin-Hsin Chang ◽

Barbara A. Zand ◽

Miao Jiang ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Rat Kidney ◽

Late Pregnancy ◽

Inhibitory Effect ◽

Female Rats ◽

Male Rats ◽

Pregnant Rats ◽

Renal Vasoconstriction ◽

Dependent Inhibition

20-Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P-450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm, indicating the formation of a ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about twofold higher than that of CYP4A1. Incubation of SNP or peroxynitrite (PN; 0.01–1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65 and 59%, respectively. We previously showed that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis are decreased in late pregnancy. Therefore, we investigated whether such a decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of NG-nitro-l-arginine methyl ester (l-NAME) to pregnant rats for 6 days ( days 15- 20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2/NO3 excretion decreased by 40 and 52% in l-NAME- and l-NAME + ABT-treated groups, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following l-NAME treatment, and this increase was diminished with coadministration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.

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Endogenous flow-induced nitric oxide reduces superoxide-stimulated Na/H exchange activity via PKG in thick ascending limbs

AJP Renal Physiology ◽

10.1152/ajprenal.00583.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. F444-F449 ◽

Cited By ~ 5

Author(s):

Nancy J. Hong ◽

Jeffrey L. Garvin

Keyword(s):

Nitric Oxide ◽

Soluble Guanylate Cyclase ◽

Inhibitory Effect ◽

Dependent Protein Kinase ◽

Two Factors ◽

Endogenous Nitric Oxide ◽

Dependent Protein ◽

Acid Load ◽

Luminal Flow ◽

Ly 83583

Luminal flow stimulates endogenous nitric oxide (NO) and superoxide (O2−) production by renal thick ascending limbs (TALs). The delicate balance between these two factors regulates Na transport in TALs; NO enhances natriuresis, whereas O2− augments Na absorption. Endogenous, flow-stimulated O2− enhances Na/H exchange (NHE). Flow-stimulated NO reduces flow-induced O2−, a process mediated by cGMP-dependent protein kinase (PKG). However, whether flow-stimulated, endogenously-produced NO diminishes O2−-stimulated NHE activity and the signaling pathway involved are unknown. We hypothesized that flow-induced NO reduces the stimulation of NHE activity caused by flow-induced O2− via PKG in TALs. Intracellular pH recovery after an acid load was measured as an indicator of NHE activity in isolated, perfused rat TALs. l-Arginine, the NO synthase substrate, decreased NHE activity by 34 ± 5% ( n = 5; P < 0.04). The O2− scavenger tempol decreased NHE activity by 46 ± 8% ( n = 6; P < 0.004) in the absence of NO. In the presence of l-arginine, the inhibitory effect of tempol on NHE activity was reduced to −19 ± 6% ( n = 6; P < 0.03). The soluble guanylate cyclase inhibitor LY-83583 blocked the effect of l-arginine thus restoring tempol's effect on NHE activity to −42 ± 4% ( n = 6; P < 0.0005). The PKG inhibitor KT-5823 also inhibited l-arginine's effect on tempol-reduced NHE activity (−43 ± 5%; n = 5; P < 0.03). We conclude that flow-induced NO reduces the stimulatory effect of endogenous, flow-induced O2− on NHE activity in TALs via an increase in cGMP and PKG activation.

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Haloperidol increases spreading and nitric oxide production in macrophages from tumor-bearing mice: a possible mechanism for its antitumoral effect

International Journal of Immunopharmacology ◽

10.1016/s0192-0561(99)00036-3 ◽

1999 ◽

Vol 21 (9) ◽

pp. 575-580 ◽

Cited By ~ 14

Author(s):

Silvia R Kleeb ◽

Márcia dos S Rizzo ◽

Maria L.Z Dagli ◽

Roberto Frussa-Filho

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Production ◽

Antitumoral Effect ◽

Tumor Bearing ◽

Oxide Production

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Inhibitory Effect of Trimidox on Lipopolysaccharide-Induced Nitric Oxide Production in RAW 264.7 Macrophages

Journal of Pharmacological Sciences ◽

10.1254/jphs.sc0070073 ◽

2007 ◽

Vol 104 (3) ◽

pp. 278-281 ◽

Cited By ~ 3

Author(s):

Syu-ichi Kanno ◽

Mai Kakuta ◽

Yasue Kitajima ◽

Yuu Osanai ◽

Kaori Kurauchi ◽

...

Keyword(s):

Nitric Oxide ◽

Inhibitory Effect ◽

Raw 264.7 ◽

Nitric Oxide Production ◽

Raw 264.7 Macrophages ◽

Oxide Production

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IFN-γ + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38 mapk in a mouse macrophage cell line

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.3.c441 ◽

2001 ◽

Vol 280 (3) ◽

pp. C441-C450 ◽

Cited By ~ 246

Author(s):

Edward D. Chan ◽

David W. H. Riches

Keyword(s):

Nitric Oxide ◽

Cell Line ◽

Inhibitory Effect ◽

Interferon Γ ◽

Dominant Negative ◽

Jnk Pathway ◽

Mutant Proteins ◽

Inos Promoter ◽

Ifn Γ ◽

Inos Induction

Nitric oxide (NO·) produced by inducible nitric oxide synthase (iNOS) mediates a number of important physiological and pathophysiological processes. The objective of this investigation was to examine the role of mitogen-activated protein kinases (MAPKs) in the regulation of iNOS and NO· by interferon-γ (IFN-γ) + lipopolysaccharide (LPS) in macrophages using specific inhibitors and dominant inhibitory mutant proteins of the MAPK pathways. The signaling pathway utilized by IFN-γ in iNOS induction is well elucidated. To study signaling pathways that are restricted to the LPS-signaling arm, we used a subclone of the parental RAW 264.7 cell line that is unresponsive to IFN-γ alone with respect to iNOS induction. In this RAW 264.7γNO(−) subclone, IFN-γ and LPS are nevertheless required for synergistic activation of the iNOS promoter. We found that extracellular signal-regulated kinase (ERK) augmented and p38 mapk inhibited IFN-γ + LPS induction of iNOS. Dominant-negative MAPK kinase-4 inhibited iNOS promoter activation by IFN-γ + LPS, also implicating the c-Jun NH2-terminal kinase (JNK) pathway in mediating iNOS induction. Inhibition of the ERK pathway markedly reduced IFN-γ + LPS-induced tumor necrosis factor-α protein expression, providing a possible mechanism by which ERK augments iNOS expression. The inhibitory effect of p38 mapk appears more complex and may be due to the ability of p38 mapk to inhibit LPS-induced JNK activation. These results indicate that the MAPKs are important regulators of iNOS-NO· expression by IFN-γ + LPS.

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