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PubMed2004

Magnetic resonance and biochemical studies during pentylenetetrazole-kindling development: the relationship between nitric oxide, neuronal nitric oxide synthase and seizures.

The major aim of this study was to elucidate the role of nitric oxide (NO) in the development of pentylenetetrazole (PTZ)-kindling as an animal model of primary generalized epilepsy. The daily administration of PTZ is associated with an increase in the amount of neuronal nitric oxide synthase (nNOS). NO generation was measured directly by in vivo and ex vivo electron paramagnetic resonance on rodents undergoing progressive convulsions. We found that primary generalized epilepsy is caused by NO induction during the persistent up-regulation of nNOS expression, but that NO induction is not associated with severe generalized seizures following long-term kindling phenomena after PTZ withdrawal. Morphological changes in the brain structure of rats were measured by magnetic resonance imaging during epileptic convulsions induced by repetitive administration of PTZ. Cerebellum volume for kindled rats decreased 20% but not in rats treated with the nNOS inhibitor, 3Br-7NI, suggesting that generation of NO in the cerebellum is related to decrease in cerebellum volume following PTZ-kindling.

Analysis of Variance↗

PubMed1997

Nitric oxide and nitric oxide synthase: biology, pathology, localization.

Nitric oxide (NO) has opened a new and vigorous field of biological and clinical experimentation as evidenced presently by about one hundred original publications every week. Being a biological signal under physiological conditions, NO may be < > to pathologically affected tissues. Major insights into the biology and pathology of this unorthodox biomolecule have come from the histochemical analysis of NO synthase (NOS) and its molecular isoforms that are responsible for the formation of NO. Immunocytochemistry as well as NADPH-diaphorase histochemistry are most widely used to visualize NOS in various tissues. There are several constraints regarding specificity and sensitivity of the techniques used and, therefore, apparent discrepancies in the literature concerning the cellular and subcellular distribution of NOS and its isoforms. Despite such inconsistencies there is a wealth of data that has an important impact on further investigation of NO-mediated processes underlying a vast number of NO-mediated physiological and pathological mechanisms.

Animals↗

PubMed1993

Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine.

Nitric oxide (NO) in oxygen-containing aqueous solution has a short half-life that is often attributed to a rapid oxidation to both NO2- and NO3-. The chemical fate of NO in aqueous solution is often assumed to be the same as that in air, where NO is oxidized to NO2 followed by dimerization to N2O4. Water then reacts with N2O4 to form both NO2- and NO3-. We report here that NO in aqueous solution containing oxygen is oxidized primarily to NO2- with little or no formation of NO3-. In the presence of oxyhemoglobin or oxymyoglobin, however, NO and NO2- were oxidized completely to NO3-. Methemoglobin was inactive in this regard. The unpurified cytosolic fraction from rat cerebellum, which contains constitutive NO synthase activity, catalyzed the conversion of L-arginine primarily to NO3- (NO2-/NO3- ratio = 0.25). After chromatography on DEAE-Sephacel or affinity chromatography using 2',5'-ADP-Sepharose 4B, active fractions containing NO synthase activity catalyzed the conversion of L-arginine primarily to NO2- (NO2-/NO3- ratio = 5.6) or only to NO2-, respectively. Unpurified cytosol from activated rat alveolar macrophages catalyzed the conversion of L-arginine to NO2- without formation of NO3-. Addition of 30 microM oxyhemoglobin to all enzyme reaction mixtures resulted in the formation primarily of NO3- (NO2-/NO3- ratio = 0.09 to 0.20). Cyanide ion, which displaces NO2- from its binding sites on oxyhemoglobin, inhibited the formation of NO3-, thereby allowing NO2- to accumulate. These observations indicate clearly that the primary decomposition product of NO in aerobic aqueous solution is NO2- and that further oxidation to NO3- requires the presence of additional oxidizing species such as oxyhemoproteins.

Amino Acid Oxidoreductases↗

PubMed1999

Nitric oxide. II. Nitric oxide protects in intestinal inflammation.

This article examines the evidence for nitric oxide (NO) as a protective agent in splanchnic ischemia-reperfusion and other forms of acute intestinal inflammation. Four major points emerge from this body of data. First, acute intestinal inflammation results in an early (i.e., <5 min) and severe decrease in endothelium-derived NO. Thus the early trigger event in this condition is a functional loss of NO. Second, administration of exogenous NO, NO donors, or NO precursors ameliorate splanchnic ischemia-reperfusion and other forms of acute intestinal inflammation (i.e., splanchnic trauma). These beneficial effects occur at physiological levels of NO when given early in the course of the inflammatory state. Third, blockade of nitric oxide synthase (NOS) or gene deletion of NOS exacerbates intestinal inflammation. Fourth, there are a variety of signaling mechanisms that may mediate the protective effect of NO.

Animals↗

PubMed2004

Physiologic role of nitric oxide and nitric oxide synthase in female lower urinary tract.

PURPOSE OF REVIEW: In recent years nitric oxide (NO) has gained increasing recognition as an important neurotransmitter and cell signaling molecule with a broad range of functions in the lower urinary tract. This review discusses recently published data related to the physiologic and pathophysiologic roles of NO and nitric oxide synthase (NOS) in the female lower urinary tract. RECENT FINDINGS: Expression of three isoforms of NOS, namely endothelial NOS, neuronal NOS and inducible NOS, has been identified in various tissues of the lower urinary tract in animals and humans. In addition to its relaxation effects on bladder and urethra, NO also serves as a neurotransmitter in the lower urinary tract. The physiologic roles of NO in overactive bladder, bladder outlet obstruction, diabetic cystopathy, interstitial cystitis, and bladder inflammation have been demonstrated. SUMMARY: NO plays an important role in the micturition process and in disorders of the lower urinary tract. Improved understanding of the pathophysiologic role of NO/NOS system and of the L-arginine-NO-cGMP pathway may allow us to identify suitable therapeutic targets for lower urinary tract disorders. However, there is a need for further investigation to determine the precise function of NO in human lower urinary tract because most work thus far has been done in animal models.

Cystitis↗

PubMed1998

Evidence for the involvement of nitric oxide and nitric oxide synthase in the modulation of opioid-induced antinociception and the inhibitory effects of exposure to 60-Hz magnetic fields in the land snail.

The attenuation of opioid peptide-mediated antinociception is a well-established effect of extremely low frequency (ELF) electromagnetic fields with alterations in calcium channel function and/or calcium ion flux and protein kinase C activity being implicated in the mediation of these effects. The present study was designed to examine the effects of nitric oxide (NO) and calcium ion/calmodulin-dependent nitric oxide synthase (NOS) on opioid-induced antinociception and their involvement in mediating the inhibitory effects of exposure to ELF magnetic fields. We observed that enkephalinase (SCH 34826)-induced, and likely enkephalin-mediated, antinociception in the land snail, Cepaea nemoralis, as measured by the enhanced latency of a foot withdrawal response to a thermal (40 degreesC) stimulus, was reduced by the NO releasing agent, S-nitro-N-acetylpenicillamide (SNP), and enhanced by the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME). Exposure of snails to an ELF magnetic field (15 min, 60 Hz, 141 microT peak) also reduced the enkephalinase-induced antinociception. The inhibitory effects of the 60-Hz magnetic field were significantly reduced by the NO synthase inhibitor, l-NAME, and significantly enhanced by the NO releasing agent, SNP, at dosages which by themselves had no evident effects on nociceptive sensitivity. These results suggest that: (1) NO and NO synthase have antagonistic effects on opioid-induced analgesia in the snail, Cepaea and (2) the inhibitory effects of ELF magnetic fields on opioid analgesia involve alteration in NO and NO synthase activity.

Animals↗

PubMed2000

Effect of nitric oxide and nitric oxide donors on red blood cell oxygen transport.

A mechanism has been proposed in which nitric oxide (NO) may bind to cysteine beta93 and be transported by haemoglobin from the lungs to the tissues and modify vascular tone. In addition, it has been reported that treatment of sickle cell anaemia blood with 80 p.p.m. NO gas in air shifts the oxygen affinity, as measured by P50 to the left. We exposed normal and sickle cell anaemia blood to 80 p.p.m. NO in air for 1 h in vitro and found no change in P50 of either normal or sickle cell blood. In addition, we exposed normal and sickle cell blood in buffer to aqueous NO (NO gas dissolved in buffer) at varying concentrations and found that the induced left shift in P50 correlates strongly and linearly with methaemoglobin formation. We also treated normal and sickle cell blood with other nitric oxide donors, such as sodium 2-(N, N-diethylamino)-diazenolate-2-oxide (DEANO), S-nitrosocysteine (CysNO) and sodium trioxodinitrate (OXINO, or Angeli's salt). In all cases, we found a dose-dependent increase in methaemoglobin that was strongly correlated with the dose-dependent P50 reduction. Our data do not support the report that low NO concentrations can selectively increase the oxygen affinity of sickle cell blood without affecting methaemoglobin levels significantly. NO, however, may have benefit in sickle cell disease by other mechanisms.

Anemia, Sickle Cell↗

PubMed2001

Nitric oxide- and nitric oxide donors-induced relaxation and its modulation by oxidative stress in piglet pulmonary arteries.

Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary hypertension while inhaled NO donors have been suggested as an alternative therapy. The differential susceptibility to inactivation by oxidative stress and oxyhaemoglobin of NO and two NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetyl-penicillamine (SNAP) were analysed in isolated endothelium-denuded pulmonary arteries from 2-week-old piglets stimulated with U46619. NO, SNAP and SNP relaxed the arteries (pIC(30)=7.73+/-0.12, 7.26+/-0.17 and 6.43+/-0.13, respectively) but NO was not detected electrochemically in the bath after the addition of SNP and only at concentrations at which SNAP produced more than 50% relaxation. The sGC inhibitor ODQ (10(-6) M) or the sarcoplasmic Ca(2+)-ATPase thapsigargin (2x10(-6) M) markedly inhibited the relaxation induced by NO, SNAP and SNP. Addition of oxyhaemoglobin (3x10(-7) M) or diethyldithiocarbamate (1 mM) markedly inhibited NO- (pIC(30)=6.88+/-0.07 and 6.92+/-0.18, respectively), weakly inhibited SNAP- and had no effect on SNP-induced relaxation. Xanthine oxidase (5 mu ml(-1)) plus hypoxanthine (10(-4) M) markedly inhibited NO- (pIC(30)=6.96+/-0.12) but not SNAP- or SNP-induced relaxation. Superoxide dismutase (SOD), MnCl(2), diphenileneiodonium and exposing the luminal surface of the rings outwards (inversion) potentiated the relaxant responses of NO (pIC(30)=8.52+/-0.16, 8.23+/-0.11, 8.01+/-0.11 and 8.20+/-0.10, respectively). However, SOD did not modify the NO detected by the electrode and had no effect on SNAP- or SNP-induced relaxation. Therefore, the kinetics and local distribution of NO release of NO donors influence the susceptibility to the scavenging effects of oxyhaemoglobin and superoxide.

Animals↗

PubMed2005

Effect of Helicobacter pylori infection on gastric mucosal pathologic change and level of nitric oxide and nitric oxide synthase.

AIM: To investigate the level of nitric oxide (NO) and nitrous oxide synthase (NOS) enzyme and its effect on gastric mucosal pathologic change in patients infected with Helicobacter pylori (H pylori), and to study the pathogenic mechanism of H pylori. METHODS: The mucosal tissues of gastric antrum were taken by endoscopy, then their pathology, H pylori and anti-CagA-IgG were determined. Fifty H pylori positive cases and 35 H pylori negative cases were randomly chosen. Serum level of NO and NOS was detected. RESULTS: One hundred and seven cases (71.33%) were anti-CagA-IgG positive in 150 H pylori positive cases. The positive rate was higher especially in those with pre-neoplastic diseases, such as atrophy, intestinal metaplasia and dysplasia. The level of NO and NOS in positive group was higher than that in negative group, and apparently lower in active gastritis than in pre-neoplastic diseases such as atrophy, intestinal metaplasia and dysplasia. CONCLUSION: H pylori is closely related with chronic gastric diseases, and type I H pylori may be the real factor for H pylori-related gastric diseases. Infection with H pylori can induce elevation of NOS, which produces NO.

Chronic Disease↗

PubMed2002

Regulation of caspases by nitric oxide.

Nitric oxide can prevent or induce apoptosis depending on its concentration, cell type, and the oxidative milieu. Nitric oxide inhibits apoptosis and inflammation by S-nitrosylation of the active site cysteine of caspases, the central effector molecules of cell death as well as maturation of IL-1beta and IL-18. The ability of nitric oxide to S-nitrosylate caspases depends on multiple factors including the presence of free iron and intracellular redox potential. There are no known direct effects of nitric oxide on promoting caspase activation or activity. However, nitric oxide has been shown to promote apoptotic pathways in numerous cell types through the indirect activation of caspases. In this article we review the relationship of nitric oxide and caspase activity, modulation of this effect by iron, and clinical implications for the use of nitric oxide in regulating inflammation and apoptosis.

Animals↗

PubMed2002

Nitric oxide and nitric oxide synthases in the fetal cerebral cortex of rats following transient uteroplacental ischemia.

The effect of transient uteroplacental ischemia on nitric oxide (NO) levels, enzymatic activity, and expression of NO synthase (NOS) isoforms was studied in fetal rat brains. Fetuses were subjected to ischemia by clamping the uterine arteries for 5 min on gestational day 17 (GD17). At different times after ischemia, fetuses were delivered by Cesarean section under anesthesia to obtain the brains. Transient uteroplacental ischemia produced a time dependent increase in nitrite levels in the brain, reaching a maximum value (300 +/- 25% of baseline) 24 h after uterine artery occlusion and remaining elevated as long as 48 h. Significantly increased nitrite levels were found in the cerebral cortex but not in the mesencephalon and cerebellum. The ischemia-induced increment in nitrite levels was totally blocked by either L-NAME (10 mg/kg) or AMT (0.65 mg/kg) administered i.p. 1 h before uterine artery occlusion. Both Ca(2+)-dependent and Ca(2+)-independent NOS activities in the cerebral cortex remained significantly increased with respect to controls after 24 h following the ischemia. Reverse transcriptase-polymerase chain reaction showed augmented levels of mRNAs for both nNOS and iNOS when compared with controls at 8 h after ischemia. At 36 h, nNOS mRNA returned to basal levels whereas eNOS mRNA levels increased and iNOS mRNA remained elevated. Our results show that the three NOS isoforms participate in increasing NO levels after transient ischemia and suggest a biphasic and differential regulation of the expression of constitutive NOS isoforms in the rat cerebral cortex.

Animals↗

PubMed1993

Nitric oxide and nitric oxide synthase mRNA induction in mouse islet cells by interferon-gamma plus tumor necrosis factor-alpha.

It has been shown that nitric oxide (NO) is involved in islet cell damage induced by interleukin-1 (IL-1). Here we show that interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) synergistically induced NO production and inducible NO synthase (iNOS) mRNA expression in mouse islet cells. Cycloheximide (CXH) did not prevent the iNOS mRNA expressions. The combination of IFN-gamma and TNF-alpha, which is highly cytotoxic to mouse islet cells, failed to destruct islet cells in the absence of L-arginine or in the presence of NG-monomethyl-L-arginine (NMMA). These observations suggest that NO is a primary effector in islet cell damage caused by IFN-gamma plus TNF-alpha.

Amino Acid Oxidoreductases↗

PubMed1997

Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-kappaB binding to DNA.

Treatment of astroglial cells with interleukin 1beta and interferon gamma transcriptionally activates the nitric oxide synthase (NOS)-2 gene. The duration of mRNA expression is brief because of transcript instability. In addition, NO donors reduce the expression of NOS-2 mRNA dramatically by reducing the rate of transcription. In this study we observed that the NO donor, spermine NONOate did not inhibit the activation and translocation of NF-kappaB, a key transcription factor in the induction of NOS-2, but inhibited formation of the NF-kappaB-DNA complex. This effect was reversed by methaemoglobin (acting as an NO trap) and by the reducing agent dithiothreitol. Formation of the interferon-regulatory factor-DNA complex was unaffected by NO. These results suggest that NO can modulate its own production by interfering with NF-kappaB interaction with the promoter region of the NOS gene, a negative feedback effect that may be important for limiting NO production in vivo.

Animals↗

PubMed1999

Effects of age and parasitemia on nitric oxide production/leukocyte nitric oxide synthase type 2 expression in asymptomatic, malaria-exposed children.

Age appears to influence not only the acquisition of clinical immunity to malaria but also the susceptibility to and clinical manifestations of severe malaria. Asymptomatic malaria-exposed Tanzanian children have high production of nitric oxide (NO) and universal expression of leukocyte NO synthase type 2 (NOS2), which may protect against disease. To determine the effects of age and parasitemia on NO production, we measured urine and plasma NO metabolites and leukocyte NOS2 expression in 45 fasting, asymptomatic, malaria-exposed children of different ages, stratifying parasitemia by thick film and polymerase chain reaction (PCR) analysis. Although NO production was significantly higher in thick film-positive children than in thick film-negative children, after adjusting for age and gender, we were unable to detect a difference in NO production in thick film-negative children between those who were PCR positive and PCR negative. The relationship between age and NO production was determined using a generalized additive model adjusted for the effects of gender and parasitemia. Production of NO using all three measures was highest in infancy, decreasing after the first year of life, and then increasing again after 5 years of age. This pattern of age-related NO production is the reverse of the pattern of age-related morbidity from cerebral malaria in coastal Tanzanian children. Elevated production of NO in both infants and older children may be related to age per se and malaria infection respectively, and may be one of the mediators of the anti-disease immunity found most commonly in these two age groups.

Aging↗

PubMed2004

Effects of estrous synchronization on response to nitric oxide donors, nitric oxide synthase inhibitors, and endothelin-1 in vitro.

Two experiments were conducted to determine the effects of nitric oxide (NO) donors, endothelin-(ET-1), and NO synthase (NOS) inhibitors on bovine luteal function in vitro. In experiment 1, estrus in Brahman cows was synchronized with Synchro-Mate-B (SMB) and day-13-14 corpora luteal slices were weighed, diced and incubated in vitro. Treatments (100 ng/ml) were: vehicle, N[see symbol in text]-nitro-L-arginine-L-methyl ester (L-NAME), N(G)-monomethyl-L-arginine acetate (L-NMMA), diethylenetriamine (DETA), DETA-NONOate, sodium nitroprusside (SNP), or ET-1. In experiment 2, estrus was synchronized with Lutalyse, a Controlled Intravaginal Progesterone Releasing Device (CIDR), or cows were not synchronized. Corpora lutea were collected, weighed, and luteal slices were weighed, diced and incubated in vitro with treatments. Treatments (100ng/ml) were: vehicle, L- NAME, L-NMMA, DETA, DETA-NONOate, sodium nitroprusside, S-nitroso-N-acetylpenicillamine (SNAP) or endothelin-1. Tissues were incubated in M- 199 for 1 h without treatments and for 4 and 8 h in both experiments with treatments in both experiments. Media were analyzed for progesterone, prostaglandins E2 and F2alpha (PGE2, PGF2alpha) by radioimmunoassay (RIA). Hormone data in experiments 1 and 2 were analyzed by 2 x 7 and 3 x 2 x 8 factorial design for analysis of variance (ANOVA), respectively. Luteal weights in experiment 2 were analyzed by a one-way ANOVA. Concentrations of progesterone in media were similar (P > or = 0.05) among treatments within experiments. Concentrations of PGE2 in media in experiment 1 were undetectable in 90 and 57% of the samples at 4 and 8 h, respectively. PGF2alpha increased (P < or = 0.05) with time, but did not differ (P > or = 0.05) among treatments. Secretion of PGF2alpha was not affected by treatments (P > or = 0.05). In experiment 2, luteal weights of the induced estrous cycle were decreased (P < or = 0.05) by Lutalyse. Concentrations of PGE2 and PGF2alpha increased (P < or = 0.05) with time in control of all three synchronization regimens. DETA-NONOate, SNAP, sodium nitroprusside (NO donors) and ET-1 increased (P < or = 0.05) PGE2 except in the CIDR synchronized group (P > or = 0.05). No treatment increased (P > or = 0.05) PGF2alpha in any synchronization regimen. It is concluded that either SMB containing norgestomet or a CIDR containing progesterone alters luteal secretion of PGE2, Lutalyse lowers luteal weights in the induced estrous cycle, and NO or ET-1 given alone are not luteolytic agents. It is suggested that NO and ET-1 could have indirect antiluteolytic/luteotropic effects via increasing PGE2 secretion by luteal tissue rather than being luteolytic.

Animals↗

PubMed1995

Coordinate up- and down-modulation of inducible nitric oxide synthase, nitric oxide production, and tumoricidal activity in rat bone-marrow-derived mononuclear phagocytes by lipopolysaccharide and gram-negative bacteria.

Simultaneous incubation of primary rat bone-marrow-derived mononuclear phagocytes (BMMo) and tumor cells with gram-negative agents triggers within 24 h interferon gamma (IFN gamma)- and tumor necrosis factor (TNF alpha)-independent tumoricidal activity. On the other hand, BMMo that had been incubated for 24 h with gram-negative agents prior to re-exposure to the same agent had largely lost their ability to generate tumoricidal activity, although their ability to bind lipopolysaccharide (LPS) was not diminished. Parallel measurements of the kinetics of inducible nitric oxide synthase (iNOS), nitrite secretion, and tumoricidal activity triggered in primary BMMo by LPS revealed that these parameters take a coordinate course, reaching a peak within 24 h and then rapidly decaying. Down-regulation of expression of NOS protein and iNOS activity could be attributed neither to down-regulation of LPS receptors nor to L-arginine depletion.

Amino Acid Oxidoreductases↗

PubMed2004

Nitric oxide and nitric oxide synthase activity in plants.

Research on NO in plants has gained considerable attention in recent years mainly due to its function in plant growth and development and as a key signalling molecule in different intracellular processes in plants. The NO emission from plants is known since the 1970s, and now there is abundant information on the multiple effects of exogenously applied NO on different physiological and biochemical processes of plants. The physiological function of NO in plants mainly involves the induction of different processes, including the expression of defence-related genes against pathogens and apoptosis/programmed cell death (PCD), maturation and senescence, stomatal closure, seed germination, root development and the induction of ethylene emission. NO can be produced in plants by non-enzymatic and enzymatic systems. The NO-producing enzymes identified in plants are nitrate reductase, and several nitric oxide synthase-like activities, including one localized in peroxisomes which has been biochemically characterized. Recently, two genes of plant proteins with NOS activity have been isolated and characterized for the first time, and both proteins do not have sequence similarities to any mammalian NOS isoform. However, different evidence available indicate that there are other potential enzymatic sources of NO in plants, including xanthine oxidoreductase, peroxidase, cytochrome P450, and some hemeproteins. In plants, the enzymatic production of the signal molecule NO, either constitutive or induced by different biotic/abiotic stresses, may be a much more common event than was initially thought.

Nitric Oxide↗

PubMed1995

Comparative pharmacology of nitric oxide and nitric oxide generators on cardiac contractility in mammalian species.

Nitric oxide (NO) is a potent vasorelaxing agent at nanomolar concentrations. At low nanomolar concentrations, NO also inhibits platelet aggregation, attenuates leukocyte adherence to the vascular endothelium, and quenches superoxide radicals. At high nanomolar concentrations, NO attenuates smooth muscle cells growth and stimulates proliferation of vascular endothelial cells. However, even at micromolar concentrations, NO fails to significantly alter cardiac contractility in isolated rat or cat cardiac muscle. Moreover, L-arginine, even at millimolar concentrations, fails to exert a decrease in cardiac contractility significantly greater than that produced by D-arginine.

Animals↗