Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study is to investigate the possible mechanism of beneficial effects of tetramethylpyrazine (TMP) on endotoxic shock which we showed in our preliminary study (Liao et al. 1998; Proc Natl Sci Counc Repub China B 22:46-54). Here, we have confirmed the beneficial effects of TMP on the hypotension, vascular hyporeactivity to noradrenaline (NA), release of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). In addition, we further examined the expression of inducible NO synthase in the lung and in the aorta from these rats and evaluated the effect of TMP on the 36-h survival rate in a murine model of endotoxaemia. Male Wistar-Kyoto rats were anaesthetised and instrumented for the measurement of mean arterial pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg(-1), i.v.) resulted in an acute fall followed by a substantial fall in MAP within 4 h and an increase in HR. In contrast, animals pretreated with TMP (10 mg kg(-1), i.p.; at 30 min prior to LPS) maintained a significantly higher MAP but the tachycardia was further enhanced at 1-2 h when compared to rats given only LPS (LPS rats). The pressor effect of NA (1 microg kg(-1), i.v.) was also significantly reduced after the treatment of rats with LPS. Similarly, the thoracic aorta obtained from rats at 4 h after LPS showed a significant reduction in the contractile responses elicited by NA (1 microM). Pretreatment of LPS rats with TMP partially, but significantly, prevented this LPS-induced hyporeactivity to NA in vivo and ex vivo. The injection of LPS resulted in a bell-shaped change in plasma TNF-alpha level which reached a maximum at 1 h, whereas the effect of LPS on the plasma level of nitrate (an indicator of NO formation) was increased in a time-dependent manner. This increment of both TNF-alpha and nitrate levels was significantly reduced in LPS rats pretreated with TMP. Endotoxaemia for 4 h caused a significantly increased protein expression of iNOS in the lung and the aorta. In LPS rats pretreated with TMP, iNOS protein expression in lung and aorta homogenates was attenuated by 75+/-3% and 57+/-6%, respectively. In addition, the lack of evidence of pressor effect of TMP on rats with endotoxaemia for 4 h suggested that TMP inhibits the induction of iNOS rather than directly inhibiting NOS activity. Treatment of conscious ICR mice with a high dose of endotoxin (60 mg kg(-1), i.p.) resulted in a survival rate of only 15% at 36 h (n=20). However, therapeutic application of TMP (10 mg kg(-1), i.p.; at 0, 6, 15 and 24 h after LPS) increased the 36 h survival rate to 55% (n=20). Thus, TMP inhibits the expression of iNOS and mitigates the delayed circulatory failure caused by endotoxic shock in the rat. In addition, TMP also improves survival in a murine model of severe endotoxaemia.
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PMID:Tetramethylpyradizine prevents inducible NO synthase expression and improves survival in rodent models of endotoxic shock. 1055 Dec 81

We investigated the pathogenic role of nitric oxide (NO) in indomethacin-induced intestinal ulceration in rats. Nonfasting animals responded to a single administration of indomethacin (10 mg/kg, s.c.), resulting in multiple hemorrhagic lesions in the small intestine, mostly the jejunum and ileum. The damage was first observed 6 hr after indomethacin, the severity increasing progressively with time up to 24 hr later, accompanied with the gene expression of inducible NO synthase (iNOS) and the increase of nitrite and nitrate (NOx) contents in the mucosa. The ocurrence of damage was significantly prevented when iNOS induction was inhibited by dexamethasone given either once 0.5 hr before or twice 0.5 hr before and 6 hr after indomethacin. Likewise, aminoguanidine (a relatively selective iNOS inhibitor) reduced the severity of damage, irrespective whether given twice or as a single injection 6 hr after indomethacin. By contrast, the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) exhibited a biphasic effect, depending on the time of administration; the pre-administration worsened the damage, while the later administration reduced the severity of these lesions, yet both responses occureed in a L-arginine-sensitive manner. Pre-administration of L-NAME, but not aminoguanidine, significantly decreased NOx production in the intestinal mucosa of normal rats, while the increase of NOx production following indomethacin was significantly suppressed by the later administration of aminoguanidine as well as L-NAME. These results suggest that NO exerts a dual action in the pathogenesis of indomethacin-induced intestinal ulceration; NO generated by cNOS is protective against indomethacin, by maintaining the integrity of intestinal mucosa, while NO derived by iNOS plays a key pathogenic role in the ulcerogenic process.
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PMID:Dual action of nitric oxide in pathogenesis of indomethacin-induced small intestinal ulceration in rats. 1057 70

We have recently shown that felodipine, a long-acting dihydropyridine L-type calcium channel blocker (CCB), up-regulates nitric oxide (NO) production and endothelial NO synthase (eNOS) expression and activity in cultured endothelial cells as well as in animals with chronic renal failure. This study was intended to compare the effects of prototypes of the three classes of L-type CCBs on the NO system in cultured human coronary artery endothelial cells. Thus, cultured endothelial cells were incubated either with nifedipine, diltiazem, or verapamil for 24 h at 10(-5) to 10(-7) M concentrations. Cells incubated with inactive vehicle served as controls. NO production, as discerned from total nitrate plus nitrite recovered in the medium, was significantly increased by nifedipine (P <.03) and by diltiazem (P <.05). However, NO production remained unchanged with verapamil (P = NS). Similarly, eNOS protein abundance was increased significantly by nifedipine (P <.05) and diltiazem (P <.05). In contrast, eNOS expression was not changed by verapamil (P = NS). Likewise, NOS activity, as measured from [(3)H]L-arginine to [(3)H]L-citrulline conversion, significantly increased with nifedipine (P <.01) and diltiazem (P <.01). However, incubation with verapamil failed to alter NOS activity of the cultured endothelial cells (P = NS). We concluded that prototypes of dihydropyridine and benzothiazepine classes, but not phenylalkylamine class of CCBs, up-regulate the NO system. This may, in part, account for the different biological properties of these agents.
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PMID:Nifedipine and diltiazem but not verapamil up-regulate endothelial nitric-oxide synthase expression. 1064 Feb 97

Adrenal zona glomerulosa (ZG) cells do not contain nitric oxide (NO) synthase (NOS). We conferred endothelial NOS activity onto adrenal ZG cells through transduction with a recombinant adenovirus encoding the endothelial NOS gene (AdeNOS) to determine the effect of endogenous NO on aldosterone synthesis. A 135-kDa protein band immunoreactive to anti-endothelial NOS antibody was observed in Western blots of AdeNOS-transduced ZG cells but not in control cells or cells transduced with adenovirus encoding the beta-galactosidase gene (AdbetaGal). Nitrate/nitrite production in AdeNOS-transduced ZG cells increased from 0.15+/-0.01 to 0.27+/-0.01 micromol/L after stimulation with 1 nmol/L angiotensin II. The treatment of AdeNOS-transduced cells with 30 micromol/L L-nitro-arginine decreased angiotensin II-stimulated nitrite production from 0.27+/-0. 01 to 0.17+/-0.01 micromol/L. Basal and angiotensin II-stimulated nitrite production was not increased in AdbetaGal-transduced or control cells. AdeNOS-transduced cells demonstrated diaminofluorescein-2 diacetate fluorescence, which was blocked by pretreatment with L-nitro-arginine. Angiotensin II-stimulated aldosterone synthesis decreased from 5123+/-177 pg/mL in AdbetaGal-transduced ZG cells to 72+/-27 pg/mL in AdeNOS-transduced cells. Treatment with the NOS inhibitor thiocitrulline (30 micromol/L) increased angiotensin II-stimulated aldosterone synthesis to 2158+/-45 pg/mL after AdeNOS transduction. These data demonstrate that adenovirus-mediated gene transfer of eNOS in ZG cells results in the expression of active endothelial NOS enzyme and that this endogenous NO production by ZG cells decreases aldosterone synthesis.
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PMID:Inhibition of adrenal cell aldosterone synthesis by endogenous nitric oxide release. 1064 19

Oxidative stress is a key event in the pathogenesis of several cardiovascular diseases and may be similarly induced by long-term treatment with organic nitrates. We examined the effects of inhibiting extracellular oxidative stress in the rostral ventrolateral medulla (RVLM), the brain stem area which primarily controls sympathetic tone. Superoxide dismutase (SOD, 10 U/microl) was microinjected into the RVLM of anesthetized pigs that were either untreated (control, n=10), treated for 4 weeks with the organic nitrate isosorbidedinitrate (ISDN, 4 mg kg(-1) day(-1), n=6) or ISDN-treated followed by a 2-week recovery period (recovery, n=4). In control animals SOD produced moderate inhibitory effects on baseline sympathetic activity, indicated by decreases in renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate (HR) without causing changes in femoral vascular conductance (FC). These effects of SOD were greatly enhanced in ISDN-treated pigs. Following the recovery period, SOD again produced smaller effects in the RVLM but they were, however, still significantly greater than in untreated animals. In contrast, the transmission of sympathoexcitatory reflexes by the RVLM, as evoked by sciatic nerve stimulation, was not affected by SOD injections in either experimental group. Furthermore, the number of NO-synthase-positive neurons in the RVLM region was significantly reduced both in ISDN-treated and the recovery pigs, suggesting that oxidative stress caused sustained changes in NOS activity within the brain stem. These data suggest that excitatory actions of oxidative stress contribute significantly to the generation of baseline sympathetic tone in the RVLM during long-term treatment with organic nitrates. Similar mechanisms could promote sympathetic tone in cardiovascular diseases that are associated with endogenous oxidative stress for longer periods.
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PMID:Chronic oxidative stress in the RVLM modulates sympathetic control of circulation in pigs. 1067 47

Long-term exposure to stress has detrimental effects on several brain functions in many species, including humans and leads to neurodegenerative changes. However, the underlying neural mechanisms by which stress causes neurodegeneration are still unknown. We have investigated the role of endogenously released nitric oxide (NO) in this phenomenon and the possible induction of inducible NO synthase (iNOS) isoform. In adult male rats, stress (immobilisation for 6 h during 21 days) increases the activity of a calcium-independent NOS and induces the expression of iNOS in cortical neurons as seen by immunohistochemical and Western blot analysis. Three weeks of repeated immobilisation increases immunoreactivity for nitrotyrosine, a nitration product of peroxynitrate. Repeated stress causes NO2(-) + NO3- (NOx) accumulation in cortex, and these changes occurs in parallel with lactate dehydrogenase (LDH) release and impairment of glutamate uptake in synaptosomes. The administration of the preferred iNOS inhibitor aminoguanidine (400 mg/kg i.p. daily from days 7 to 21 of stress) prevents NOx- accumulation in cortex, LDH release and impairment of glutamate uptake in synaptosomes, as well as other markers of oxidative stress such as lipid peroxidation and decrease in glutation. Taken together, these findings indicate that a sustained overproduction of nitric oxide via iNOS expression may be responsible, at least in part, of some of the neurodegenerative changes caused by stress, and support a possible neuro-protective role for specific iNOS inhibitors in this situation.
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PMID:[Stress and neurodegeneration: pharmacologic strategies]. 1068 99

Increased nitric oxide (NO) synthesis by the inducible nitric oxide synthase (iNOS) has been shown to contribute to the development of acute lung injury and delayed hypotension in animals injected with bacterial lipopolysaccharides (LPS). Recent evidence indicates that endothelin-1 (ET-1) is also elevated in septic humans and in animals. To assess the contribution of ETs to LPS-induced pulmonary NO production and iNOS expression, we used P1/fl, a 22 amino acid peptide, to selectively antagonize endothelin-A receptors. Anesthetized, mechanically ventilated rats were injected with either saline or LPS (E. coli endotoxin, 20 mg/kg) and studied for 5 h. Two other groups of rats were pretreated 15 min earlier with P1/fl peptide (20 microg/kg). Unlike saline-treated rats, rats injected with LPS showed a progressive decline in arterial pressure and a significant rise in plasma ET concentration and serum nitrite-nitrate level. In the lungs, LPS injection elicited a several-fold rise in lung iNOS activity and exhaled NO concentration and increased lung wet/dry ratio significantly. Pretreatment with P1/fl peptide eliminated the decline in arterial pressure, the rise in lung wet/dry ratio, lung NOS activity, and iNOS protein expression and significantly attenuated the increase in pulmonary exhaled NO production but had no effect on plasma ET concentration. We conclude that activation of ET-A receptors by rising ET-1 concentration enhances NO production and iNOS expression in the respiratory and vascular systems and contributes to both LPS-induced hypotension and acute lung injury.
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PMID:Endothelin receptor blockade attenuates lipopolysaccharide-induced pulmonary nitric oxide production. 1071 52

Expression of the inducible isoform of nitric oxide synthase (iNOS) is stimulated by cytokines in human epithelial cells. This work indicates that incubation of human umbilical cord endothelial cells with combinations of interleukin-1beta, tumor necrosis factor alpha, and interferon-gamma stimulated the synthesis of iNOS mRNA, as detected by reverse transcriptase-polymerase chain reaction. It is important to note that 50, 100, and 200 microM hydrogen peroxide was able to stimulate iNOS directly. Furthermore, 100 microM H2O2 enhanced synthesis of the oxidation products, nitrite (NO2-) and nitrate (NO3-) at 12 and 36 h. iNOS protein, detected by Western blot analysis, as well as L-citrulline levels, were also increased. When endothelial cell monolayers were incubated for 1 h with 100 microM H2O2 and subsequently with cytokines, iNOS mRNA was further augmented. Under the same conditions, we regularly observed an inhibition (25%) of intercellular adhesion molecule-1 (ICAM-1/CD54) expression. The latter was reversed when the NOS inhibitor N(G)-monomethyl-L-arginine was added, as shown by flow cytometry. These data suggest a specific effect of endogenous hydroperoxides on the biosynthesis and processing of the human endothelial iNOS isoform. We propose that H2O2 induces a temporary NO-dependent modulation of adhesion molecule expression to limit the tissue destruction that accompanies the vascular recruitment of leukocytes.
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PMID:Regulation of ICAM-1/CD54 expression on human endothelial cells by hydrogen peroxide involves inducible NO synthase. 1073 92

(1S,5S,6R,7R)-7-Chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714), a novel cyclic amidine analogue, inhibits human inducible nitric oxide (iNOS) with a K(i) of 1.88 nM and rodent iNOS with similar potency in vitro. ONO-1714 was found to be 10-fold selective for human iNOS over human endothelial NOS (ecNOS). When the inhibitory activity of ONO-1714 was compared for iNOS, it was found to be 451-fold and >20,000-fold more potent than L-NMMA and aminoguanidine (AG), respectively. In terms of human iNOS selectivity, ONO-1714 was approximately 34- and 2-fold more selective for iNOS than L-NMMA and AG, respectively. ONO-1714 inhibited the LPS-induced elevation of plasma nitrate/nitrite in mice with an ID(50) value of 0.010 mg/kg, s.c. The maximum tolerated dose of ONO-1714 was 30 mg/kg, i.v. Thus, ONO-1714 represents one of the most potent iNOS inhibitors in vitro and in vivo to date and has great potentials for use as an inhibitor for clarifying the pathophysiological roles of iNOS and for use as a therapeutic agent.
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PMID:A potent inhibitor of inducible nitric oxide synthase, ONO-1714, a cyclic amidine derivative. 1075 80

Temporal changes in tumor necrosis factor-alpha (TNF-alpha) and nitric oxide synthase 2 (NOS 2) were evaluated in segments of duodenum, jejunum, and ileum removed from male Sprague-Dawley rats 30, 60, 120, 180, and 240 min after lipopolysaccharide (LPS), 5 mg/kg, intraperitoneally. Plasma was assayed for TNF-alpha and for nitrate/nitrite (NOx). Intestinal and plasma TNF-alpha were elevated by 60 min after LPS and were back to control levels by 180 min. For control rats, NOS 2 was detected in the ileum, but not in the duodenum or the jejunum. In rats treated with LPS, NOS 2 was detected in all areas of the intestine at 120 min and was greatest at 240 min. Plasma NOx was elevated at 120 min and continued to increase to 240 min. The time course of changes in intestinal TNF-alpha and NOS 2 were similar to those reported for other tissues and suggest that the early and late actions of the LPS on the intestine may involve both mediators.
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PMID:Temporal expression of tumor necrosis factor-alpha and nitric oxide synthase 2 in rat small intestine after endotoxin. 1075 45


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