Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Comparative studies were performed on the spasmolytic and hypotensive effects of pentacyanoferrates with different ligands (NO, NO2, NOS, NH3, H2O) and of hexacyanoferrates and other nitrosyl compounds. Besides sodium nitroprusside, the nitro and thionitro complexes in equimolar doses were found to cause hypotension and relaxation of the aortic strip of rabbits contracted by adrenaline and spasmolytic effects on the contracted guinea pig ileum. The liberated nitrosyl cation or its secondary product, nitrous acid, is thought to be responsible for the pharmacodynamic effects of these complex compounds. This is in agreement with the fact that also other nitrosyl compounds (nitrosyl perchlorate, nitrosyl-bis(dimethylglyoximato)cobaltIII) and free undissociated nitrous acid produce transient spasmolytic effects. Pentacyanoaquoferrate and hexacyanoferrateIII exert, presumably because of the oxydation of sulfhydryl groups, spasmolytic effects in vitro. Accordingly, their effects are prevented in the presence of sulfhydryl compounds such as glutathion or dithioerythrit.
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PMID:[Pharmacological effect of pentacyanonitrosylferrate and similar complex compounds]. 73 17

Nitric oxide synthase produces NO, citrulline, water, and NADP at the expense of arginine, NADPH, and dioxygen. While citrulline has been considered to be an inert by-product of the high output inducible isoform of NO synthase (iNOS), we show here that immunostimulants induce a metabolic pathway in vascular smooth muscle cells, which enables them to regenerate arginine from citrulline. Regeneration of arginine from citrulline is accomplished by two urea cycle enzymes: arginino-succinate synthetase (AS) and argininosuccinate lyase (AL). Whereas AL is constitutive to vascular smooth muscle cells, AS mRNA and enzyme activity is markedly induced in cells by treatment with bacterial lipopolysaccharide (LPS). The induction of AS mRNA and activity by LPS follows a time course which mirrors that for iNOS but lags 1-2 h behind. As shown for iNOS, interferon-gamma does not itself induce AS but is synergistic with LPS. AS induction is suppressed by glucocorticoids, actinomycin D, and, to a lesser extent, cycloheximide. On the other hand, AS induction is unaffected by an excess of citrulline or the inhibitor of iNOS, N omega-methyl-L-arginine. Our results show the urea cycle enzymes AS and AL confer cells with the capacity to produce NO without a need for exogenous arginine. In conjunction with NOS, citric acid cycle enzymes that covert fumarate to oxaloacetate (fumarase and malate dehydrogenase) and oxaloacetate to aspartate (aspartate transaminase), AS and AL form a novel arginine-citrulline cycle that enables high output NO production by cells.
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PMID:Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. Role in the regeneration or arginine for nitric oxide synthesis. 751 85

Nitric oxide (NO.) plays a central role in the physiology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 758 76

Nitric oxide (NO.) plays a central role in the Physioliology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 770 93

The Gram-positive bacterium, Nocardia opaca, is a source of substances with adjuvant effect, ability to stimulate macrophages and natural killer cells for enhanced cytotoxity and cytokine production and B lymphocytes for polyclonal immunoglobulin secretion. We determined the immunogenicity of isolated N. opaca fractions and prepared MoAbs against immunogenic water-soluble mitogen (NWSM). Two main proteins of molecular mass 15 and 56 kD were detected in western blot analysis and isolated by affinity chromatography using anti-NWSM MoAb B7/7. Both these isolated nocardial antigens were found to stimulate mouse peritoneal macrophage NOS. The effect of 5 micrograms NWSM was comparable to that of 5 micrograms lipopolysaccharide (LPS) or 20 U of interferon-gamma (IFN-gamma) added to cell cultures. The MoAb B7/7 decreased No2- production induced by NWSM or by isolated nocardial antigens, but did not significantly influence the production elicited by LPS or IFN-gamma. On the other hand, NOS activation by NWSM was not affected by anti-IFN-gamma MoAb. The possible independent pathway for IFN-gamma and NWSM macrophage activation is discussed.
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PMID:Macrophage nitric oxide synthase (NOS) activation by Nocardia opaca fractions and 15- and 56-kD isolated antigens. 862 11

Clinical and experimental studies indicate that nonimmunologic factors may modulate the alloreactivity of a renal transplant. Nitric oxide (NO) is an essential modulator of endothelial function. It was postulated that, in renal allografts, inhibition of constitutive NO synthase may lead to an aggravation of immunologic damage to endothelia and therefore may enhance dysfunction of the graft. Male Lewis (RT1l) rats received syngeneic or allogeneic Brown Norway (RT1n) renal grafts and were treated with cyclosporin A (CyA) or with CyA and an NO synthase blocker (NOS-B): N omega-nitro-L-arginine (L-NNA) or NG-monomethyl-L-arginine (L-NMMA). CyA was given at a dose of 3.5 mg/kg body weight for 14 days and the NOS-B at a dose of 66 mg/L drinking water for up to 28 days postoperatively. Animals (N = 6/group) were studied at 4 to 7, 14, and 28 days posttransplantation. Four to 5 days posttransplantation, renal blood flow and glomerular filtration rate of allogeneic grafts did not differ between animals treated only with CyA and those treated with CyA and NOS-B. Mean arterial pressure was significantly elevated by NOS-B (CyA+L-NNA: 115 +/- 13 versus CyA: 78 +/- 16 mm Hg). Combined NOS-B and CyA administration led to a pronounced increase in vascular and tubulointerstitial damage. The number of mononuclear cells in vessels, glomeruli, and tubulointerstitium increased significantly in allografts upon treatment with NOS-B. During NOS-B administration, adhesion molecules (intracellular adhesion molecule-1; leukocyte-function-associated molecules-1 alpha and-beta) were strongly expressed in endothelial and leukocytic cells of the allograft. A pronounced positivity for mRNA and protein of cytokines tumor necrosis factor-alpha and transforming growth factor-beta could be demonstrated in the inflammatory infiltrate. With L-NNA treatment, the total vascular injury index was 10-fold higher (14 days posttransplantation, CyA+L-NNA: 59.8 +/- 11.7 versus CyA: 6.0 +/- 1.8; p < 0.05). The tubulointerstitial damage score rose more than 2.5-fold after CyA and L-NNA therapy (28 days posttransplantation: CyA+L-NNA: 83 +/- 1 versus CyA:29 +/- 1). L-NNA was more potent than L-NMMA at the dosages used. Thus, pronounced vascular leukostasis, vasculitis, and T-cell and monocyte infiltration of the tubulointerstitium led to a severe damage of the allograft under therapy with CyA and NOS-B. Inhibition of NO synthesis may aggravate alloreactive immunemediated injury in kidney transplants acting primarily by a disturbance of endothelial function.
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PMID:Enhanced renal allograft rejection by inhibitors of nitric oxide synthase: a nonimmunologic influence on alloreactivity. 878 Jan 67

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.
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PMID:Renal and pressor effects of aminoguanidine in cirrhotic rats with ascites. 898 51

The pathogenesis of renal sodium and water retention in cirrhosis involves extrarenal mechanisms because when kidneys from cirrhotic patients are transplanted into persons with normal livers, renal sodium and water retention no longer occurs. Cirrhosis is accompanied by portal hypertension, which leads to a hyperdynamic circulatory state. The Peripheral Arterial Vasodilation Hypothesis incriminates a relative underfilling of the arterial vascular compartment, which leads to the same neurohumoral responses that occurs in low cardiac output. Activation of the renain-angiotensin-aldosterone axis and the sympathetic system as well as non-osmotic release of vasopressin are well documented in cirrhosis. This sequence of events results in renal water and sodium retention, failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. Dilutional hyponatremia is the strongest predictor of the occurrence of hepatorenal syndrome. The pathogenesis of the peripheral arterial vasodilation is not completely elucidated, but there is evidence for a major role of nitric oxide (NO). Increased vascular NO production has been demonstrated in cirrhosis. In the rat model of cirrhosis, normalization of vascular NO production with a NOS inhibitor corrects the hyperdynamic circulation, improves sodium and water excretion, and decreases neurohumoral activation. This insight into the mechanism(s) of the peripheral arterial vasodilation in cirrhosis should provide new tools in the treatment of edema and ascites, a major cause of morbidity and mortality in cirrhosis.
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PMID:Pathogenesis of water and sodium retention in cirrhosis. 918 4

Although nitric oxide (NO) has been shown to play an important role in the pathophysiology of cerebral ischemia, its contribution to the pathogenesis of experimentally induced thromboembolic stroke is unknown. In this study, we pharmacologically manipulated NO levels in the acute post-thrombotic stage and determined the effects on behavior and histopathology. The following drugs were used: nitro-L-arginine-methyl ester (L-NAME), a non-specific endothelial and neuronal nitric oxide synthase (eNOS and nNOS) inhibitor, 3-bromo-7-nitroindazole (7-NI), a specific inhibitor for nNOS, the NO precursor, exogenous L-arginine and the NO-donor, 3-morpholino-sydnonimine (SIN-1). Male Wistar rats (n = 76) were randomly assigned to receive vehicle or drug immediately after common carotid artery thrombosis (CCAT). Regional measurements of cortical NOS activity using the [3H]L-arginine to [3H]L-citrulline conversion assay were decreased 1 h after treatment with L-NAME and 7-NI by 50 and 65%, respectively; hippocampal NOS activity was reduced with L-NAME by 35% and with 7-NI by 65%. L-NAME significantly worsened forelimb placing as compared to other groups. 7-NI accelerated sensorimotor recovery. Water maze retention deficits were noted 48 h after CCAT and these were exacerbated by L-NAME treatment. Histopathological protection was conferred in the hippocampus by 7-NI and SIN-1; conversely, L-NAME increased neuronal injury in the contralateral cortex. L-arginine had no effect on these outcomes. In conclusion, both structural and functional consequences of CCAT can be aggravated by limiting endothelial NO production in the acutely post-thrombotic brain. In contrast, inhibition of nNOS and infusion of an NO donor has a beneficial effect on pathology.
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PMID:The role of nitric oxide in the pathophysiology of thromboembolic stroke in the rat. 921 60

Changes in gastric mucosal constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) activities with the development of gastric mucosal lesions induced by water immersion restraint (WIR) stress were investigated in rats pretreated with and without NOS inhibitors. A decrease in cNOS activity and an increase in iNOS activity in the gastric mucosa occurred with gastric mucosal lesion development. Pretreatment with N(G)-monomethyl L-arginine, a non-selective NOS inhibitor, enhanced gastric mucosal lesion development with inhibition of gastric mucosal cNOS and iNOS activities, although the inhibited iNOS activity was still higher than the normal level. Pretreatment with aminoguanidine, a selective iNOS inhibitor, prevented gastric mucosal lesion development with inhibition of iNOS activity and maintenance of cNOS activity in the gastric mucosa. These results indicate that in WIR-stressed rats, an increase in iNOS activity and a decrease in cNOS activity in the gastric mucosa are closely related to the development of gastric mucosal lesions.
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PMID:Role of gastric mucosal constitutive and inducible nitric oxide synthases in the development of stress-induced gastric mucosal lesions in rats. 924 Apr 24


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