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

---

Query: EC:1.14.13.39 (NO synthase)
15,778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. We examined the pathogenic roles of nitric oxide (NO) and inducible NO synthase (iNOS) in TMEV-induced demyelinating disease (TMEV-IDD). The presence of iNOS was confirmed in the spinal cords of TMEV-infected mice using immunohistochemical staining with anti-iNOS antibody on day 0 (control) and days 15, 30, 60, and 120. Aminoguanidine (AG), a specific inhibitor of iNOS, was injected intraperitoneally (ip) on 1, 3, 5, 8, 10, and 12 days post-TMEV inoculation as induction phase or 15, 17, 19, 22, 24, and 26 days as effector phase. Control animals in each experiment received phosphate-buffered saline (PBS) ip at similar time intervals. Few iNOS-positive cells were observed in the spinal cords of naive SJL/J mice. In the early phase (day 15) of TMEV-IDD, an increase of iNOS-positive cells was detected in the leptomeninges and perivascular space of the spinal cords. The number of iNOS-positive cells was increased and reached its peak on day 60, when histology of the animals showed peak infiltration with inflammatory cells. The clinical course of TMEV-IDD on each day postintracerebral infection was significantly reduced in mice treated with AG in the effector phase, and there was no significant difference between mice treated with AG in induction phase versus those administered PBS. Thus, NO production via iNOS appears to be a pathogenic factor in the effector phase of TMEV-IDD.
...
PMID:Expression and potential role of inducible nitric oxide synthase in the central nervous system of Theiler's murine encephalomyelitis virus-induced demyelinating disease. 1038 21

To clarify the role of nitric oxide (NO) in the development and progression of acute pancreatitis, we investigated the effect of different NO synthase inhibitors and NO donors on experimental pancreatitis in rats. Closed duodenal loop (CDL)-induced pancreatitis was produced in male Wistar rats, and the animals were treated with normal saline, the NO-synthase substrate L-arginine, the NO donor S-nitroso-N-acetylpenicillamine, aminoguanidine, which is a more powerful inhibitor of inducible NO synthase (iNOS) than is endothelial NO synthase (eNOS), and N-nitro-L-arginine methyl ester (L-NAME), a more powerful inhibitor of eNOS than of iNOS. All drugs were infused intravenously during a period of 6 or 12 h in each group. Pancreatic tissue was removed at 6 and 12 h after creating the CDL. L-Arginine, S-nitroso-N-acetyl-penicillamine, and aminoguanidine treatment had no effect on the elevation of serum pancreatic enzymes, whereas L-NAME administration significantly exacerbated their elevation. Pathologically, L-NAME treatment resulted in a significantly worse histologic score at 6 and 12 h, especially in terms of the degree of hemorrhage, acinar cell necrosis, and microvascular thrombosis. Addition of L-arginine clearly reversed the effect of L-NAME. Neither the NO substrate nor NO donor could inhibit the progression of hemorrhagic pancreatitis in CDL-induced pancreatitis. Aminoguanidine had no effect on the severity of the pancreatitis. We therefore concluded that NO production by eNOS may play a significant role in preventing the development and progression of acute pancreatitis.
...
PMID:An endothelial nitric oxide synthase inhibitor aggravates CDL-induced acute pancreatitis in rats. 1054

Aminoguanidine (AMG) was prepared more than 100 years ago. During the last 10 years two important effects of AMG have been discovered which have made this molecule attract a lot of interest. Firstly, AMG inhibits, in vitro and in vivo, formation of highly reactive advanced glycosylation end products (AGEs) associated with pathogenesis of secondary complications to diabetes and with cardiovascular changes in aging. AMG ameliorates various complications to diabetes and prevents age related arterial stiffening and cardiac hypertrophy, effects probably dependent on inhibition of AGEs formation. Secondly, AMG inhibits NO synthase particularly the inducible NO synthase isoform making AMG an important pharmacological tool. The inducible NO synthase isoform is associated with production of large quantities of NO synthase in response to e. g. cytokines. When these effects of AMG were disclosed it had already been known for many years that AMG, in nM concentrations, inhibits diamine oxidase. This enzyme catalyzes degradation of biologically active diamines such as histamine and putrescine. Data obtained from studies using AMG should be interpreted with precaution since this substance interferes with several important regulatory systems. In this review these important targets for AMG are addressed.
...
PMID:Biological effects of aminoguanidine: an update. 1056 66

Mice given lipopolysaccharide (LPS) intravenously developed lung edema, which was maximum after 6 h. Tumor necrosis factor, interleukin 12 (IL-12), IL-6, and interferon-gamma (IFN-gamma) appeared in the serum, and levels of nitrogen oxide (NO) derivatives were increased in serum and bronchoalveolar fluid. Mice pretreated with neutralizing anti-IFN-gamma antibodies had lower serum levels of IFN-gamma, and fewer died. However, levels of other cytokines and NO derivatives as well as lung edema were unchanged. If IFN-gamma and LPS were given together, pulmonary edema was less, but levels of cytokines and NO derivatives in serum were raised, and the mortality was greater. IFN-gamma receptor knockout mice had more edema after LPS, but were less sensitive to the lethal effects. Treatment with anti-IL-12 antibody inhibited IFN-gamma induction and reduced mortality, but had no effect on the lung edema; exogenous IL-12 also failed to affect edema, but boosted serum cytokine levels and increased the mortality. Aminoguanidine, an inhibitor of NO synthase, protected against pulmonary edema, but did not modify the lethal effects of LPS. Clearly, in this model, early pulmonary edema and lethality are not directly related, and induced IFN-gamma has no role in causing early lung edema, but augments other events that result in death.
...
PMID:Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide. 1061 6

Nitric oxide (NO) produced by inducible NO synthase contributes to ischemic brain damage. However, the role of inducible NO synthase-derived NO on neonatal hypoxic-ischemic encephalopathy has not been clarified. We demonstrate here that aminoguanidine, a relatively selective inhibitor of inducible NO synthase, ameliorated neonatal hypoxic-ischemic brain damage and that temporal profiles of NO correlated with the neuroprotective effect of aminoguanidine. Seven-day-old Wister rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure (8% oxygen). Infarct volumes (cortical and striatal) were assessed 72 h after the onset of hypoxia-ischemia by planimetric analysis of coronal brain slices stained with hematoxylin-eosin. Aminoguanidine (300 mg/kg i.p.), administered once before the onset of hypoxia-ischemia and then three times daily, significantly ameliorated infarct volume (89% reduction in the cerebral cortex and 90% in the striatum; p<0.001). NO metabolites were measured by means of chemiluminescence using an NO analyzer. In controls, there was a significant biphasic increase in NO metabolites in the ligated side at 1 h (during hypoxia) and at 72 h after the onset of hypoxia (p<0.05). Aminoguanidine did not suppress the first peak but significantly reduced the second one (p<0.05), and markedly reduced infarct size in a neonatal ischemic rat model. Suppression of NO production after reperfusion is a likely mechanism of this neuroprotection.
...
PMID:Protective effect of aminoguanidine on hypoxic-ischemic brain damage and temporal profile of brain nitric oxide in neonatal rat. 1062 86

The purpose of this study was to analyse the influence of experimental diabetes on vascular response of rabbit carotid artery to acetylcholine (Ach). We compared the Ach-induced relaxant response of isolated arterial segments obtained from both control and diabetic animals. To assess the influence of the endothelium, this cell layer was mechanically removed in some of the arterial segments ("rubbed arteries") from each experimental group. Ach induced a concentration-related endothelium-mediated relaxation of carotid artery from control rabbits that was significantly higher with respect to that obtained in diabetic animals. Pre-treatment with N(G)-nitro-L-arginine (L-NA) induced a concentration-dependent inhibition of relaxant response to Ach, which was significantly higher in carotid arteries isolated from diabetic rabbits. Incubation of rubbed arteries with L-NA almost abolished the relaxant response to Ach in arterial segments from both control and diabetic animals. Indomethacin potentiated Ach-induced response of carotid arteries from control rabbits, without modifying that obtained in those from diabetic animals. Aminoguanidine did not significantly inhibit the relaxant action of Ach in arterial segments from either control or diabetic rabbits. These results suggest that diabetes impairs endothelial modulatory mechanisms of vascular response of rabbit carotid artery to Ach. This endothelial dysfunction is neither related with a lower release of nitric oxide (NO) or prostacyclin. Diabetes impairs the production of some arachidonic acid vasoconstrictor derivative. There has been observed an increased modulatory activity of NO, but this is not related with the expression of an inducible isoform of NO synthase.
...
PMID:Influence of experimental diabetes on regulatory mechanisms of vascular response of rabbit carotid artery to acetylcholine. 1082 46

Prolonged hyperglycemia inhibits B-cell function by mechanisms that are largely unclarified. We investigated the involvement of advanced glycation end products (AGEs), using aminoguanidine as well as the AGE-breaking compound ALT-711 in a transplantation model. Islets from Wistar-Furth rats were transplanted under the kidney capsule of syngeneic streptozocin-diabetic recipients. Aminoguanidine was administered as 1 g/L in the drinking water. Graft-bearing kidneys were isolated and perfused to investigate insulin secretion, and grafts were excised to measure preproinsulin mRNA contents. In all transplants to diabetic rats, insulin responses to 27.8 mM glucose were abolished and aminoguanidine failed to correct this abnormality. However, aminoguanidine treatment for 8 weeks following transplantation increased preproinsulin mRNA contents of the grafts (P < 0.05). In addition, treatment with aminoguanidine enhanced the insulin secretory response to arginine (P < 0.05). Arginine-induced insulin secretion was also enhanced when aminoguanidine treatment was started after an initial 2-week implantation period rather than immediately after transplantation. On the other hand, treatment with ALT-711 (0.1 mg/kg by gavage) for 8 weeks completely failed to affect B-cell function of grafts, and ALT-711 was also ineffective under in vitro conditions. Our findings indicate that aminoguanidine effects in vivo are to a major extent not coupled to AGEs or nitric oxide synthetase inhibition, but possibly to oxidative modifications accomplished by the guanidine compound.
...
PMID:Improvement by aminoguanidine of insulin secretion from pancreatic islets grafted to syngeneic diabetic rats. 1082 71

The in vivo role of nitric oxide in inflammatory cell migration, vascular permeability and the development of hyperresponsiveness to methacholine (MCh) was studied in rats 24 h following ovalbumin (OVA) challenge. The NO synthase (NOS) inhibitors N(G)-mono-methyl-L-arginine (L-NMMA; nonselective), aminoguanidine (two-fold inducible NOS-selective), N(omega)-nitro-L-arginine methyl ester (L-NAME; 2000-fold endothelial cell NOS-selective) or S-methyl-L-thiocitrulline (100-fold neuronal NOS-selective) were administered (100 mg x kg(-1) s.c.) to OVA-sensitized Piebald-Virol-Glaxo rats on 3 consecutive days during which they were challenged with allergen (1% OVA). Responses to inhaled MCh were measured in anaesthetized animals 24 h after OVA challenge. Cellular inflammation and vascular permeability were assessed using bronchoalveolar lavage (BAL) fluid collected 30 min after administration of Evans blue (50 mg x kg(-1) i.v.). OVA challenge in sensitized animals induced hyperresponsiveness to MCh, inflammatory cell influx and increased leakage of Evans blue into the BAL fluid (n=9, p<0.001). Aminoguanidine was effective in inhibiting the allergen-induced cellular influx and microvascular leakage (n=9, p<0.001) without altering responses to MCh. This effect was reserved by L-arginine. L-NAME (n=5, p<0.01) and S-methyl-L-thiocitrulline (n=6, p<0.001) further potentiated the allergen-induced hyperresponsiveness without altering cellular inflammation. L-NMMA attenuated both the OVA-induced cellular influx and Evans blue leakage (n=8, p<0.001) as well as further potentiating the hyperresponsiveness to MCh (p<0.05). From these studies, it is suggested that, in allergic Piebald-Virol-Glaxo rats, nitric oxide production by inducible nitric oxide synthase plays a role in the migration of inflammatory cells and increase in vascular permeability following allergen challenge, whereas nitric oxide produced by the constitutively expressed neuronal nitric oxide synthase limits hyperresponsiveness to methacholine.
...
PMID:Differential effects of nitric oxide synthase inhibitors in an in vivo allergic rat model. 1085 51

We used mice deficient in expression of inducible NO synthase (iNOS -/-) to directly examine the role of iNOS in impaired vasoconstrictor responses following tumor necrosis factor-alpha (TNF-alpha). In iNOS +/+ mice, contraction of carotid arteries in response to prostaglandin F(2alpha) (PGF(2alpha)) was impaired following TNF-alpha (100 microg/kg ip)(n = 10, P < 0.01). In contrast to responses in wild-type mice, contraction to low concentrations of PGF(2alpha) were normal, but maximum contraction to PGF(2alpha) was impaired in arteries from iNOS -/- mice treated with TNF-alpha [0.35 +/-.0.02 g (n = 8) following vehicle and 0.25 +/- 0.02 g (n = 7) following TNF-alpha (P < 0.05)]. Aminoguanidine, a relatively selective inhibitor of iNOS, partially restored contraction to PGF(2alpha) in vessels from iNOS +/+ mice but had no effect in iNOS -/- mice injected with TNF-alpha, suggesting that a mechanism(s) other than iNOS contributes to impaired responses. In contrast to contractile responses, relaxation of the carotid artery in response to acetylcholine and nitroprusside was not altered following TNF-alpha in iNOS +/+ or iNOS -/-mice. Responses of carotid arteries from iNOS -/- mice and effects of aminoguanidine suggest that both iNOS-dependent and iNOS-independent mechanisms contribute to impaired contractile responses following TNF-alpha.
...
PMID:Tumor necrosis factor-alpha impairs contraction but not relaxation in carotid arteries from iNOS-deficient mice. 1104 36

Inflammatory cytokines stimulate glial cells in vitro to produce nitric oxide (NO) from inducible NO synthase (iNOS). Whether the stimulation with cytokines produces NO derived from iNOS has not hitherto been demonstrated in the vivo brain. Nitrite and nitrate (NOx(-)) levels in the rat paraventricular nucleus (PVN) were measured before and after intraparenchymal microinjection of cytokines with a microdialysis technique. The cytokines, tumor necrosis factor (TNF)-alpha (10 ng), interleukin (IL)-1 beta (2 ng), and interferon (IFN)-gamma (2 ng) were microinjected. None of the cytokines alone had any effect on the NOx(-) levels for 8 h. But a combination of TNF-alpha and IFN-gamma gradually increased NOx(-) levels beginning at 140 min after the microinjection, and NOx(-) levels reached 1.8 times the basal level at 380 min. A combination of TNF-alpha and IL-1 beta increased NOx(-) beginning at 340 min, reaching 1.7 times the basal level at 440 min, whereas a combination of IL-1 beta and IFN-gamma had no effect. Microinjection of a mixture of all three cytokines increased NOx(-) levels beginning at 120 min, reaching 3.3 times the basal level at 400 min. Aminoguanidine, which is a selective inhibitor of iNOS, reduced NOx(-) levels induced by the mixed cytokine treatment. Semi-quantitative RT-PCR for iNOS mRNA was done. The intensity of the iNOS mRNA band for the cytokine-treated PVN was stronger than that for the vehicle-treated PVN. These results suggest that the increased NOx(-) after the treatment with mixed cytokines were dependent on iNOS activity. This is the first report to indicate that only cytokines induce NOS in vivo in the brain.
...
PMID:Combination of inflammatory cytokines increases nitrite and nitrate levels in the paraventricular nucleus of conscious rats. 1142 74


<< Previous 1 2 3 4 5 6 7 Next >>

---