Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-NAME (Nw-Nitro-L-arginine methylester) and L-NMMA (NG- Monomethyl-L-arginine, monoacetate) are used widely as nitric oxide (NO) synthase inhibitors. Because of their functional groups (alcohols, amines and carboxylates), it appeared that they could interact with iron in a variety of systems. Using three in vitro models we observed these two compounds had inhibitory effects on cytochrome C reduction by ferrous iron, by ferrous iron accelerated by an unsaturated fatty acid or by epinephrine. This suggests that L-NAME and L-NMMA could have effects in iron containing systems found intracellularly apart from their inhibition of (NO) synthesis.
 ...
PMID:The non specificity of specific nitric oxide synthase inhibitors. 138 21

Nitric oxide (NO) synthesis inhibition causes neutrophil adhesion to endothelium via a mast cell- and oxidant-dependent mechanism. The objective of this study was to delineate the cascade of events in the mast cell- and oxidant-induced neutrophil-endothelium interactions after NO synthesis inhibition. Mast cells were isolated and purified from the rat peritoneal cavity and coadministered with neutrophils to wells of endothelium. This system was treated with an NO synthesis inhibitor (NG-nitro-L-arginine methyl ester; L-NAME) for 60 minutes. L-NAME did not induce neutrophil-endothelium interactions in the absence of mast cells, but the addition of mast cells in a ratio as low as 1:50 mast cells to neutrophils was sufficient to induce a large increase in neutrophil adhesion to endothelium within 20 to 25 minutes. L-arginine, NO donors, and 8-bromo-cGMP reversed the L-NAME effect, whereas NG-nitro-D-arginine methyl ester alone had no proadhesive effect. The adhesion was inhibited by an anti-CD18 or an anti-intracellular adhesion molecule-1 antibody and a platelet-activating factor-receptor antagonist. Inhibition of NO in isolated endothelial monolayers induced oxidant release (reduction of cytochrome C) into extracellular fluid. The endothelium-derived superoxide contributed to the mast cell-induced adhesion, inasmuch as the extracellular antioxidant superoxide dismutase reduced the neutrophil adhesion response as did disruption of endothelial function. There was some direct activation of mast cells with L-NAME (independent of endothelium) inasmuch as intracellular calcium and oxidative stress increased within mast cells after L-NAME treatment, and this translated into increased neutrophil adhesion to nonendothelial substrata. These data demonstrate that depletion of NO increases oxidative stress within mast cells and endothelium and together these events promote neutrophil adhesion within the vasculature.
 ...
PMID:A balance between nitric oxide and oxidants regulates mast cell-dependent neutrophil-endothelial cell interactions. 888 91

Neutrophils induce lung injury by releasing superoxides (O2-) and elastases. Alveoli contain anti-neutrophil agents such as surfactant. We studied the effects of alveolar type II cells on neutrophil functions. Neutrophils were isolated from human venous blood and their O2- production was measured by the cytochrome C reduction method. Type II cells and fibroblasts were isolated from rat lungs. Neutrophil O2-production was inhibited in the presence of type II cells. This effect was specific to type II cells: fibroblasts caused no inhibition. The inhibition did not require cell-to-cell contact, and it was abolished by the nitric oxide synthase inhibitor L-NAME. These results show that type II cells can inhibit neutrophil O2-production, and suggest that anti-neutrophil activity in alveoli may involve both surfactant and type II cells.
 ...
PMID:[Inhibitory effect of rat alveolar type II cells on production of superoxide by neutrophils]. 897 75

The purpose of this study was to gain direct insights into mechanisms by which myoglobin induces proximal tubular cell death. To avoid confounding systemic and hemodynamic influences, an in vitro model of myoglobin cytotoxicity was employed. Human proximal tubular (HK-2) cells were incubated with 10 mg/ml myoglobin, and after 24 hours the lethal cell injury was assessed (vital dye uptake; LDH release). The roles played by heme oxygenase (HO), cytochrome p450, free iron, intracellular Ca2+, nitric oxide, H2O2, hydroxyl radical (-OH), and mitochondrial electron transport were assessed. HO inhibition (Sn protoporphyrin) conferred almost complete protection against myoglobin cytotoxicity (92% vs. 22% cell viability). This benefit was fully reproduced by iron chelation therapy (deferoxamine). Conversely, divergent cytochrome p450 inhibitors (cimetidine, aminobenzotriazole, troleandomycin) were without effect Catalase induced dose dependent cytoprotection, virtually complete, at a 5000 U/ml dose. Conversely, -OH scavengers (benzoate, DMTU, mannitol), xanthine oxidase inhibition (oxypurinol), superoxide dismutase, and manipulators of nitric oxide expression (L-NAME, L-arginine) were without effect. Intracellular (but not extracellular) calcium chelation (BAPTA-AM) caused approximately 50% reductions in myoglobin-induced cell death. The ability of Ca2+ (plus iron) to drive H2O2 production (phenol red assay) suggests one potential mechanism. Blockade of site 2 (antimycin) and site 3 (azide), but not site 1 (rotenone), mitochondrial electron transport significantly reduced myoglobin cytotoxicity. Inhibition of Na, K-ATPase driven respiration (ouabain) produced a similar protective effect. We conclude that: (1) HO-generated iron release initiates myoglobin toxicity in HK-2 cells; (2) myoglobin, rather than cytochrome p450, appears to be the more likely source of toxic iron release; (3) H2O2 generation, perhaps facilitated by intracellular Ca2+/iron, appears to play a critical role; and (4) cellular respiration/terminal mitochondrial electron transport ultimately helps mediate myoglobin's cytotoxic effect. Formation of poorly characterized toxic iron/H2O2-based reactive intermediates at this site seems likely to be involved.
 ...
PMID:Myoglobin toxicity in proximal human kidney cells: roles of Fe, Ca2+, H2O2, and terminal mitochondrial electron transport. 906 5

The marked impairment of hepatic drug metabolism during inflammation and infections has been known for many years and shown to result from down-regulation of cytochrome P450s (CYP) by cytokines. However, the mechanism of this repression is unknown. Using primary cultures of human hepatocytes, we show here that interleukin-6 (IL-6) rapidly and markedly decreases the expression of PXR (pregnane X receptor) and CAR (constitutively activated receptor) mRNAs, but does not affect the levels of dioxin receptor and glucocorticoid receptor mRNA. In parallel, IL-6 decreases both rifampicin- and phenobarbital-mediated induction of CYP2B6, CYP2C8, CYP2C9, and CYP3A4. As the transcriptional activity of PXR and CAR is not affected by IL-6 in cell-based reporter assays, our data suggest that the loss of CYP2 and CYP3 inducibility results from the negative regulation of PXR and CAR gene expression by this cytokine.
 ...
PMID:Interleukin-6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. 1092 40

Phenobarbital (PB) increases metabolic capability of hepatocytes by its ability to activate numerous genes encoding various xenochemical-metabolizing enzymes such as cytochrome P450s and specific transferases. More than 35 years since PB induction was first reported, the key nuclear receptor CAR that mediates the induction has now been identified, and the molecular/cellular mechanism involving multiple signal transduction pathways has begun to be unraveled. In response to PB exposure, CAR in the cytoplasm translocates into the nucleus, forms a heterodimer with the retinoid X receptor, and activates the PB response enhancer element leading to the concerted induction of numerous genes.
 ...
PMID:Phenobarbital-elicited activation of nuclear receptor CAR in induction of cytochrome P450 genes. 1102 30

Many xenobiotics are metabolized and detoxified by cytochrome P-450s (CYP). The xenobiotics metabolizing CYPs are induced by various kinds of receptors. To induce CYP1A1, the Ah receptor requires a ligand for its activation as a transcription factor. On the other hand, benzimidazole compounds can induce CYP1A1 without binding to the Ah receptor as a ligand (ligand-independent pathway). In response to phenobarbital (PB) and other PB-type inducers, the nuclear receptor CAR (the NR-constitutive active receptor) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates the PB-responsive enhancer module (PBREM) in the PB-inducible CYP2B genes. For human CYP3A4 genes, pregnane X receptor (PXR) binds to the xenobiotic-responsive enhancer module (XREM) and upon induction by rifampicin, a PXR:RXR heterodimer could transactivate XREM.
 ...
PMID:[Regulation of cytochrome P-450 (CYP) genes by nuclear receptors]. 1186 91

Besides necrosis, apoptosis is the other major mode of cardiomyocyte loss in ischemic cardiovascular disease. In the present study, we examined the hypothesis that nitric oxide (NO) protects myocardial function by improving myocardial microcirculation and attenuating cardiomyocyte apoptosis in a rat model of myocardial ischemia/reperfusion (MI/R). The left main coronary artery of anesthetized male rats was ligated for 40 min, followed by 4 h reperfusion. Four groups of animals were studied: sham operated control + saline; sham operated control + N(W)-nitro-L-arginine methyl ester (L-NAME); MI/R + saline; MI/R + L-NAME (10 mg/kg, iv, 10 min prior to reperfusion). Results show that MI/R caused a decrease in mean arterial blood pressure (MABP), cardiac index (CI), and stroke volume index (SVI). Inhibition of NO synthesis by L-NAME attenuated plasma NO levels, but increased MABP and SVR in sham control rats and rats subjected to MI/R, and further depressed left ventricular function in rats subjected to MI/R as indicated by decreased CI and SVI. Furthermore, administration of L-NAME to rats subjected to MI/R enhanced cardiomyocyte apoptosis as indicated by a significant increase in DNA fragmentation compared to rats with MI/R alone. Histological study revealed that L-NAME caused arterial constriction and congestion of red blood cells in arteries and capillaries in the peri-ischemic areas of the hearts in rats subjected to MI/R and, interestingly, also in the sham control rats. Data suggest that the mechanism of increased reperfusion injury may be attributable to a "no-reflow" phenomenon induced by L-NAME, resulting in increased cardiomyocyte apoptosis secondary to ischemia and enhanced cytochrome-c release from mitochondria. In addition, cardiac injury may be increased due to the augmented oxygen consumption of cardiomyocytes caused by the increased SVR and afterload. These results suggest that endogenous NO may act to improve myocardial microvascular perfusion, reduce SVR, and limit cardiomyocyte apoptosis, thereby, attenuating myocardial dysfunction induced by MI/R.
 ...
PMID:L-NAME enhances microcirculatory congestion and cardiomyocyte apoptosis during myocardial ischemia-reperfusion in rats. 1190 Mar 36

Although studies have reported that increase in coronary perfusion (CP) results in positive inotropic effects, the underlying mechanisms of these actions and possible alterations in myocardial diastolic function are not well defined. Hypothesis was that nitric oxide (NO) and derivatives of cytochrome (CYT) P-450 or cyclooxygenase (COX) might contribute to interplay between coronary and myocardial compartments in these conditions. Using isovolumically contracting, isolated perfused hamster heart model, coronary flow (CF) was increased mechanically, stepwise in the physiologic range (+2 to +10 ml/min), before and after inhibition of NO synthase by NG-nitro-l-arginine methyl ester (l-NAME) (30 microM), CYT P-450 by SKF525A (1 microM), or COX by indomethacin (10 microM). CP pressure, left ventricular systolic pressure (VSP) and ventricular diastolic pressure (VDP), and heart rate (HR) were monitored continuously during the experiments. Mechanical increases in CF resulted in gradual change in CP pressure (+20% to +100%), left VSP (+5% to +40%) and VDP (+2% to +25%), whereas HR was not affected. In presence of l-NAME, the positive inotropic response and negative lusitropic effect of CF changes were similar. Exposure to SKF525A did not modify cardiac response to mechanical increases in CF. In presence of COX inhibitor indomethacin, left VSP rose to a level similar to that observed in control conditions, whereas VDP deteriorated further. These results suggest that mediators originating from NO synthase, CYT P-450, or COX do not contribute to positive inotropic response elicited by increased CP. However, COX derivatives seem to attenuate impairment of myocardial relaxation observed in these conditions. Such findings may have implications in development of therapeutics for patients with myocardial diastolic dysfunction.
 ...
PMID:Role of nitric oxide synthase, cytochrome P-450, and cyclooxygenase in the inotropic and lusitropic cardiac response to increased coronary perfusion. 1207 82

The present work describes an isozyme-related effect of collagenase perfusion on hepatocyte microsomal cytochrome (CYP)-dependent monooxygenase activities: CYP 1A1/2-, 2B1/2-, 3A1/2- and 2E1-dependent activities in microsomes from rat hepatocytes after isolation were about 60% of that of liver microsomes, and CYP 4A1-dependent activity was equivalent to liver microsomes. In contrast, the microsomal protein content of the various CYP isoforms was not affected by hepatocyte isolation. This is in accordance with the hypothesis of CYP inactivation during the process of hepatocyte isolation by collagenase digestion. L-NAME (1 mM) was found unable to protect from the decline of CYP-dependent monooxygenase activities following hepatocyte isolation. It is possible that the decrease in glutathione peroxidase activity observed in the presence of L-NAME, namely depression of defense against peroxynitrite, could counteract the beneficial effect of L-NAME on nitric oxide synthesis inhibition. The present work also shows that L-NAME could not avoid the progressive, isoform-specific, most probably turnover-related, decline of CYP proteins and related monooxygenase activities in cultured hepatocytes. Dysregulations in the mechanisms of CYP expression in rat hepatocyte cultures, presently unknown but nitric oxide independent, thus appear to occur in cultured rat hepatocytes.
 ...
PMID:Time course of cytochromes P450 decline during rat hepatocyte isolation and culture: effect of L-NAME. 1253 63


1 2 3 Next >>