UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These studies were conducted in the conscious, chronically catheterized rat to determine whether the endothelial derived relaxing factor (EDRF) controls renal function in the normal state. Administration of the EDRF synthesis inhibitors N-monomethyl-L-arginine (NMA; 100 mg/kg body weight) or N-nitro-L-arginine methylester (NAME; 10 mg/kg body wt) led to a large, sustained rise in blood pressure, a large rise in renal vascular resistance, a fall in renal plasma flow, a relatively slight reduction in glomerular filtration rate, and a consequent rise in filtration fraction. In addition, a marked natriuresis occurred because of a reduction in the fractional reabsorption of sodium. In separate studies, a continuous infusion of excess L-arginine (300 mg/kg body wt bolus followed by 50 mg/kg body wt per min) attenuated the NMA- or NAME-induced rise in blood pressure and reversed the renal hemodynamic effects such that a significant rise in renal plasma flow was seen. L-Arginine alone produced a selective renal vasodilation and large increases in sodium excretion. These observations support earlier suggestions that tonic release of EDRF controls the basal blood pressure and also show that renal function in the normal unstressed rat is markedly influenced by EDRF. These studies suggest that, in addition to controlling renal plasma flow, EDRF may have other, complex actions at the glomerulus. The natriuresis seen after acute inhibition of EDRF with NMA or NAME was probably the result of a pressure natriuretic response to the abrupt rise in blood pressure and also, perhaps, reflects removal of an EDRF influence to directly enhance sodium reabsorption somewhere in the nephron.
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PMID:Endothelial derived relaxing factor controls renal hemodynamics in the normal rat kidney. 210 47

The effects of nitric oxide (NO) during small bowel preservation and reperfusion were studied in a rat model of heterotopic, syngeneic LEW-->LEW transplantation. A 6-hr preservation interval was chosen, which leads consistently to moderate graft injury permitting graft and recipient survival. To evaluate the function of NO during preservation and reperfusion, two inhibitors (NitroG-L-arginine methyl ester [L-NAME] and NG-monomethyl-L-arginine [NMA]) were administered and compared with a transplanted group receiving no treatment. The extent of preservation and reperfusion injury were delineated by histologic study and by the measurement of mucosal glutaminase on tissue specimens obtained 20 min after revascularization and 24 hr and 4 weeks postoperatively. Serum and mucosal NO(2-)+NO3- levels were determined at the same time points. Graft function and survival was inferior in all cases where NO production was inhibited. When recipients were treated with NO inhibitors, graft function and survival was more impaired when L-NAME was administered compared with NMA administration. Donor and graft pretreatment with NO inhibitors impaired graft function but not survival, and was less detrimental than recipient treatment. Mucosal NO(2-)+NO3- levels significantly increased in untreated transplanted animals 20 min after reperfusion. This increase was abolished in groups treated with NO inhibitors. Serum NO(2-)+NO3- levels increased significantly after 24 hr, and this increase was even more pronounced when NO inhibitors were administered. Furthermore, liver function deteriorated after inhibition of NO, indicating a more severe inflammatory response of the recipient after NO inhibition. These data indicate that mucosal NO production within the graft during preservation, and especially during reperfusion, has beneficial effects, but increased serum NO(2-)+NO3- levels coincided with inferior graft condition due to preservation and reperfusion injury.
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PMID:The effects of administration of nitric oxide inhibitors during small bowel preservation and reperfusion. 780 22

1. It has been proposed that in inflammatory conditions, in which both the inducible isoforms of nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) are induced, inhibition of NOS also results in inhibition of arachidonic acid metabolism. In the present study we have investigated whether mercaptoalkylguanidines, a novel class of selective iNOS inhibitors, may also influence the activity of cyclo-oxygenase (COX). Therefore, the effect of mercaptoethylguanidine (MEG) and related compounds on the activity of the constitutive (COX-1) and the inducible COX (COX-2) was investigated in cells and in purified enzymes. Aminoguanidine, NG-methyl-L-arginine (L-NMA) and NG-nitro-L-arginine methyl ester (L-NAME) were also studied for comparative purposes. 2. Western blot analysis demonstrated a significant COX-1 activity in unstimulated J774 macrophages and in unstimulated human umbilical vein endothelial cells (HUVEC). Immunostimulation of the J774 macrophages by endotoxin (lipopolysaccharide of E. coli, LPS 10 micrograms ml-1) and interferon gamma (IFN gamma, 100 u ml-1) for 6 h resulted in a significant induction of COX-2, and a down-regulation of COX-1. No COX-2 immunoreactivity was detected in unstimulated HUVEC or unstimulated J774 cells. Therefore, in subsequent studies, the effect of mercaptoalkylguanidines on COX-1 activity was studied in HUVEC stimulated with arachidonic acid for 6 h, and in J774 cells stimulated with arachidonic acid for 30 min. The effect of mercaptoalkylguanidines on COX-2 activity was studied in immunostimulated J774 macrophages, both on prostaglandin production by endogenous sources, and on prostaglandin production in response to exogenous arachidonic acid stimulation. In addition, the effect of mercaptoalkylguanidines on purified COX-1 and COX-2 activities was also studied. 3. In experiments designed to measure COX-1 activity in HUVEC, the cells were stimulated by arachidonic acid (15 microM) for 6 h. This treatment induced a significant production of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable metabolite of prostacyclin), while nitrite production was undetectable by the Griess reaction. MEG (1 microM to 3 mM) caused a dose-dependent inhibition of the accumulation of 6-keto-PGF1 alpha, with an IC50 of 20 microM. However, aminoguanidine, L-NAME or L-NMA (up to 3 mM) did not affect the production of 6-keto-PGF1 alpha in this experimental system. In experiments designed to measure COX-1 activity in J774.2 macrophages, the cells were stimulated by arachidonic acid (15 microM) for 30 min; this also induced a significant production of 6-keto-PGF1 alpha and MEG (1 microM to 3 mM), aminoguanidine (at 1 and 3 mM), but neither L-NAME nor L-NMA inhibited the production of prostaglandins. 4. In experiments designed to measure prostaglandin production by COX-2 with endogenous arachidonic acid, J774.2 cells were immunostimulated for 6 h in the absence or presence of various inhibitors. In experiments designed to measure prostaglandin production by COX-2 with exogenous arachidonic acid, J774.2 cells were immunostimulated for 6 h, followed by a replacement of the culture medium with fresh medium containing arachidonic acid and various inhibitors. Both of these treatments induced a significant production of 6-keto-PGF1 alpha. Nitrite production, an indicator of NOS activity, was moderately increased after immunostimulation. MEG (1 microM to 3 mM) caused a dose-dependent inhibition of the accumulation of COX metabolites. Similar inhibition of LPS-stimulated 6-keto PGF1 alpha production was shown by other mercaptoalkylguanidines (such as N-methyl-mercaptoethylguanidine, N,N'-dimethyl-mercaptoethylguanidine, S-methyl-mercaptoethylguanidine and guanidino-ethyldisulphide), with IC50 values ranging between 34-55 microM. However, aminoguanidine, L-NAME and L-NMA (up to 3 mM) did not affect the production of prostaglandins.5. In comparative experiments indomethacin, a non selective COX inhibitor, and NS-398, a selective COX-2 inhibitor, reduced (LPS) stimulated 6-keto-PGF1alpha production in J774 macrophages in a dose-dependent manner without affecting nitrite release. Indomethacin, but not NS-398, inhibited 6-keto-PGF1alpha production in the HUVECs. 6.The inhibitory effect of MEG was due to direct inhibition of the catalytic activity of COX as indicated in experiments with purified COX-1 and COX-2. MEG dose-dependently inhibited the purified COX-1 and COX-2 activity with IC50 values of 33microM and 36microM, respectively. Aminoguanidine (at the highest concentrations) inhibited the formation of COX-1 metabolites, without affecting COX-2 activity. High doses of L-NAME (3mM) decreased COX-1 activity only, while L-NMA (up to 3mM) had no effect on the activity of either enzyme. 7.These results suggest that MEG and related compounds are direct inhibitors of the constitutive and the inducible cyclo-oxygenases, in addition to their effects on the inducible NOS. The additional effect of mercaptoalkylguanidines on COX activity may contribute to the beneficial effects of these agents in inflammatory conditions where both iNOS and COX-2 are expressed.
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PMID:The inhibitory effects of mercaptoalkylguanidines on cyclo-oxygenase activity. 903 36

Nitric oxide (NO) is a short-lived mediator, the synthesis of which is induced by various cytokines during inflammatory processes. Recently, it has been proposed that zymosan, a nonbacterial agent, causes inflammation by inducing the production of various cytokines and proinflammatory mediators. In the present study we investigated the role of NO in a nonseptic shock model induced by zymosan administration in the rat. Administration of zymosan (500 mg/kg, intraperitoneally) in the rat induced acute peritonitis, as assessed by a marked increase in the leukocytes count in the exudate, as well as by an increase in the exudate nitrate/nitrite concentration. Zymosan-treated rats developed a severe hypotension and showed signs of systemic illness, significant loss of body weight, and a high mortality rate (53% of animals died within 72 h). Elevated plasma levels of nitrite and nitrate were also observed in zymosan-treated rats compared with control rats (67 +/- 4 microM and 23 +/- 2 microM, respectively; p < .01). In ex vivo experiments, vascular reactivity was studied in thoracic aorta rings of zymosan-treated rats. The contractile responses to norepinephrine (100 nM) and endothelin-1 (5 nM) were significantly reduced. An impairment of the endothelial-dependent relaxation in response to acetylcholine was also observed. Pretreatment of zymosan-shocked rats with NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMA), (10 mg/kg, subcutaneously, 15 min before zymosan) decreased mortality, prevented the development of peritonitis, improved ex vivo vascular reactivity, and significantly reduced hypotension. Our data suggest that overproduction of NO plays a role in the zymosan-induced peritonitis and cardiovascular derangements in the rats.
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PMID:Role of nitric oxide in a nonseptic shock model induced by zymosan in the rat. 916 70

The purpose of this study was to examine whether nitric oxide (NO) synthase dysfunction accompanied with decrease in tetrahydrobiopterin (BH4) content increases H2O2-induced endothelial cell death. Endothelial cell death was measured by the release of intracellular lactate dehydrogenase (LDH). Intracellular BH4 content was changed by pretreatment with 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of GTP cyclohydrolase I, or pretreatment with sepiapterin, a substrate for the salvage pathway of BH4 synthesis, and the intracellular content was measured by high performance liquid chromatography equipped with a fluorescence detector. Moreover, production of superoxide was detected by a chemiluminescence technique using MCLA, a Cypridina luciferin analogue, for the superoxide-sensitive probe. Pretreatment with DAHP (10 mM) for 24 h decreased intracellular BH4 content to 14% and increased H2O2-induced cell death. The toxic effect of DAHP was reduced by co-pretreatment with sepiapterin (100 microM) or treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mM), an inhibitor of NO synthase, but not by N(G)-methyl-L-arginine (L-NMA, 1 mM), the other inhibitor of NO synthase. Moreover, production of superoxide in endothelial cells induced by Ca2+-ionophore ionomycin (1 microM) increased by the pretreatment with DAHP, and the increase in superoxide production was blocked by L-NAME (1 mM) but not L-NMA (1 mM). Co-pretreatment with sepiapterin decreased the production of superoxide. These findings suggested that dysfunction of NO synthase with a decrease in BH4 content in endothelial cells produced superoxide instead of NO and increased the oxidative stress-induced endothelial cell death.
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PMID:Acceleration of oxidative stress-induced endothelial cell death by nitric oxide synthase dysfunction accompanied with decrease in tetrahydrobiopterin content. 925 48

The roles of nitric oxide derived from either the constitutive endothelial NO synthase (eNOS or NOS3) or the inducible NOS (iNOS or NOS2) in hepatic injury during endotoxemia remain controversial. To investigate this further, rats received a bolus of lipopolysaccharide (LPS) following implantation of osmotic pumps containing one of two nonselective NOS inhibitors (NMA or NAME), one of two inducible NOS inhibitors (NIL or AG), or saline. The inhibitors were infused continuously into the liver via the portal vein. Treatment of LPS-injected rats with NMA and NAME resulted in 106 and 227% increases, respectively, in circulating hepatic enzyme levels compared to LPS-treated control rats. In contrast, infusion of the iNOS-selective inhibitors had no effect on the LPS-induced hepatic necrosis. In rats receiving NAME, LPS induced greater neutrophil infiltration and ICAM-1 expression than in the LPS + saline group, whereas NIL infusion did not. The increased hepatic necrosis and PMN infiltration in the LPS + NAME group was partially prevented by a simultaneous infusion of a liver-selective NO donor. Inhibition of PMN accumulation using an anti-ICAM-1 antibody or by PMN depletion using vinblastine pretreatment, however, did not reverse the increased necrosis with NAME infusion during endotoxemia. In contrast to the assessment for necrosis, increased apoptosis was observed in the livers of LPS-treated rats receiving infusions of either NAME or NIL, but not with LPS alone. These data indicate that NO produced by eNOS may be adequate to prevent necrosis by a mechanism independent of PMN, while induced NO appears to prevent apoptosis.
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PMID:Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and neutrophil accumulation during endotoxemia. 944 11

The inducible human cationic amino acid transporter hCAT-2B was expressed in Xenopus laevis oocytes, and this system was used to test the effect of several NO synthase (NOS) inhibitors and/or L-arginine analogues on L-arginine transport by this y+ carrier. L-NG-Methyl-L-arginine (L-NMA), asymmetrical L-NG, NG-dimethyl-L-arginine (L-ADMA), L-N5-(1-iminoethyl)-ornithine (L-NIO), L-NG-nitro-L-arginine (L-NNA), and L-NG-nitro-L-arginine methyl ester (L-NAME) all inhibited the inducible NOS II extracted from RAW 264.7 macrophages induced with bacterial lipopolysaccharide. L-NMA, L-ADMA, and L-NIO also competed with L-arginine for transport by hCAT-2B, whereas L-NNA and L-NAME did not. The two L-arginine analogues, symmetrical NG, NG-dimethyl-L-arginine (L-SDMA) and alpha-amino-delta-isothioureidovaleric acid (AITV), as well as L-lysine, did not block enzymatic activity of NOS II, but did compete for L-arginine transport mediated by hCAT-2B. L-Lysine and L-SDMA were transported efficiently by hCAT-2B and exchanged against intracellular L-arginine, resulting in an L-arginine depletion of the cells. AITV was a much poorer substrate of hCAT-2B and had only little effect on intracellular L-arginine concentrations. These data indicate that substrate recognition differs markedly between the inducible L-arginine transporter hCAT-2B and the inducible NOS II, with different L-arginine analogues having affinity to only one or both of these proteins.
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PMID:Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. 970 Oct 46

In adult mammalian cardiomyocytes, stimulation of muscarinic receptors counterbalances the beta-adrenoceptor-mediated increase in myocardial contractility and heart rate by decreasing the L-type Ca2+ current (ICa) (1, 2). This effect is mediated via inhibition of adenylyl cyclase and subsequent reduction of cAMP-dependent phosphorylation of voltage-dependent L-type Ca2+ channels (3). Little is known, however, about the nature and origin of this pivotal inhibitory pathway. Using embryonic stem cells as an in vitro model of cardiomyogenesis, we found that muscarinic agonists depress ICa by 58 +/-3% (n=34) in early stage cardiomyocytes lacking functional beta-adrenoceptors. The cholinergic inhibition is mediated by the nitric oxide (NO)/cGMP system since it was abolished by application of NOS inhibitors (L-NMA, L-NAME), an inhibitor of the soluble guanylyl cyclase (ODQ), and a selective phosphodiesterase type II antagonist (EHNA). The NO/cGMP-mediated ICa depression was dependent on a reduction of cAMP/protein kinase A (PKA) levels since application of the catalytic subunit of PKA or of the PKA inhibitor PK) prevented the carbachol effect. In late development stage cells, as reported for ventricular cardiomyocytes (2, 4), muscarinic agonists had no effect on basal ICa but antagonized beta-adrenoceptor-stimulated ICa by 43 +/-4% (n=16). This switch in signaling pathways during development is associated with distinct changes in expression of the two NO-producing isoenzymes, eNOS and iNOS, respectively. These findings indicate a fundamental role for NO as a signaling molecule during early embryonic development and demonstrate a switch in the signaling cascades governing ICa regulation.
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PMID:Regulation of the L-type Ca2+ channel during cardiomyogenesis: switch from NO to adenylyl cyclase-mediated inhibition. 997 19

Chronic exposure to hypoxia from birth increased the tolerance of the rabbit heart to subsequent ischemia compared with age-matched normoxic controls. The nitric oxide donor GSNO increased recovery of post-ischemic function in normoxic hearts to values not different from hypoxic controls, but had no effect on hypoxic hearts. The nitric oxide synthase inhibitors L-NAME and L-NMA abolished the cardioprotective effect of hypoxia. Message and catalytic activity for constitutive nitric oxide synthase as well as nitrite, nitrate, and cGMP levels were elevated in hypoxic hearts. Inducible nitric oxide synthase was not detected in normoxic or chronically hypoxic hearts. Increased tolerance to ischemia in rabbit hearts adapted to chronic hypoxia is associated with increased expression of constitutive nitric oxide synthase.
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PMID:Adaptation to chronic hypoxia confers tolerance to subsequent myocardial ischemia by increased nitric oxide production. 1041 35

Diesel exhaust particles (DEP) have been proved to induce serious pulmonary injury, among which lethal pulmonary edema has been assumed to be mediated by vascular endothelial cell damage. In the present study, we investigated the cytotoxic mechanism of DEP on human pulmonary artery endothelial cells focusing on the role of active oxygen species. Endothelial cell viability was assessed by WST-8, a novel tetrazolium salt. Nitric oxide (NO) production was measured by using a new fluorescence indicator, diaminofluorescein-2 (DAF-2). Organic compounds in DEP were extracted by dichloromethane and methanol. DEP-extracts damaged endothelial cells under both subconfluent and confluent conditions. The DEP-extract-induced cytotoxicity was markedly reduced by treatment with SOD, catalase, N-(2-mercaptopropionyl)-glycine (MPG), or ebselen (a selenium-containing compound with glutathione peroxidase-like activity). Thus superoxide, hydrogen peroxide, and other oxygen-derived free radicals are likely to be implicated in DEP-extract-induced endothelial cell damage. Moreover, L-NAME and L-NMA, inhibitors of NO synthase, also attenuated DEP-extract-induced cytotoxicity, while sepiapterin, the precursor of tetrahydrobiopterin (BH(4), a NO synthase cofactor) interestingly enhanced DEP-extract-induced cell damage. These findings suggest that NO is also involved in DEP-extract-mediated cytotoxicity, which was confirmed by direct measurement of NO production. These active oxygen species, including peroxynitrite, may explain the mechanism of endothelial cell damage upon DEP exposure during the early stage.
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PMID:The cytotoxic effects of diesel exhaust particles on human pulmonary artery endothelial cells in vitro: role of active oxygen species. 1118 26

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