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

Experiments were designed to test the hypothesis that elevated levels of endothelin 1 (ET-1) in the vasculature activate NADPH oxidase and/or uncoupled nitric-oxide synthase (NOS), resulting in O2-* production, and mediate increased constriction. Rat aortic rings were incubated with ET-1 or vehicle in the presence and absence of superoxide dismutase (SOD), ebselen (glutathione peroxidase mimetic), apocynin (NADPH oxidase inhibitor), L-NAME (Nomega-nitro-L-arginine methyl ester) (NOS inhibitor), tetrahydrobiopterin (BH4) (NOS cofactor), or selective ETA and ETB receptor antagonists (BQ-123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] and A-192621 [[2R-(4-propoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N-(2,6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]], respectively). O2-* production was monitored by oxidized dihydroethidine staining and/or lucigenin chemiluminescence. ET-1 significantly increased O2-* production compared with vehicle. SOD, ebselen, and apocynin inhibited the ET-1-induced increase in O2-* in intact and endothelium-denuded aorta. L-NAME and BH4 inhibited the ET-1-induced increase in O2-* in intact tissue, whereas these two compounds had no effect on ET-1-induced O2-* in endothelium-denuded aorta. Preincubation with BQ-123 or A-192621, individually, had no effect on ET-1-induced O2-*; however combining both antagonists inhibited the ET-1-stimulated increase in O2-*. Rat aortic rings were incubated with ET-1 or vehicle in the presence or absence of sepiapterin (BH4 synthesis substrate) or apocynin and mounted on wire myographs to determine isometric force generation in response to increasing KCl concentrations. ET-1 increased the contractile response to KCl compared with vehicle. Treatment with either sepiapterin or apocynin attenuated the ET-1-mediated increase with no effect of sepiapterin or apocynin alone. These data support the hypothesis that ET-1 increases vascular tone, in part, through ETA/ETB receptor activation of O2-* production from NADPH oxidase and NOS uncoupling.
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PMID:Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. 1614 72

Maple syrup urine disease (MSUD) is an inherited neurometabolic disorder biochemically characterized by the accumulation of the branched-chain alpha-keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-keto-beta-methylvaleric (KMV) and alpha-ketoisovaleric (KIV) and their respective branched-chain alpha-amino acids in body fluids and tissues. Affected MSUD patients have predominantly neurological features, including cerebral edema and atrophy whose pathophysiology is not well established. In the present study we investigated the effects of KIC, KMV and KIV on cell morphology, cytoskeleton reorganization, actin immunocontent and on various parameters of oxidative stress, namely total antioxidant reactivity (TAR), glutathione (GSH) and nitric oxide concentrations, and on the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in C6 glioma cells. We initially observed that C6 cultivated cells exposed for 3 h to the BCKA (1 and 10 mM) changed their usual rounded morphology to a fusiform or process-bearing cell appearance, while 24 h exposure to these organic acids elicited massive cell death. Rhodamine-labelled phalloidin analysis revealed that these organic acids induced reorganization of the actin cytoskeleton with no modifications on total actin content. It was also observed that 3h cell exposure to low doses of all BCKA (1 mM) resulted in a marked reduction of the non-enzymatic antioxidant defenses, as determined by TAR and GSH measurements. In addition, KIC provoked a reduced activity of SOD and GPx, whereas KMV caused a diminution of SOD activity. In contrast, CAT activity was not modified by the metabolites. Furthermore, nitric oxide production was significantly increased by all BCKA. Finally, we observed that the morphological features caused by BCKA on C6 cells were prevented by the use of the antioxidants GSH (1.0 mM), alpha-tocopherol (trolox; 10 microM) and Nomega-nitro-L-arginine methyl ester (L-NAME; 500 microM). These results strongly indicate that oxidative stress might be involved in the cell morphological alterations and death, as well as in the cytoskeletal reorganization elicited by the BCKA. It is presumed that these findings are possibly implicated in the neuropathological features observed in patients affected by MSUD.
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PMID:Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. 1682 90

Ischemia-reperfusion (I/R) injury induces an inflammatory response and production of oxygen-derived reactive species which affect many organs including heart, brain, kidney and gastrointestinal tract. The aim of this study was to assess the hepatic changes after renal I/R injury. Male Sprague Dawley rats were subjected to either sham operation or treatment with L-NAME, L-arginine and BQ-123 during 30 min renal ischemia and 2 h reperfusion injury. Hepatic superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px) activities, and thiobarbituric acid-reactive substances (TBARS) and nitric oxide (NO) levels were evaluated to show hepatic response to renal I/R injury. Catalase and SOD activities showed significant differences between the control and the other groups after I/R. On the other hand, GSH-Px activity did not show any significant changes between the control and the other experimental groups mentioned under above conditions. Meanwhile, levels of TBARS were not different between the control and the other experimental groups, whereas NO level showed changes between the control and experimental groups except the one to which endothelin receptor antagonist agent (BQ-123) subjected. Experimental period may not be enough to determine the changes in GSH-Px activity and level of TBARS. However, catalase and SOD activities decreased in experimental groups treated by chemical agents. NO level decreased in chemicalagent-applied experimental groups but not in the group to which endothelin receptor antagonist BQ-123 was applied alone.
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PMID:Effect of BQ-123 and nitric oxide inhibition on liver in rats after renal ischemia-reperfusion injury. 1691 32

Alterations of pancreatic antioxidative defense (AD) and possible nitric oxide (NO) role in AD organization of adult rats receiving l-arginine.HCl (2.25%) or N(omega)-nitro-l-arginine methyl ester (L-NAME.HCl, 0.01%) as drinking liquids and maintained at room (22+/-1 degrees C) or low (4+/-1 degrees C) temperature for 45 days were studied. For that purpose, copper, zinc- and manganese superoxide dismutase (CuZnSOD, MnSOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) and glutathione reductase (GR) activities were determined. Cold-induced decrease of CuZnSOD was inhibited with L-NAME, while l-arginine produced the same effect as cold in both supplemented groups. Cold acclimation elevated GSH-Px activity. l-Arginine and L-NAME expressed no effect on GSH-Px in rats kept at room temperature. L-NAME additionally elevated cold-induced GSH-Px activity, l-arginine expressing a similar trend. Cold-induced increase in GST activity was inhibited by L-NAME, while l-arginine inhibited this enzyme in both supplemented groups. Cold acclimation increased GR activity in control and L-NAME-treated group and l-arginine expressed a similar trend. Neither of the treatments affected MnSOD and CAT activities. Cold-induced changes of pancreatic AD were additionally affected by the alterations in l-arginine-NO-producing pathway. Some AD changes in the same direction with l-arginine or L-NAME point to the complexity of nitrogen compounds metabolism and function, accompanied by tissue-specific response.
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PMID:The effects of cold acclimation and nitric oxide on antioxidative enzymes in rat pancreas. 1739 42

In an attempt to elucidate molecular mechanisms and factors involved in beta cell regeneration, we evaluated a possible role of the L-arginine-nitric oxide (NO)-producing pathway in alloxan-induced diabetes mellitus. Diabetes was induced in male Mill Hill rats with a single alloxan dose (120 mg kg(-1)). Both non-diabetic and diabetic groups were additionally separated into three subgroups: (i) receiving L-arginine . HCl (2.25%), (ii) receiving L-NAME . HCl (0.01%) for 12 days as drinking liquids, and (iii) control. Treatment of diabetic animals started after diabetes induction (glucose level > or = 12 mmol l(-1)). We found that disturbed glucose homeostasis, i.e. blood insulin and glucose levels in diabetic rats was restored after L-arginine treatment. Immunohistochemical findings revealed that L-arginine had a favourable effect on beta cell neogenesis, i.e. it increased the area of insulin-immunopositive cells. Moreover, confocal microscopy showed colocalization of insulin and pancreas duodenum homeobox-1 (PDX-1) in both endocrine and exocrine pancreas. This increase in insulin-expressing cells was accompanied by increased cell proliferation (observed by proliferating cell nuclear antigen-PCNA immunopositivity) which occurred in a regulated manner since it was associated with increased apoptosis (detected by the TUNEL method). Furthermore, L-arginine enhanced both nuclear factor-kB (NF-kB) and neuronal nitric oxide synthase (nNOS) immunopositivities. The effect of L-arginine on antioxidative defence was observed especially in restoring to control level the diabetes-induced increase in glutathione peroxidase activity. In contrast to L-arginine, diabetic pancreas was not affected by L-NAME supplementation. In conclusion, the results suggest beneficial L-arginine effects on alloxan-induced diabetes resulting from the stimulation of beta cell neogenesis, including complex mechanisms of transcriptional and redox regulation.
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PMID:Beneficial effects of L-arginine nitric oxide-producing pathway in rats treated with alloxan. 1771 15

Acute intravenous Tempol reduces mean arterial pressure (MAP) and heart rate (HR) in spontaneously hypertensive rats. We investigated the hypothesis that the antihypertensive action depends on generation of hydrogen peroxide, activation of heme oxygenase, glutathione peroxidase or potassium conductances, nitric oxide synthase, and/or the peripheral or central sympathetic nervous systems (SNSs). Tempol caused dose-dependent reductions in MAP and HR (at 174 micromol/kg; DeltaMAP, -57+/- 3 mmHg; and DeltaHR, -50 +/- 4 beats/min). The antihypertensive response was unaffected by the infusion of a pegylated catalase or by the inhibition of catalase with 3-aminotriazole, inhibition of glutathione peroxidase with buthionine sulfoximine, inhibition of heme oxygenase with tin mesoporphyrin, or inhibition of large-conductance Ca(2+)-activated potassium channels with iberiotoxin. However, the antihypertensive response was significantly (P < 0.01) blunted by 48% by the activation of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channels with cromakalim during maintenance of blood pressure with norepinephrine and by 31% by the blockade of these channels with glibenclamide, by 40% by the blockade of nitric oxide synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME), and by 40% by the blockade of ganglionic autonomic neurotransmission with hexamethonium. L-NAME and hexamethonium were additive, but glibenclamide and hexamethonium were less than additive. The central administration of Tempol was ineffective. The acute antihypertensive action of Tempol depends on the independent effects of potentiation of nitric oxide and inhibition of the peripheral SNS that involves the activation of K(ATP) channels.
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PMID:Acute antihypertensive action of Tempol in the spontaneously hypertensive rat. 1793 67

The mechanism by which acetylcholine (ACh) decreases systemic arterial pressure and hindlimb vascular resistance was investigated in the anesthetized rat. ACh injections caused dose-dependent decreases in systemic arterial pressure and hindlimb vascular resistance. N(omega)-nitro-L-arginine methyl ester (L-NAME) had little effect on the magnitude of depressor and vasodilator responses but decreased response duration when baseline parameters were corrected by a nitric oxide (NO) donor infusion. The decrease in the duration of the ACh depressor response was prevented by the administration of excess L-arginine. The L-NAME-resistant component of the depressor response to ACh was attenuated by ebselen, a glutathione peroxidase mimic. The calcium-activated potassium (K(Ca)) antagonists charybdotoxin (ChTX) and apamin decreased the magnitude but not the duration of the hindlimb vasodilator response to ACh. The combination of L-NAME, ChTX, and apamin reduced the magnitude and duration of the vasodilator response to ACh but not to sodium nitroprusside. Vasodepressor and hindlimb vasodilator responses to ACh were not modified by cytochrome P-450 and cyclooxygenase pathway inhibitors. These results suggest that the hindlimb vasodilator response to ACh has an initial L-NAME-resistant component mediated by the activation of K(Ca) channels and a sustained L-NAME-dependent component. The results with ebselen suggest that the L-NAME-resistant component of the depressor response involves a peroxide-sensitive mechanism. The present study suggests that vasodilator responses to ACh are not mediated by cytochrome P-450 products, since miconazole and 1-aminobentriazole alone or in combination did not affect either component of the response. The present data suggest that the hindlimb vasodilator response to ACh in the rat is mediated by two mechanisms with an initial ChTX- and apamin-sensitive, L-NAME-resistant phase not mediated by cytochrome P-450 products and a secondary sustained phase mediated by NO.
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PMID:Analysis of L-NAME-dependent and -resistant responses to acetylcholine in the rat. 1803 19

Early in cold acclimation (1-7 days), heat is produced by shivering, while late in cold acclimation (12-45 days), skeletal muscle contributes to thermogenesis by tissue metabolism other than contractions. Given that both thermogenic phases augment skeletal muscle aerobic power and reactive species production, we aimed in this study to examine possible changes in skeletal muscle antioxidative defence (AD) during early and late cold acclimation with special emphasis on the influence of the L-arginine/nitric oxide (NO)-producing pathway on the modulation of AD in this tissue. Adult Mill Hill hybrid hooded rat males were divided into two main groups: a control group, which was kept at room temperature (22+/-1 degrees C), and a group maintained at 4+/-1 degrees C for 45 days. The cold-acclimated group was divided into three subgroups: untreated, L-arginine treated and N(omega)-nitro-L-arginine methyl ester (L-NAME) treated. The AD parameters were determined in the gastrocnemius muscle on day 1, 3, 7, 12, 21 and 45 of cold acclimation. The results showed an improvement of skeletal muscle AD in both early and late cold acclimation. Clear phase-dependent changes were seen only in copper, zinc superoxide dismutase activity, which was increased in early cold acclimation but returned to the control level in late acclimation. In contrast, there were no phase-dependent changes in manganese superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase, the activities of which were increased during the whole cold exposure, indicating their engagement in both thermogenic phases. L-Arginine in early cold acclimation accelerated the cold-induced AD response, while in the late phase it sustained increases achieved in the early period. L-NAME affected both early and late acclimation through attenuation and a decrease in the AD response. These data strongly suggest the involvement of the L-arginine/NO pathway in the modulation of skeletal muscle AD.
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PMID:Antioxidative defence alterations in skeletal muscle during prolonged acclimation to cold: role of L-arginine/NO-producing pathway. 1808 39

The major role of reactive oxygen species (ROS) in the pathomechanism of ischemia have been widely recognized. Still, measurements of the precise time course and regional distribution of ischemia-induced ROS level changes in acute brain slices have been missing. By using acute hippocampal slices and the fluorescent dye CM-H2DCFDA, we showed that reoxygenation after in vitro ischemia (oxygen-glucose deprivation; OGD) increased ROS levels in the hippocampal CA1 layers vulnerable to ischemia but did not have significant effects in the resistant stratum granulosum in the dentate gyrus (DG). Production of ROS started during OGD, but, contrary to reoxygenation, it manifested as a ROS level increase exclusively in the presence of catalase and glutathione peroxidase inhibition. The mechanism of ROS production involves the activation of NMDA receptors and nitric oxide synthases. The inhibition of ROS response by either AP-5 or L-NAME together with the ROS sensitivity profile of the dye suggest that peroxynitrite, the reaction product of superoxide and nitric oxide, plays a role in the response. Direct visualization of layer-specific effects of ROS production and its scavenging, shown for the first time in acute hippocampal slices, suggests that distinct ROS homeostasis may underlie the different ischemic vulnerability of CA1 and DG.
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PMID:Layer-specific differences in reactive oxygen species levels after oxygen-glucose deprivation in acute hippocampal slices. 1820 24

To explore detrimental effects of advanced oxidation protein products-bovine serum albumin (BSA) on endothelial function and compare the favorable effects of angiotensin-converting enzyme (ACE) inhibitors: captopril and enalapril. Male Sprague-Dawley rats were randomly divided into groups: control, advanced oxidation protein products-BSA, captopril (10, 20 mg/kg/day), enalapril (15 mg/kg/day), and N(G)-nitro-l-arginine methyl ester (l-NAME, 300 mg/kg/day) plus captopril (20 mg/kg/day) groups. All animals were given advanced oxidation protein products-BSA (100 mg/kg/day, i.v.) except for control group (iv. equal volume of PBS). Rats in other groups were received different drugs intragastrically after advanced oxidation protein products-BSA administration. Endothelium-dependent relaxation of thoracic aorta was assayed. Content of nitrite/nitrate (NO), malondialdehyde (MDA), activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and of ACE in Sera, as well as renal function index including blood urea nitrogen and creatinine were measured. After 30 days, the endothelium-dependent relaxation of blood vessels in received advanced oxidation protein products-BSA rats was significantly impaired compared with control rats. The impairment was accompanied by decreases of serum NO, activity of GSH-Px and SOD. Administration of captopril and enalapril not only decreased damage of endothelium-dependent relaxation, but also reverse the changes of MDA levels, NO content and activity of SOD. The protective effect of captopril was abolished by L-NAME. Blood urea nitrogen and creatinine had no significant differences between various groups. ACE activities were decreased in high captopril and enalapril groups, but did not significantly change in other groups. The results suggested that captopril and enalapril have similar effects on endothelial dysfunction induced by advanced oxidation protein products-BSA, which indicated that protective effects of captopril are not related to sulfhydryl group.
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PMID:Protective effects of ACE inhibitors on vascular endothelial dysfunction induced by exogenous advanced oxidation protein products in rats. 1833 54


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