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)

The potent endothelial-derived vasodilator nitric oxide (NO) has been identified as a protective agent in acute renal failure. However, some recent studies have suggested a detrimental effect of NO on rat proximal tubules exposed to hypoxia and reoxygenation. We determined whether NO metabolites cause intracellular oxidation during hypoxia and reoxygenation and whether this oxidative stress is linked to irreversible cell injury. Primary cultures of rat proximal tubular epithelial cells were studied in a subconfluent stage and subjected to 60 min hypoxia and 30 min reoxygenation. Intracellular oxidation was assessed by monitoring the conversion of nonfluorescent dihydrorhodamine 123 (DHR) to fluorescent rhodamine 123 as a probe for the long-lived oxidant peroxynitrite. Hypoxia and reoxygenation produced a marked increase in cellular generation of oxidant species. Intracellular oxidation of DHR was reduced by approximately 40% when cells were also exposed to the NO synthase inhibitor L-NAME. Oxidation of DHR following hypoxia and reoxygenation was not affected by SOD or DMTU. A combination of SOD and L-NAME was no more effective than L-NAME alone. Hypoxia and reoxygenation produced substantial injury (as LDH release). There was a 40% reduction in LDH release when cells were pretreated with a NO synthase inhibitor. In summary, increased generation of NO capable of inducing intracellular oxidizing reactions and cell death occurred during renal hypoxia and reoxygenation.
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PMID:Nitric oxide-mediated renal epithelial cell injury during hypoxia and reoxygenation. 960 34

1. Nitric oxide (NO)-mediated, endothelium-dependent vasodilator function in rat aortic smooth muscle was investigated in an in vitro model of endogenous vascular superoxide anion stress, generated by pretreatment with the Cu/Zn superoxide dismutase (SOD, EC 1.15.1.1) inhibitor, diethyldithiocarbamate (DETCA). 2. Contraction to noradrenaline (NA, 1 nM - 1 microM) in endothelium-intact vessels was augmented after a 30 min pretreatment with DETCA (10 mM) followed by 30 min washout. This effect was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME, 0.3 mM) and removal of the endothelium and partially reversed by exogenous Cu/Zn SOD (200 u ml(-1)). 3. Endothelium- and basal NO-dependent vasorelaxation to the phosphodiesterase (PDE) type V inhibitor ONO- 1 505 (4-[2-(2-hydroxyethoxy)ethylamino]-2-(1H-imidazol-1-yl)-6-methoxyquin azoline methanesulphonate) (0.1-10 microM) was inhibited after DETCA (10 mM) pretreatment. In addition, the ability of L-NAME (0.3 mM) to enhance established contractile tone was effectively absent. 4. In contrast, DETCA pretreatment did not significantly affect vasorelaxation to acetylcholine (ACh, 1 nM - 3 microM) or S-nitroso-N-acetyl penicillamine (SNAP, 0.03-30 microM). However, L-NAME (0.3 mM) unmasked an inhibitory effect of DETCA pretreatment on vasorelaxation to SNAP in endothelium-intact vessels while markedly potentiating vasorelaxation to SNAP in control tissue. 5. L-NAME (0.3 mM)- and exogenous catalase (200 u ml(-1))-sensitive vasorelaxation to exogenous Cu/ Zn SOD (200 u ml(-1)) was greater after DETCA (10 mM) pretreatment in endothelium-intact aortic rings. This difference was abolished by catalase (200 u ml(-1)). 6. In conclusion, tissue Cu/Zn SOD inhibition elicited a selective lesion in basal endothelial function in rat isolated aortic smooth muscle, consistent with the inactivation of basal NO by superoxide anion. The resulting leftward shift in nitrovasodilator reactivity, due to the loss of the tonic depression by basal NO, is likely to mask the inhibitory effect of superoxide anion on agonist-stimulated endothelial function and nitrovasodilator-derived NO, thereby accounting for the differential pattern of endothelial dysfunction after DETCA pretreatment.
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PMID:Interaction between superoxide anion and nitric oxide in the regulation of vascular endothelial function. 963 Mar 65

1. The aim of this study was to determine the response of porcine small pulmonary arteries to intralumenal flow and to identify the cellular mechanisms and potential mediators involved in the response. 2. Porcine small pulmonary arteries were isolated from a branch of the main intrapulmonary artery of the lower lung lobe and studied in a perfusion myograph system that allowed independent control of transmural pressure and intralumenal flow. At a transmural pressure of 20 mmHg, the baseline internal diameter (BID) of the arteries was 251.2+/-16.1 microm (n=16). 3. Under quiescent conditions or during constriction with U46619 to approximately 60% of BID, intralumenal flow caused reversible constriction in arteries with endothelium (in the presence of U46619, flow decreased diameter from 60.0+/-2.5% to 49.5+/-3.0% BID at 10 microl min(-1), n=16, P<0.05) but no change in diameter of arteries without endothelium. 4. In the presence of superoxide dismutase (SOD, 150 u ml(-1)), the response to flow was converted from constriction to vasodilatation (in presence of U46619 and SOD, flow increased diameter from 54.2+/-3.4% to 76.7+/-4.5% BID at 10 microl min(-1), n=10, P<0.05). Inhibition of NO synthase with L-NAME (3 x 10(-5) M) abolished the flow-induced vasodilatation occurring in the presence of SOD and the flow-induced constriction occurring in the absence of SOD. In arteries with endothelium, L-NAME (3 x 10(-5) M) caused significant vasoconstriction, whereas SOD did not alter vasomotor tone. 5. Acetylcholine (10(-8) to 10(-6) M) caused endothelium-dependent relaxation of small pulmonary arteries that was not significantly affected by SOD (150 u ml(-1)) but was inhibited by L-NAME (3 x 10(-5) M). 6. These results suggest that in small, porcine, isolated pulmonary arteries, intralumenal flow increases the production of NO but this is obscured by the generation of superoxide which causes vasoconstriction.
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PMID:Superoxide and endothelium-dependent constriction to flow in porcine small pulmonary arteries. 964 50

In the present investigation involvement of endothelial-derived reactive oxygen species (ROS) and their interaction with nitric oxide (NO), during norepinephrine (NE)-induced contraction of rat aortic rings was studied. NE (1x10(-10) M to 1x10(-5) M) caused concentration-dependent contractio n of the endothelium intact aortic rings. In the presence of hydroxyl radical scavengers, histidine (1x10(-3) M), mannitol (3x10(-3) M), dimethyl sulfoxide (50x10(-3) M) or thiourea (1x10(-3) m), superoxide dismutase (superoxide radical scavenger, SOD 10 or 100 U ml-1) or catalase (hydrogen peroxide inactivator 3, 10, or 100 U ml-1) the concentration-response curve of NE was shifted towards the right. Interestingly, in NG-nitro-l-arginine methyl ester (L-NAME) (1x10(-5) M, a NO synthase inhibitor) pretreated rings, NE-induced contractions were not inhibited by SOD or extracellular hydroxyl radical scavengers (mannitol and histidine). However, in these rings NE-induced contractions were found to be attenuated by endogenous hydroxyl radical scavengers (thiourea and DMSO) or catalase. In the endothelium denuded rings no significant effect of these scavengers on NE-induced contractions was observed. These results thus indicate the involvement of endothelium-derived hydrogen peroxide, superoxide and hydroxyl radicals in the NE-induced contractions. In addition, endothelial NO interacts with the ROS generated during rat aortic ring contractions.
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PMID:Role of endothelial-derived reactive oxygen species and nitric oxide in norepinephrine-induced rat aortic ring contractions. 977 89

In a guinea pig model of allergic asthma, we have recently established that a deficiency of nitric oxide (NO) contributes to the increased ex vivo responsiveness of isolated perfused tracheae to methacholine after the early asthmatic reaction at 6 h after inhalational challenge of the animals with ovalbumin aerosol. Because this deficiency could be caused by a reaction of NO with enhanced levels of inflammation-induced superoxide anion (O-2), we examined the effect of endogenous O-2 on the regulation of methacholine-induced constriction by NO of intact perfused tracheal tube preparations from unchallenged (control) guinea pigs and from animals 6 h after ovalbumin challenge. In the presence of the NO synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 100 microM), tracheae obtained from unchallenged guinea pigs showed a 1.7-fold increase in the maximal response to intraluminally applied methacholine (p < 0.05). By contrast, the maximal airway response to methacholine was significantly decreased in the presence of the O-2 scavenger superoxide dismutase (SOD; 100 U/ml), by approximately 45% (p < 0.01). The SOD-induced decrease in responsiveness to methacholine was reversed by L-NAME. Tracheal preparations obtained at 6 h after allergen challenge showed a 1. 8-fold increased responsiveness to intraluminally applied methacholine compared with controls (p < 0.001), which was not further enhanced in the presence of L-NAME. SOD had neither an effect on the increased responsiveness nor did it restore the potentiating effect of L-NAME. These results indicate that (1) in normoreactive tracheal preparations, the regulatory role of NO is partially counteracted by endogenous O-2, and ( 2) the deficiency of NO in hyperreactive tracheae obtained at 6 h after ovalbumin challenge is not caused by its reaction with O-2, but rather to decreased cNOS activity. De Boer J, Pouw FMH, Zaagsma J, Meurs H. Effects of endogenous superoxide anion and nitric oxide on cholinergic constriction of normal and hyperreactive guinea pig airways.
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PMID:Effects of endogenous superoxide anion and nitric oxide on cholinergic constriction of normal and hyperreactive guinea pig airways. 984 68

The present study analyses the influence of hypertension and endothelium on the effect induced by hydrogen peroxide (H2O2) on basal tone in aortic segments from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) of 6-month-old, as well as the possible mechanisms involved. Single (1 mM) or cumulative (100 nM-10 mM) concentrations of H2O2 produced a transient contraction or a concentration-dependent increase of basal tone, respectively, in segments from WKY and SHR. In both cases, the contractions were higher in intact segments from hypertensive than from normotensive rats, and increased by endothelium removal in both strains. Catalase (1000 u ml(-1), a H2O2 scavenger) abolished the contraction elicited by 1 mM H2O2 in both strains. Superoxide dismutase (SOD, 150 u ml(-1)) and dimethylsulphoxide (DMSO, 7 mM), scavengers of superoxide anions and hydroxyl radicals, respectively, did not alter H2O2-induced contractions in intact segments from both strains. However, L-NG-nitroarginine methyl ester (L-NAME, 100 microM, a nitric oxide synthase inhibitor) increased the response to H2O2 in normotensive rats, although the increase was less than that produced by endothelium removal. Incubation of segments with 1 mM H2O2 for 15 min and subsequent washout reduced the contractile responses induced by 75 mM KCl in intact segments from SHR and in endothelium-denuded segments from both strains; this effect being prevented by catalase (1000 u ml(-1)). Indomethacin (10 microM, a cyclo-oxygenase inhibitor) and SQ 29,548 (10 microM, a prostaglandin H2/thromboxane A2 receptor antagonist) practically abolished the contractions elicited by H2O2 in normotensive and hypertensive rats. We conclude that: (1) the oxidant stress induced by H2O2 produces contractions mediated by generation of a product of the cyclo-oxygenase pathway, prostaglandin H2 or more probably thromboxane A2, in normotensive and hypertensive rats; (2) oxygen-derived free radicals are not involved in the effect of H2O2; (3) in normotensive rats, endothelium protects against H2O2-mediated injury to contractile machinery, determined by the impairment of KCl-induced contractions; and (4) endothelial nitric oxide has a protective role on the contractile effect induced by H2O2, that is lost in hypertension.
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PMID:Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved. 986 64

ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0-12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml(-1))], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml(-1))] and inhibition of endothelial nitric oxide synthase (eNOS) [with, Nomega-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 microM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0-12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0 12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 microM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA. Increased oxygen tensions > 500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from approximately 20 to approximately 120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.
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PMID:Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries. 988 88

The superoxide anion (O-2.) appears to be an important modulator of nitric oxide (NO.) bioavailability. The present study was designed to characterize the role of copper/zinc superoxide dismutase (Cu/Zn SOD) in endothelium-dependent relaxations. Cu/Zn SOD was inhibited with the Cu2+ chelator diethyldithiocarbamic acid (DETCA). In isolated canine basilar arteries, DETCA (7.6 x 10(-3) M) inhibited total vascular SOD activity by 46% (P < 0.0001, n = 6-8 dogs). DETCA (7.6 x 10(-3) M) significantly reduced relaxations to bradykinin and A-23187 (P < 0.05, n = 7-11). The inhibitory effect of DETCA was abolished by the O-2. scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron; 9.4 x 10(-3) M; P < 0.05, n = 6-13). Tiron significantly potentiated the relaxations to bradykinin in control rings (P < 0.05, n = 13), and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-4) M) abolished these relaxations (P < 0.0001, n = 6). DETCA and Tiron had no effect on the relaxations to diethylamine-NONOate or forskolin (P > 0.05, n = 6). Our results demonstrate that endothelium-dependent relaxations mediated by NO. are impaired after the inhibition of Cu/Zn SOD. Relaxations to bradykinin (but not A-23187) were significantly augmented by Tiron. Pharmacological scavenging of O-2. reverses the effect of Cu/Zn SOD inhibition.
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PMID:Inhibition of copper/zinc superoxide dismutase impairs NO.-mediated endothelium-dependent relaxations. 1007 90

The effects of hydrogen peroxide (H2O2, 1 nM-5 mM) on the tone of the rings of aorta precontracted with phenylephrine (PE) were studied in 4-5 months streptozotocin (STZ)-diabetic rats and their age-matched controls. H2O2 induced brief contraction before relaxation in endothelium-containing rings that was more pronounced in diabetic rats. Removal of the endothelium or pretreatment of rings with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM) abolished H2O2-induced immediate and transient increase in tone, but preincubation with indomethacin (10 microM) had no effect on contractions induced by H2O2 in both group of animals. Pretreatment with L-NAME or indomethacin as well as absence of endothelium produced an inhibition of H2O2-induced relaxation that was more pronounced in diabetic rings. Chronically STZ-diabetes resulted in a significant increase in H2O2-induced maximum relaxation that was largely endothelium-dependent. Decreased sensitivity (pD2) of diabetic vessels to vasorelaxant action of H2O2 was normalized by superoxide dismutase (SOD, 80 U/ml). Pretreatment with SOD had no effect on H2O2-induced maximum relaxations in both group of animals but led to an increase in H2O2-induced contractions in control rats. When the rings pretreated with diethyldithiocarbamate (DETCA, 5 mM), H2O2 produced only contraction in control rats, and H2O2-induced relaxations were markedly depressed in diabetic rats. H2O2 did not affect the tone of intact or endothelium-denuded rings in the presence of catalase (2000 U/ml). Aminotriazole (AT, 10 mM) failed to affect H2O2-induced contractions or relaxations in all rings. Our observations suggest that increased production of oxygen-derived free radicals (OFRs) in diabetic state leads to a decrease in SOD activity resulting an increase in endogenous superoxide anions (O2*-), that is limited cytotoxic actions, and an increase in catalase activity resulting a decrease in both H2O2 concentrations and the production of harmful hydroxyl radical (*OH) in diabetic aorta in long-term. Present results indicate that increased vascular activity of H2O2 may be an important factor in the development of vascular disorders associated with chronically diabetes mellitus. Enhanced formation of *OH, that is a product of exogenous H2O2 and excess O2*, seems to be contribute to increased relaxations to exogenously added H2O2 in chronically diabetic vessels.
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PMID:Increased activity of H2O2 in aorta isolated from chronically streptozotocin-diabetic rats: effects of antioxidant enzymes and enzymes inhibitors. 1044 15

Although endothelium-derived hyperpolarizing factor (EDHF) is thought to be a cytochrome P-450 product (arachidonic acid metabolite) in some tissues, in porcine coronary arteries (PCAs) its nature remains unclear. Because phospholipase A2 and C are involved in the synthesis and/or release of EDHF in the PCA, the arachidonic acid (AA) pathway may be involved. In the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) and the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M), both bradykinin (BK; 10(-9)-10(-6) M) and AA (10(-7)-10(-4) M) induced dose-dependent relaxation of PGF2alpha-contracted PCA rings, which was blocked by a high extracellular concentration of KCl (30 mM) or pretreatment with ouabain, a Na+/K+-adenosine triphosphatase (ATPase) inhibitor (5 x 10(-7) M). Eicosatetraynoic acid (ETYA; 20 microM), which inhibits all AA pathways, slightly affected the response to BK and AA; however, lipoxygenase or cytochrome P-450 inhibitors had no effect, suggesting that relaxation is independent of these enzymatic pathways. Because endothelial cells can generate reactive oxygen species (ROS) via metabolism of AA and independent of cyclooxygenase activity, we also studied (a) whether ROS can relax the PCA, as well as the mechanism(s) involved, and (b) the role of ROS in BK- and AA-induced relaxation. Xanthine (X; 100 microM) plus xanthine oxidase (XO; 0.02 U/ml) induced time-dependent relaxation of PGF2alpha-contracted PCA rings in the presence of indomethacin and L-NAME. Dilatation was not affected by superoxide dismutase (SOD; 500 U/ml) but was abolished by catalase (300 U/ml), suggesting that hydrogen peroxide (H2O2) is involved. When rings were contracted by depolarizing them with 30 mM KCl, X/XO failed to elicit relaxation. Ouabain abolished the response to X/XO, suggesting that X/XO may induce relaxation by hyperpolarizing vascular smooth muscle cells via stimulation of the Na+/K+-ATPase pump. We therefore questioned whether ROS might be involved in BK- and AA-induced relaxation. Because catalase combined with SOD had little or no effect, we concluded that in the PCA, the relaxation induced by BK via EDHF involves some mechanism independent of NO, AA metabolism, or ROS.
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PMID:Reactive oxygen species: role in the relaxation induced by bradykinin or arachidonic acid via EDHF in isolated porcine coronary arteries. 1051 Nov 33


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