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)

1. Methacholine relaxed phenylephrine-contracted aorta of the rat with the endothelium intact. This effect was inhibited by haemoglobin, methylene blue, gossypol, phenidone and L-NG-nitroarginine methyl ester (L-NAME). Rat aorta denuded of endothelium failed to relax in response to methacholine, histamine and the peptidoleukotrienes C4, D4 and E4. 2. Methacholine and histamine but not leukotrienes C4, D4 and E4 relaxed phenylephrine-contracted rat aorta without endothelium when surrounded by rabbit epithelium-intact bronchus. The muscarinic antagonist atropine antagonized the methacholine-induced relaxation. 3. Removal of the epithelium either mechanically or chemically, abolished methacholine-induced relaxation of rat aorta in the co-axial bioassay. These data indicate that the epithelium is responsible for the observed relaxant effect to methacholine and histamine. 4. The cyclo-oxygenase inhibitor, indomethacin, the phospholipase A2 inhibitor, mepacrine and the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), failed to inhibit methacholine-induced relaxation of rat aorta in the co-axial bioassay. This indicates that the epithelium-derived inhibitory factor (EpDIF) is not a product of the cyclo-oxygenase or lipoxygenase pathway or a product derived from activation of phospholipase A2. 5. Haemoglobin, methylene blue, phenidone, gossypol and L-NAME failed to inhibit the relaxation of rat aorta in the co-axial bioassay. These results demonstrate that EpDIF detected in the co-axial bioassay is not endothelium-derived relaxing factor (EDRF) or nitric oxide. Similarly, catalase was without effect. 6. EpDIF is unlikely to be a peptide since papain and alpha-chymotrypsin failed to alter the methacholine-induced relaxation of rat aorta in the co-axial bioassay. Furthermore, thiorphan, captopril and aprotinin were also without effect, suggesting that EpDIF is not a substrate for airway peptidases. 7. The results presented in this paper demonstrate the release of a vasoactive epithelium-derived inhibitory factor (EpDIF) from rabbit intrapulmonary bronchi by use of a co-axial bioassay preparation.
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PMID:The release of a non-prostanoid inhibitory factor from rabbit bronchus detected by co-axial bioassay. 185 18

Ischemia and reperfusion have been shown to cause damage to the endothelium as well as to the cardiac myocyte. Although the vasodilator response has been shown to be impaired following ischemia and reperfusion, the effect of a short period of global ischemia on the contractile response of the coronary vasculature is not clear. In the present study, coronary vasoconstriction in response to U46619, PGF2 alpha, 5-HT, and KCl was found to be depressed for at least 15 min following 15 min of in vitro global ischemia in rats hearts. Vasodilator blockers or inactivators were used in an effort to restore this depressed coronary response. Indomethacin (5 microM) was used to block production of vasodilator prostaglandins, L-NAME (30 microM) to block production of nitric oxide (NO), and adenosine deaminase (2.4 units/ml of coronary flow) to inactivate adenosine. None of these agents restored the normal coronary constrictor response following ischemia. When superoxide dismutase and catalase (both 20 micrograms/ml of coronary flow) were infused for 5 min before and after ischemia, the coronary response recovered more than 100% of its preischemic value by 15 min of reperfusion, but still remained depressed at 5 min reperfusion. These data suggest that free radicals produced during ischemia and/or reperfusion may be at least partly responsible for this temporary "stunning" of the coronary vasculature. Since the impaired contractile response was still present at 5 min reperfusion when the buffer was supplemented with oxygen radical scavengers, another mechanism must also be involved in this "stunning" process.
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PMID:Effects of short term ischemia and reperfusion on coronary vascular reactivity and myocardial function. 747 69

Mechanisms underlying production of vascular free radicals are unclear. We hypothesized that changes in blood flow might serve as a physiological stimulus for endothelial free radical release. Intact isolated aortas from 45 rabbits were perfused with the spin trap alpha-phenyl-N-tert-butylnitrone (PBN, 20 mmol/L) and formed radical adducts detected by electron paramagnetic resonance spectroscopy (EPR). Sequential perfusion at 2, 7.5, and 12 mL/min changed cumulative vascular PBN radical adduct yields, respectively, from 3.2 +/- 0.9 to 4.1 +/- 0.7 (P < .05) and 7.0 +/- 1.5 (P < .005) pmol/mg with endothelium and from 3.6 +/- 1.6 to 3.8 +/- 1.4 and 2.2 +/- 0.8 pmol/mg without endothelium (P = NS). In endothelialized aortas, superoxide dismutase (SOD) completely blocked flow-induced free radical production, whereas inactivated SOD, indomethacin, and the nitric oxide synthetase antagonist nitro-L-arginine methyl ester (L-NAME) had no effect; relaxations to acetylcholine remained unchanged with higher flows. To assess the role of flow on in vivo radical production, femoral arterial plasma levels of the ascorbyl radical, a stable ascorbate oxidation product, were measured by direct EPR in 56 other rabbits. Ascorbyl levels were assessed at baseline (30.2 +/- 0.7 nmol/L) and at peak-induced iliac flow changes. Flow increases from 25% to 100% due to saline injections through an extracorporeal aortic loop induced significant dose-dependent increases in ascorbyl levels (n = 5). In addition, after papaverine bolus injections, flow increased by 114 +/- 8% versus baseline, and ascorbyl levels increased by 5.4 +/- 0.7 nmol/L (n = 31, P < .001); similar results occurred with adenosine, isoproterenol, or hyperemia after 30-second occlusions (P < .05, n = 4 or 5 in each group). Active SOD completely blocked papaverine-induced ascorbyl radical increase, despite preserved flow response (delta ascorbyl = 0.02 +/- 1.6 nmol/L, P = NS); inactivated SOD, catalase, indomethacin, and L-NAME had no effect. Blood flow decreases of 65% to 100% due to phenylephrine or 60-second balloon occlusions were accompanied by an average decrease of 4.4 nmol/L (P < .05) in ascorbyl levels. No change in ascorbyl signal was observed when rabbit blood alone was submitted to in vitro flow increases through a tubing circuit. Thus, increases in blood flow trigger vascular free radical generation; such a response seems to involve endothelium-derived superoxide radicals unrelated to cyclooxygenase or nitric oxide synthetase activities. This mechanism may contribute to explain vascular free radical generation in physiological or pathological circumstances.
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PMID:Vascular free radical release. Ex vivo and in vivo evidence for a flow-dependent endothelial mechanism. 751 Oct 72

The objective of this study was to assess the potential contribution of hydrogen peroxide (H2O2) to the leukocyte-endothelial cell adhesion and increased microvascular permeability observed in rat mesenteric venules after inhibition of nitric oxide synthesis with NG-nitro-L-arginine methyl ester (L-NAME). Leukocyte adherence and emigration and leakage of fluorescein isothiocyanate-labeled albumin were monitored in postcapillary venules before and after exposure of the tissue to L-NAME. H2O2 production in mesenteric tissue was monitored by using dihydrorhodamine 123 (DHR), the H2O2-sensitive fluorochrome. L-NAME elicited a rapid increase in both the rate of albumin extravasation and oxidation of DHR, which was followed by an increased adherence and emigration of leukocytes in postcapillary venules. Treatment with either catalase or dimethylthiourea attenuated the L-NAME-induced oxidative stress, albumin leakage, and leukocyte-endothelial cell adhesion. Oxidation of DHR was enhanced in animals treated with either 3-amino-1,2,4-triazole (ATZ), an inhibitor of endogenous catalase, or a combination of ATZ and maleic acid diethyl ester, which depletes intracellular glutathione. Animals receiving a CD11/CD18-specific antibody to prevent leukocyte adhesion/emigration exhibited a reduced oxidation of DHR in response to L-NAME. These findings indicate that most of the H2O2 (and secondarily derived oxidants) generated in mesenteric tissue exposed to an inhibitor of nitric oxide production is due to accumulation of activated leukocytes.
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PMID:Microvascular responses to inhibition of nitric oxide production. Role of active oxidants. 752 12

L-Arginine is the substrate for synthesis of nitric oxide (NO.) by NO synthase which physiologically produces vasodilation. The reaction of NO. or its metabolites with O2 or its metabolites, however, can produce toxic reactive species which may cause cellular injury. We hypothesized that excessive NO. production in isolated perfused rabbit lungs at elevated PO2 could support the production of toxic nitrogen metabolites. In isolated perfused rabbit lungs ventilated with 95% O2, 1.0 mM L-arginine caused significant pulmonary hypertension and edema. These effects of L-arginine were attenuated by the NO. synthase inhibitor, L-NAME (0.5 mM), not affected by SOD pretreatment (100 u/ml) and reversed by pretreatment with catalase (200 u/ml), suggesting a mechanism involving H2O2. This mechanism was supported by producing L-arginine mediated injury in normoxic lungs in the presence of a H2O2 generating system. This injury also was attenuated by L-NAME. On the basis of these results, we conclude that H2O2 interacts with NO. or one of its oxidized metabolites to contribute to acute lung injury during hyperoxia. Such a mechanism may involve peroxynitrite anion, although direct proof of its formation is lacking under these conditions.
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PMID:L-arginine enhances injury in the isolated rabbit lung during hyperoxia. 754 44

The ability of glutamate to stimulate generation of intracellular oxidant species was determined by microfluorescence in cerebellar granule cells loaded with the oxidant-sensitive fluorescent dye 2,7-dichlorofluorescin (DCF). Exposure of cells to glutamate (10 microM) produced a rapid generation of oxidants that was blocked approximately 70% by MK-801 (a noncompetitive NMDA-receptor antagonist). To determine if nitric oxide (NO) or reactive oxygen species (ROS) contributed to the oxidation of DCF, cells were treated with compounds that altered their generation. NO production was inhibited with NG-nitro-L-arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor) and reduced hemoglobin (NO scavenger). Alternatively, cells were incubated with superoxide dismutase (SOD) and catalase, which selectively metabolize O2-. and H2O2. Concurrent inhibition of O2-. and NO production nearly abolished intracellular oxidant generation. Pretreatment of cells with either chelerythrine (1 microM, protein kinase C inhibitor) or quinacrine (5 microM, phospholipase A2 inhibitor) before addition of glutamate also blocked oxidation of DCF. Generation of oxidants by glutamate was significantly reduced by incubating the cells of Ca(2+)-free buffer. In cytotoxicity studies, a positive correlation was observed between glutamate-induced death and oxidant generation. Glutamate-induced cytotoxicity was blocked by MK-801 and attenuated by treatment with L-NAME, chelerythrine, SOD, or quinacrine. It is concluded that glutamate induces concurrent generation of NO and ROS by activation of both NMDA receptors and non-NMDA receptors through a Ca(2+)-mediated process. Activation of NO synthase and phospholipase A2 contribute significantly to this response. It is proposed that simultaneous generation of NO and ROS results in formation of peroxynitrite, which initiates the cellular damage.
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PMID:NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death. 759 85

The present study in isolated rat lungs demonstrates that nitric oxide gas (.NO, 70 nM) added to the perfusate containing a small amount of hemolysate [175 microliters of lysed red blood cells (RBC) per 50 ml of Earle's balanced salt solution (EBSS)] triggered profound and sustained vasoconstriction. Vasoconstriction was not observed when .NO was added to lungs perfused with washed intact rat or human RBC or with oxyhemoglobin (Hgb 20 microM). The presence of hemolysate in the perfusate also caused vasoconstriction in response to n-acetylcysteine (50 microM), glutathione (10(-4) M), or ascorbic acid (10(-4) M) and potentiated greatly the vasoconstrictor response to 5 mM KCl. Not only .NO, but also nitroprusside (SNP) or L-arginine and paradoxically three .NO synthesis inhibitors, including N-monomethyl L-arginine, L-NAME, and nitroblue tetrazolium, which have different mechanisms of action, each caused in the presence of hemolysate large vasoconstrictive responses. Hemolysate itself enhanced O2 consumption by slices of lung; no effects of this dose of .NO on lung slice respiration were seen in the absence of hemolysate. Both Hgb and hemolysate lowered perfusate cGMP levels to the same degree suggesting that the vasoconstrictive response was not due to unique effects of hemolysate on guanylyl cyclase. Addition of superoxide dismutase (SOD) and catalase (CAT) to the hemolysate containing perfusate, or addition of a cyclooxygenase or 5-lipoxygenase inhibitor, virtually abolished the .NO induced vasoconstriction. The latter data are consistent with the concept that exposure of the vasculature to hemolysate may result in the formation of peroxynitrite. However, SOD and CAT did not abolish the pulmonary vasoconstriction induced by L-arginine or by NAC. Our data indicate that hemolysate has profound effects on lung vessel tone regulation and on lung tissue mitochondrial function, yet the precise molecular mechanisms responsible for the action of hemolysate are likely to be very complex.
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PMID:Nitric oxide-related vasoconstriction in lungs perfused with red cell lysate. 789 7

The objective of the present study was to determine whether prolonged inhibition of nitric oxide synthesis in endothelial cells increased the surface adhesion of these cells for neutrophils. Human umbilical vein endothelial cells (HUVECs) were grown to confluence in 48-well microtiter plates. Exposure of HUVECs to the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) did not cause neutrophil adhesion at 1 hour but increased adhesion at 4 hours in a dose-dependent manner. The increased adhesion was prevented with L-arginine or nitric oxide donors but not an analogue of cGMP. The increased adhesion was inhibited by monoclonal antibodies directed against the beta 2-integrin CD18 and endothelial cell adhesion molecule ICAM-1. Platelet-activating factor (PAF) receptor antagonist WEB 2086 also prevented the L-NAME-induced neutrophil adhesion. Intracellular oxygen radical scavengers (dimethyl sulfoxide, butylated hydroxytoluene, and alpha, alpha'-dipyridyl), the iron chelator desferrioxamine, and the mitochondrial inhibitor azide inhibited the L-NAME-induced neutrophil adhesion, whereas extracellular oxygen radical scavengers (superoxide dismutase and catalase) had no effect. HUVECs were loaded with 2',7'-dichlorodihydrofluorescein diacetate, and oxidation to the fluorescent dichlorodihydrofluorescein (DCHF) was monitored. Fluorescence was enhanced in the L-NAME-treated HUVECs throughout the 4-hour incubation, an event inhibitable by an antioxidant and azide. The magnitude of the intracellular oxidation of DCHF was equivalent to approximately 0.8 mumol/L H2O2. These data suggest that prolonged nitric oxide synthesis inhibition in HUVECs causes an oxidant- and PAF-associated rise in adhesion on the surface of these endothelial cells for neutrophils.
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PMID:Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils. 791 May 28

In perfused rat mesenteric arteries without endothelium, pyrogallol (Pyr) or methylthioninium chloride (methylene blue, Met) produced a concentration-dependent relaxation. Superoxide dismutase abolished inhibition by Pyr, but not Met, of vasoconstrictor responses to transmural nerve stimulation (TNS). Neither catalase nor deferoxamine had any effect on vasodilator responses to Pyr or Met. Vasodilator responses to Pyr were unaltered by N omega-nitro-L-arginine methyl ester (L-NAME), indomethacin, or capsaicin. Similarly, the relaxing effect of Met was unaffected by indomethacin or capsaicin. These findings suggest that vasodilator responses to Pyr may be due to endothelial-independent generation of superoxide anion. In contrast the relaxation produced by Met appears to be due to a direct action on vascular smooth muscle independent of superoxide anion generation.
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PMID:Mechanisms of relaxation by pyrogallol and methylthioninium chloride in perfused rat mesenteric artery. 801 Jan 9

Anandamide (AN, arachidonyl ethanolamide) has been isolated from the brain and shown to be an endogenous ligand for the delta 9-tetrahydrocannabinol (delta 9-THC) receptor. The purpose of these studies was to determine whether AN or delta 9-THC can affect the cerebral circulation. With the use of the closed cranial window AN and delta 9-THC (10(-13)-10(-3) M) were topically applied to rabbit cerebral arterioles and effects on diameter were measured with a microscope. AN and delta 9-THC similarly induced a dose-dependent dilation starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation, whereas the free radical scavengers superoxide dismutase and catalase or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) had no effect on AN-induced dilation. The cerebrospinal fluid level of prostaglandin E2 increased only in response to 10(-7) M and greater AN and was not affected by delta 9-THC. [3H]AN superfused through the cranial window was 20% converted to arachidonic acid. These results show that AN and delta 9-THC can modulate cerebral arterioles, likely by stimulating release and metabolism of endogenous arachidonic acid. Whether dilation is due to vasodilator eicosanoids, or other vasoactive agents whose synthesis or release is cyclooxygenase dependent, is uncertain.
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PMID:Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. 859 93


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