Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conversion of L-[3H]arginine to L-[3H]citrulline in the absence of calcium can be used to assay selectively the activity of inducible nitric oxide synthase (NOS) in rat spleen homogenates 6 h after lipopolysaccharide administration. Using similar assay conditions, changes in inducible NOS activity were measured within ischemic brain tissue between 2 h and 7 days following permanent middle cerebral artery (MCA) occlusion in Sprague-Dawley rats and SV-129 mice. Total (constitutive and inducible) NOS activity was measured in the presence of 0.5 mM CaCl2. Whereas total NOS activity in rat decreased dramatically to 16% and 6% of baseline 6 and 12 h after MCA occlusion, inducible NOS activity remained undetectable before 2 days after occlusion, became maximal at 3 days, and decreased to less than 10% of maximal iNOS activity at 7 days. In the mouse, total NOS activity decreased after MCA occlusion but inducible NOS activity was undetectable from 2 h to 4 days after occlusion. Sustained NO production by inducible NOS activity does not contribute to ischemic injury within 24 h after MCA occlusion, but may contribute to infarct maturation 2-4 days after ischemia in some but not all species.
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PMID:Induction of nitric oxide synthase activity in rodent brain following middle cerebral artery occlusion. 747 41

End organ ischemia, fragmentation of elastic membranes, and aneurysm formation in patients with giant cell vasculitis results from an inflammation destroying the mural layers of large and medium sized arteries. Although the inflammatory infiltrate extends through all layers of the affected blood vessel, the most pronounced changes involve the intima and the internal elastic lamina. Analysis of the functional profile of tissue infiltrating CD68+ cells demonstrates that different subsets of macrophages can be distinguished. TGFbeta1-expressing CD68+ cells coproduce IL-1beta and IL-6, are negative for inducible nitric oxide synthase (iNOS), and exhibit a strong preference for localization in the adventitia. The adventitial homing of TGFbeta1+ CD68+ cells places them in the vicinity of IFN-gamma secreting CD4+ T cells which also accumulate in the exterior layer of the artery. Conversely, iNOS expressing CD68+ cells are negative for TGFbeta and are almost exclusively found in the intimal layer of the inflamed artery. The intimal-medial junction is the preferred site for 72-kD collagenase expressing CD68+ cells. Thus, TGFbeta1-producing macrophages colocalize with activated CD4+ T cells and home to an area of inflammation which is distant from the site of tissue damage but critical in regulating cellular influx, suggesting that TGFbeta1 functions as a proinflammatory mediator in this disease. iNOS- and 72-kD collagenase-producing macrophages accumulate at the center of pathology implying a role of these products in tissue destruction. These data indicate that the microenvironment controls the topographical arrangement as well as the functional commitment of macrophages.
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PMID:Correlation of the topographical arrangement and the functional pattern of tissue-infiltrating macrophages in giant cell arteritis. 883 14

Nitric oxide (NO) generated from L-arginine and molecular oxygen by nitric oxide synthase (NOS) has been shown to influence hepatocellular function and pathology in response to ischemia and certain hepatotoxins. In the present study, we examined the liver of a transgenic line of sickle cell mice for hepatocellular injury and localization of two isoforms of NOS, the endothelial constitutively expressed isoform (EcNOS) and the inducible isoform (iNOS) by immunohistochemistry. Diffuse expression of EcNOS was observed in hepatocytes of control and sickle cell animals maintained under room air conditions. In contrast, iNOS was observed only in the sickle cell mice, well-localized to hepatocytes surrounding the central veins of the lobules. When normal mice were exposed to hypoxic conditions for 4 to 5 days, iNOS immunostaining appeared de novo in a patchy distribution throughout the liver lobules. In the sickle cell mice, hypoxia appeared to increase the subjective intensity of pericentral staining of iNOS. Liver histology was normal in the sickle cell mice maintained under room air conditions, but showed multifocal areas of necrosis when sickling was exacerbated by chronic hypoxic conditions. However, a pericentral zone of preserved architecture was present, corresponding to the region of iNOS staining. We postulate that pericentral induction of iNOS under ambient conditions occurs in transgenic sickle cell mice in response to particularly intense hypoxic conditions near the central veins of the liver. Increases in NO synthesis may occur in this region, which would serve to protect these cells from ischemic damage either directly or by maintaining blood flow. These findings could be relevant to liver pathophysiology in patients with sickle cell disease.
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PMID:Immunohistochemical localization of hepatic nitric oxide synthase in normal and transgenic sickle cell mice: the effect of hypoxia. 889 27

The purpose of this study was to determine whether inducible nitric oxide synthase (iNOS) was implicated in the pathogenesis of retinal ischemia-reperfusion injury. Semi-quantitative reverse transcription-polymerase chain reaction showed that the level of iNOS mRNA expression was markedly increased in rat retina following transient ischemia, with peak expression at 12 hr after reperfusion (15.7-fold increase over pre-ischemic levels). In situ hybridization showed that iNOS mRNA was expressed by resident retinal cells, most likely glial cells in the innermost retina, and also by the neutrophils that had infiltrated the retina. Intraperitoneal administration of NG-(1-iminoethyl)-L-ornithine (L-NIO), an inhibitor of iNOS, significantly increased the rate of b-wave recovery compared to that of control animals. The values (mean +/- S.E.M.) were 55.0 +/- 4.4% versus 40.1 +/- 5.1% (P < 0.05) at 1 day and 68.6 +/- 6.6% versus 45.8 +/- 3.5% (P < 0.05) at 3 days. This study shows that iNOS mRNA is highly expressed by non-neuronal cells of the inner retina during reperfusion following transient retinal ischemia. It also shows that L-NIO treatment provides some protection against ischemia-reperfusion injury. We suggest that nitric oxide produced by iNOS may mediate retinal ischemia-reperfusion injury.
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PMID:Inducible nitric oxide synthase in retinal ischemia-reperfusion injury. 899 53

Ischemia is one of the strongest stimuli for gene induction in the brain. More than 80 different mRNAs have been found to be induced by brain ischemia so far. Many of these genes encode protein products that are involved directly or indirectly in neuronal survival. These include genes that promote recovery by enhanced gene expression (for example, heat shock proteins or growth factors) or attempt to protect them from delayed neuronal death (for example anti-apoptosis genes). Neuronal degeneration can be promoted by induction of apoptosis genes or genes that cause a stress to the cells, such as free radical production by nNOS or iNOS. Even though so many ischemia-inducible genes have been identified, the general reduction of gene transcription and inhibition of protein translation affect neuronal survival the most. The lack of protein synthesis is especially significant when the cells are challenged by ischemia followed by the attack of free radicals during the subsequent recirculation. Even though the ischemia-induced gene expression has a dichotomy to beneficial and harmful genes, several genes such as those encoding transcription factors may participate in both cellular responses. Therefore, pinpointing the receptors and signal transduction mechanisms responsible for the induction of different genes is of interest. So far, only NMDA (Fig. 1) and possibly KA/ AMPA receptor and to some extent alpha 2-adrenoreceptor have proved to be involved in the regulation of perifocal gene induction. Nevertheless, interfering with gene expression offers a potential opportunity for the development of a novel stroke therapy.
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PMID:Altered gene expression in brain ischemia. 908 Apr 12

We investigated the density and distribution of nitric oxide synthase (NOS) binding by quantitative autoradiography using [3H]L-NG-nitroarginine ([3H]L-NNA) after transient focal ischemia or intrastriatal injection of N-methyl-D-aspartate (NMDA) in wild-type (SV-129 and C57black/6) and type I (neuronal) and type III (endothelial) NOS-deficient mice. The middle cerebral artery (MCA) was occluded by an intraluminal filament for 3 h followed by 10 min to 7 days of reperfusion. Specific [3H]L-NNA binding, observed in the wild-type and type III mutant mouse at baseline, increased by 50-250% in the MCA territory during ischemia and the first 3 h of reperfusion. The density of binding sites (Bmax), but not the dissociation constant (Kd), increased significantly during the ischemic period as did type I NOS mRNA as detected by quantitative reverse transcription polymerase chain reaction. [3H]L-NNA binding after intrastriatal NMDA injection also increased by 20-230%. In the type I NOS-deficient mouse, [3H]L-NNA binding was low and only a very small increase was observed after ischemia or excitotoxicity. Under conditions of this study, [3H]L-NNA did not bind to type II NOS as there was no difference in the distribution or density of [3H]L-NNA binding in the rat spleen obtained after lipopolysaccharide treatment despite induction of NOS type II catalytic activity. Our data suggest that an ischemic/excitotoxic insult up-regulates type I NOS gene expression and [3H]L-NNA binding and that this up-regulation may play a pivotal role in the pathogenesis of ischemic/excitotoxic diseases.
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PMID:[3H]L-NG-nitroarginine binding after transient focal ischemia and NMDA-induced excitotoxicity in type I and type III nitric oxide synthase null mice. 918 89

Pretreatment with monophosphoryl lipid A (MLA) can pharmacologically mimic the second window of ischemic preconditioning (SWOP) to protect the heart from prolonged ischemia and reperfusion injury. Based on the delayed time course for development of MLA associated cardioprotection, this study was designed to test if MLA's cardioprotective effect is mediated by signalling through production of inducible nitric oxide synthase (iNOS), a proposed effector of SWOP. Rabbits were assigned to one of four groups: (1) vehicle control; (2) MLA: (3) vehicle+aminoguanidine (AMG) control; or (4) MLA+AMG. Monophosphoryl lipid A (35 micrograms/kg) or vehicle was given intravenously 24 h before ischemia. The selective iNOS inhibitor AMG (300 mg/ kg) was injected subcutaneously 1 h before ischemia. All rabbits experienced 30 min coronary artery occlusion followed by 3 h of reperfusion. Infarct size was measured by triphenyltetrazolium chloride (TTC) staining. followed by 3 h of reperfusion. Infarct size was measured by triphenyltetrazolium chloride (TTC) staining. Myeloperoxidase activity, an index of neutrophil infiltration, was also quantified in heart tissue collected from the post-ischemic viable border zone surrounding the infarct area. MLA pretreatment significantly reduced infarct size and neutrophil infiltration in rabbit hearts compared to control (P < 0.05). Inhibition of iNOS activity by AMG abolished the infarct size reductive effect of MLA. Aminoguanidine also blocked the ability of MLA to significantly reduce neutrophil infiltration. Although measurement of iNOS activity did not show induction of the enzyme in normal myocardial tissue 24 h after MLA pretreatment, an increase in iNOS activity in ischemic tissue relative to non-ischemic tissue was found after either 15 or 30 min of coronary occlusion in MLA treated rabbits. These results suggest that MLA pretreatment may enhance iNOS enzyme activity by MLA during ischemia which may be responsible for the observed cardioprotection.
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PMID:Role of inducible nitric oxide synthase in pharmacological "preconditioning" with monophosphoryl lipid A. 922 Mar 42

Although it is well known that brain ischemia is dominantly caused by hypoxia and hypoglycemia, it is still unclear how hypoxia participates in ischemia. We studied the changes in neuronal nitric oxide synthase (nNOS) and the effect of the NOS inhibitor NG-nitro-L-arginine (NNA) on hypoxia. In vivo hypoxia (5% O2/95% N2 for 30 min) induced mild degenerative neuronal changes (shrunken and eosinophilic somata with picnotic nuclei) in neurons of the CA3, the hilus of the dentate gyrus (DG) and the DG, but not in the CA1. At 3 and 7 days after hypoxia, levels of nNOS protein were significantly enhanced to 153 and 209%, but iNOS protein could not be detected. The numbers of nNOS-immunopositive neurons were significantly enhanced to 145 and 191% in the CA3, 145 and 178% in the hilus of the DG, and 243 and 387% in the DG after 3 and 7 days, respectively. In contrast, no statistical difference was determined in the CA1. We further examined the effect of NNA administered at 5 min and 3, 6, and 24 h after hypoxia. Administration of NNA (0.1 and 1 mg/kg, i.p.) significantly decreased the number of damaged neurons in the hilus of the DG and the DG. However, higher doses of NNA (10 mg/kg, i.p.) did not prevent damage. These results suggest that hypoxia alone induces enhancement of nNOS protein and nNOS immunoreactivity in neurons of the hippocampus and that NNA has biphasic effects against hypoxia-induced neuronal damage in the hilus of the DG and the DG.
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PMID:In vivo hypoxia-induced neuronal damage with an enhancement of neuronal nitric oxide synthase immunoreactivity in hippocampus. 922 38

Ischemia-reperfusion (IR) lung injury occurs after various clinical procedures, including cardiopulmonary bypass. It is not clear whether endogenous nitric oxide (NO) is protective or injurious in lungs subjected to IR. Thus, in this study we examined the contribution of endogenous NO to IR injury in isolated, blood-perfused rat lungs. Lungs of male Wistar rats (300 g) were subjected to 30 min ischemia and 180 min reperfusion (I30R180). Lungs were sampled for inducible nitric oxide synthase (i-NOS) mRNA expression (each n = 3) and NOS enzyme activity (each n = 4) at different time points. NOS inhibitors NG-nitro-L-arginine-methyl ester (10[-4] M) and aminoguanidine (10[-4] M) were used to study the contribution of NO to IR injury in lungs subjected to I30R30 and I30R180. The contribution of i-NOS to IR lung injury was studied by inducing i-NOS enzyme with Salmonella lipopolysaccharide, followed by I30R30. We found that ischemia-reperfusion alone can upregulate i-NOS mRNA and i-NOS enzyme activity (p < 0.05, ANOVA), but downregulate constitutive NOS enzyme activity over 180 min reperfusion. Endogenously produced NO is protective against lung injury in I30R180 in normal rats and lung injury in I30R30 in septic rats. NO is also pivotal in maintaining pulmonary vascular homeostasis in septic rat lungs undergoing IR.
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PMID:The role of endogenous nitric oxide in modulating ischemia-reperfusion injury in the isolated, blood-perfused rat lung. 944 9

The effect of ischemia produced by bilateral occlusion of the common carotid arteries (30 min) followed by 4 hours of reperfusion on total and inducible nitric oxide synthase (NOS) activity and the production of nitric oxide (NO), superoxide and peroxynitrite in the cerebral hemispheres was determined in the rat. Compared to sham-operated controls, cerebral ischemia-reperfusion resulted in a significant increase in total and inducible NOS activity and a significant increase in the production of NO and superoxide in the cerebral hemispheres. The level of NO in the plasma and the peripheral leukocyte count were also significantly increased. Immunohistochemical staining for nitrotyrosine (a marker of peroxynitrite production) showed that ischemia-reperfusion resulted in increased synthesis of cerebral peroxynitrite. Administration of the irreversible NOS inhibitor, Nomega-nitro-L-arginine (L-NA), increased superoxide levels in the brain and significantly reduced plasma NO. Total and inducible NOS activity as well as NO and immunoreactive nitrotyrosine, in the cerebral hemispheres were reduced with L-NA administration. The number of leukocytes in the plasma was unaffected by administration of L-NA. These findings suggest that cerebral ischemia-reperfusion causes increased production of reactive oxygen species in the cerebral hemispheres and that the production of peroxynitrite, and not superoxide, may be dependent upon the availability of NO.
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PMID:Augmentation of nitric oxide, superoxide, and peroxynitrite production during cerebral ischemia and reperfusion in the rat. 947 7


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