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)

We recently demonstrated that reactive astrocytes express NADPH diaphorase activity, a marker for Nitric Oxide Synthase, following transient global ischemia (Neuroscience Letters 154: 125-128). There has been little evidence that astrocytes express Nitric Oxide Synthase or produce NO (nitric oxide) in vivo; although in vitro experiments have shown that cultured astrocytes can produce NO. To determine whether reactive astrocytes express inducible form of NOS (iNOS) in vivo, we studied the pathological changes of rat hippocampus by immunohistochemistry after 10 minutes of transient global ischemia, which results in the selective delayed death of CA1 pyramidal cells and marked gliosis in the CA1 subfield. In the normal hippocampus, astrocytes express neither NADPH diaphorase activity nor iNOS. After ischemia, the temporal and spatial pattern of iNOS, NADPH diaphorase, and GFAP are very similar, indicating that reactive astrocytes express iNOS. Double staining for NADPH diaphorase and GFAP, or iNOS and GFAP confirmed that reactive astrocytes express both NADPH diaphorase activity and iNOS immunoreactivity. These changes were observed three day after ischemia and increased in prominence from one week to one month. The staining pattern of OX42, an antibody that recognizes both microglia and macrophages, is spatially and temporally distinct from the pattern of NADPH diaphorase and iNOS staining. Thus, we conclude that transient global ischemia induces iNOS primarily in reactive astrocytes. This increase in NOS expression and, presumably, NO production by reactive astrocytes may play a role in the process of delayed neuronal death or in the remodeling responses that occur after ischemic damage.
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PMID:Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. 752 35

Nitric oxide synthase-containing neurons are presumed to be resistant to neurodegeneration and neurotoxicity, however this resistance has not been demonstrated after focal cerebral ischemia. We therefore measured the temporal profile of neuronal nitric oxide synthase (NOS-I) mRNA and immunoreactivity and NADPH-diaphorase reactivity over a one week period after permanent middle cerebral artery (MCA) occlusion in 48 male Wistar rats and compared these data to ischemic cell damage as evaluated on hematoxylin and eosin (H & E) stained sections by light microscopy. NOS-I mRNA increased as early as 15 min after MCA occlusion in the ipsilateral striatum and maximal expression of NOS-I was found in the ipsilateral cortex and striatum 1 h after MCA occlusion. The numbers of NOS-I-containing neurons in the ipsilateral cortex and striatum were significantly greater (P < 0.05) than NOS-I-containing neurons in the contralateral hemisphere at 2-48 h after the onset of ischemia. The number of NOS-I-containing neurons peaked at 4 h after MCA occlusion. Neurons exhibited shrinkage or were swollen at 1 to 4 h after MCA occlusion. At 24-48 h after ischemia, neurons in the ischemic lesion appeared to be eosinophilic or ghost like on H & E stained sections. However, some of these neurons retained morphological integrity on the NOS-I immunohistochemical sections. At 168 h after ischemia, all neurons within the lesion appeared necrotic on H & E stained sections; however, scatterred neurons expressed NOS-I and NADPH-diaphorase. The rapid upregulation of NOS-I and mRNA in the ischemic lesion suggests that NOS-I is involved in focal cerebral ischemic injury; the expression of NOS-I by neurons that retain their morphological structure in the area of the infarct suggests that NOS-I-containing neurons are more resistant to the ischemic insult. Our data also indicate a close association of NOS-I immunoreactivity and NADPH-diaphorase reactivity in ischemic brain.
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PMID:Upregulation of neuronal nitric oxide synthase and mRNA, and selective sparing of nitric oxide synthase-containing neurons after focal cerebral ischemia in rat. 752 66

We sought to determine whether expression of the inducible, calcium-independent isoform of nitric oxide synthase (iNOS) contributes to the tissue damage produced by focal cerebral ischemia. The middle cerebral artery was occluded in halothane-anesthetized spontaneously hypertensive rats. Twenty-four hours later rats received intraperitoneal injections of the iNOS inhibitor aminoguanidine (100 mg/kg twice per day; n = 10) or of aminoguanidine + L-arginine (300 mg/kg four times per day; n = 7), aminoguanidine + D-arginine (n = 7), arginine alone (n = 6), or vehicle (n = 9). Drugs were administered for 3 consecutive days. Infarct volume was determined by image analysis in thionin-stained brain sections 4 days after induction of ischemia. Administration of aminoguanidine reduced infarct volume by 33 +/- 4% (P < 0.05 from vehicle; analysis of variance and Tukey's test), a reduction that was antagonized by coadministration of L- but not D-arginine. Administration of L-arginine alone did not affect infarct size (P > 0.05 vs. vehicle). In separate rats (n = 10), aminoguanidine attenuated calcium-independent NOS activity in the infarct (P < 0.05 vs. vehicle) without affecting calcium-dependent activity (P > 0.05). Aminoguanidine did not affect resting cerebral blood flow or the cerebrovascular vasodilation elicited by hypercapnia, as determined by laser-Doppler flowmetry (n = 4). We conclude that aminoguanidine selectively inhibits iNOS activity in the area of infarction and reduces the volume of the infarct produced by middle cerebral artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. 753 Sep 27

To quantify peroxynitrite production during shock, we measured oxidation of dihydrorhodamine 123 in rats. In endotoxic and hemorrhagic shock and splanchic ischemia-reperfusion, dihydrorhodamine oxidation rapidly increased, which was prevented by inhibition of endothelial nitric oxide (.NO) synthase (ecNOS). Thus, peroxynitrite is already formed at early stages of shock from ecNOS-derived .NO. Overproduction of .NO by the inducible NOS at late shock was not associated with additional increases in dihydrorhodamine oxidation. ecNOS inhibition enhanced dihydrorhodamine oxidation in control rats. These latter findings may be explained by .NO-mediated inhibition of peroxynitrite-induced dihydrorhodamine oxidation, a phenomenon also observed in vitro.
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PMID:Peroxynitrite-mediated oxidation of dihydrorhodamine 123 occurs in early stages of endotoxic and hemorrhagic shock and ischemia-reperfusion injury. 755 74

Nitric oxide (NO.) plays a central role in the physiology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 758 76

Elevation of the ocular pressure in the anterior chamber of the rat eye caused major ischemic damage, manifested as changes in retinal morphology. The two most affected structures were the inner plexiform layer, which decreased in thickness by 90%, and the number of ganglion cells, which decreased by 80%. Pretreatment of the animals with N omega-nitro-L-arginine, a nitric oxide (NOS) inhibitor, almost completely abolished the ischemic damage. Administration of aminoguanidine, a NOS inhibitor selective for the inducible enzyme, partially abolished the ischemic damage. Moreover, administration of the NOS inhibitors 1 h after ischemia, also protected the retina from damage, suggesting that similarly acting drugs could be used clinically to limit ischemic injury in humans. We conclude that NOS, and therefore NO, may be involved in the mechanism of ischemic injury to the retina.
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PMID:Nitric oxide synthase inhibitors protect rat retina against ischemic injury. 758 79

Nitric oxide (NO.) plays a central role in the Physioliology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 770 93

Ischemia-reperfusion injury as a general rule is accompanied by dramatic changes in basal and reactive vascular function in most organs. There are similarities in altered organ vascular function, particularly in the first 24 to 48 hours, with decreased basal organ blood flow, hypersensitivity to vasoconstrictor stimuli, attenuated responses to vasodilators, and increased vascular permeability. The reduced responsiveness to endothelium-dependent vasodilators may be due to reduced endothelial NOS activity or to spontaneous maximal activation of NOS/NO activity, which cannot be stimulated further by endothelium-dependent agents. There are also notable quantitative and qualitative differences in ischemia-reperfusion injury vasoreactive response in organs such as kidney, heart, and brain, the basis of which is unexplored, but may reflect regional differences in endothelium and/or organ parenchyma. Further examination of both the mechanisms and consequences of ischemia-reperfusion injury to the vasculature, as well as the clinical implications, should be a rewarding pursuit in organ pathophysiology.
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PMID:Abnormal vascular function following ischemia-reperfusion injury. 852 54

We performed experiments to investigate the participation of nitric oxide (NO) in the delayed neuronal death (DND) of gerbil hippocampal CA1 neurons, following 5-min forebrain ischemia with pretreatment of stereotaxic intraventricular administration of several types of NO synthase inhibitors and biologically inactive control drugs. The number of surviving neurons in the control drug groups administered NG-monomethyl-D-arginine or NG-nitro-D-arginine methyl ester was comparable to that in the group administered artificial cerebro-spinal fluid, while the groups administered NOS inhibitors, such as NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester, showed significant preservation of the neuronal densities compared with the control drug groups, to over 60% of the sham operation group value. Furthermore, intraventricular administration of N omega-nitro-L-arginine at various concentrations disclosed a dose-dependent protection against the DND. These results suggest that the generation of NO may act to promote the establishment of DND.
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PMID:Intraventricular administration of nitric oxide synthase inhibitors prevents delayed neuronal death in gerbil hippocampal CA1 neurons. 858 29

Reactive oxygen species such as nitric oxide (NO) and/or superoxide have been proposed as mediators in the pathogenesis of reperfusion injury and acute endotoxemia. The purpose of this study was to examine the role of NO in a model of hepatic ischemia-reperfusion with endotoxemia (I/R + LPS). Rats subjected to 30 min of partial hepatic ischemia followed by reperfusion and LPS (Salmonella enteritidis, 1 mg/kg, i.v.,) administration, exhibited a marked, time-dependent increase in plasma alanine aminotransferase (ALT) levels compared to sham controls. An abrupt increase in liver nitrite/nitrate levels was also observed in I/R + LPS rats in association with the increases in plasma ALT. Although liver NO production in I/R + LPS rats increased with time, exacerbation of liver damage was not evident. Administration of L-NAME decreased NO production in plasma and liver but did not affect the liver damage in rats subjected to I/R + LPS. Superoxide levels in livers from I/R + LPS rats increased by threefold after 90 min reperfusion as compared to sham controls but dropped to control levels after 4 hr. There was a significant increase in neutrophils in liver lobes subjected to ischemia-reperfusion and LPS compared to sham controls and to non-ischemic lobes which received LPS. The number of neutrophils in the liver increased further in rats given L-NAME. These results suggest that the progressive injury seen in livers of I/R + LPS rats was possibly due to NO interaction with superoxide forming another reactive oxygen species such as peroxynitrite. However, inhibition of NO synthesis did not ameliorate liver damage, possibly because of an increase in tissue accumulation of activated polymorphonuclear leukocytes (PMN). Lung NO production increased in I/R + LPS rats after 4 hr reperfusion compared to sham controls. Prior administration of L-NAME did not prevent a significant rise in pulmonary NO generation (P < 0.05 at 90 min and 4 hr, compared to sham controls). This unexpected rise of pulmonary NO in the L-NAME treated group of rats was associated with a tendency for increased PMN accumulation (based on myeloperoxidase data) and superoxide generation. The results suggest that endogenous NO protected against excessive neutrophil infiltration in the lung in this model of hepatic ischemia-reperfusion and endotoxemia, and the use of L-NAME, a nonselective NOS inhibitor, may aggravate lung injury.
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PMID:Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia. 884 95


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