Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HBO treatment affects many of the components involved in I/R injury, including PMNL function, endothelial CAM expression, NO production, NOS expression, cellular energetics, lipid peroxidation, and microvascular blood flow. Given the variety of models used to study the individual components involved in I/R injury, it is difficult to determine which is the predominant factor affected by HBO and which generates the observed beneficial outcomes in most systems. Experimental differences in the types of I/R injury, the timing of HBO treatment relative to the I/R injury (before, during, after, or delayed), the duration of HBO treatment pressure and duration, and the time of outcome measurements confound our ability to compare studies and determine the key beneficial factor. Upon review, it is likely that the sum of many of these effects is responsible for the final outcome. We have been presented with many of the pieces of the puzzle with respect to the beneficial effect of HBO in ischemia-reperfusion injury states. Hopefully, future studies will unite them into a clear picture of the basic mechanism(s) responsible for the benefits of hyperbaric oxygen therapy.
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PMID:Basic mechanisms of hyperbaric oxygen in the treatment of ischemia-reperfusion injury. 1072 71

We examined characteristics of spreading depression (SD) induced on the rat cortex 1 day after transient focal ischemia. Male Wistar rats (n=21) were subjected to transient intraluminal thread occlusion of the right middle cerebral artery for 75 min. Twenty-four hours after the reperfusion, cerebral blood flow (CBF) was determined using laser Doppler flowmeter during multiple SDs elicited on both non-stroke (left) and stroke (right) cortex by the topical application of 2 M KCl. We also examined CBF responses before and after the intravenous administration of the nonspecific NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) in normal and stroke cortex. Animals were divided into two groups; Group 1 (n=12), animals with subcortical infarction and Group 2 (n=9), animals with subcortical plus cortical infarction. There were no differences between non-stroke and stroke sides in the duration or amplitude of the DC potential shifts in either group. The transient CBF hyperemia during SD was not different between non-stroke (372+/-23% of baseline, mean+/-S.E.) and stroke sides (383+/-30%) in Group 1. However, in Group 2, CBF was significantly restricted on the stroke side (192+/-15% vs. non-stroke side, 374+/-33%). In four normal animals without ischemia, there were no differences in CBF response between both sides. L-NAME had no effect on the transient CBF hyperemia during SD in any of the groups. These data suggest that the CBF responses during SD in the peri-infarction area is restricted 1 day after the transient focal ischemia, while CBF responses are intact in normal cortex overlapping a subcortical infarct. Further, our results indicate that nitric oxide does not promote CBF responses during SD in normal cortex or in tissue surrounding infarction.
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PMID:Characteristics of induced spreading depression after transient focal ischemia in the rat. 1076 Apr 93

Nitric oxide synthesis by inducible nitric oxide synthase (iNOS) has been postulated to contribute to ischemia-reperfusion neurotoxicity. The expression of this enzyme has been demonstrated in cells present in the postischemic brain. The mechanisms of iNOS expression after cerebral ischemia are a subject of current research. We therefore decided to investigate whether glutamate, which is released in ischemia and is implicated in neurotoxicity, might be involved in the mechanisms by which oxygen and glucose deprivation (OGD) leads to the expression of iNOS in rat forebrain slices. In this model, we have shown previously that 20 min of OGD causes the expression of iNOS. We have now found that the NMDA receptor antagonist MK-801 blocks the expression of iNOS, suggesting that the activation of the NMDA subtype of glutamate receptor is implicated in the mechanisms that lead to the expression of this isoform. Moreover, we have found that glutamate alone could trigger the induction process, as shown by the appearance of a Ca(2+)-independent NOS activity and by the detection of iNOS mRNA and protein in slices exposed to glutamate. Glutamate-dependent iNOS expression was concentration-dependent and was blocked by EGTA and by the inhibitors of nuclear factor kappaB (NF-kappaB) activation pyrrolidine dithiocarbamate and MG132. In addition, glutamate induced NF-kappaB translocation to the nucleus, an effect that was inhibited by MG132. Taken together, our data suggest that activation of NMDA receptors by glutamate released in ischemia is involved in the expression of iNOS in rat forebrain slices via a Ca(2+)-dependent activation of the transcription factor NF-kappaB. To our knowledge, this is the first report showing an implication of excitatory amino acids in the expression of iNOS caused by ischemia.
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PMID:Implication of glutamate in the expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices. 1080 Sep 47

The principal aim of this study was to examine the relative contributions from the neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively) in their capacity to modulate intra-ischemic cerebral blood flow (CBF) changes, in the ischemically vulnerable hippocampus and striatum. CBF changes were monitored, using laser-Doppler flowmetry, in rats subjected to 30 min of forebrain ischemia (right common carotid occlusion+hemorrhagic hypotension). Rats were pretreated with a selective nNOS inhibitor (ARR 17477), a NOS inhibitor that blocks both eNOS and nNOS (N(G)-nitro-L-arginine; L-NNA), or saline (control). In initial experiments, where ischemic MABP was targeted to exactly 30 mmHg, NOS inhibition reduced intra-ischemic cortical CBF from the control level of approximately 20% of baseline to 3% (L-NNA) or 6% (ARR 17477) of baseline. The statistically similar effects of the two NOS inhibitors confirmed that nNOS is the predominant NO source supporting intra-ischemic vasodilation in the cortex. In subsequent experiments, CBF was measured in the right hippocampus, and striatum, as well as the cortex, and, to reduce data variability, blood withdrawal was adjusted to achieve an intra-ischemic cortical CBF of 20% (controls) or 5% (NOS inhibited rats) of baseline. In those groups, mean ischemic MABP levels ranged from 28 to 32 mmHg. In controls, intra-ischemic CBF fell to 20%, 45%, and 47% of baseline in the cortex, hippocampus, and striatum, respectively. With nNOS inhibition, intra-ischemic CBF was further reduced to 5%, 15%, and 18% of baseline, respectively. However, with combined eNOS/nNOS inhibition, the CBF values were 5%, 37%, and 21%, respectively. These results suggest that the nNOS contribution to intra-ischemic vasodilation in vulnerable regions is substantially greater than eNOS. The significantly higher intra-ischemic CBF level in the hippocampus in combined eNOS/nNOS vs nNOS-inhibited rats may relate, in contrast to other regions, to a low eNOS influence on vascular function in that structure and CBF redistribution to the hippocampus when eNOS activity is blocked globally.
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PMID:Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats. 1084 75

Recently, we established a novel temporal correlation mapping (TCM) technique in combination with high-resolution functional computed tomography (CT) scanning to analyze the temporal changes in bolus transit dynamics of iodinated contrast agents in focal cerebral ischemia. Based on changes in the temporal dynamics of blood flow, we defined a new kind of penumbra and core in focal ischemia: the hemodynamic penumbra and hemodynamic core. We visualized for the first time a larger hemodynamic core and smaller hemodynamic penumbra in endothelial NOS knockout mice than in wild type mice early after focal ischemia by using the TCM analysis technique. In addition, neuroprotective effects of the water-soluble AMPA receptor antagonist YM872 were for the first time observed in the hemodynamic penumbra after focal ischemia. In conclusion, early TCM analysis could be used to directly and quantitatively evaluate the effects of neuroprotective therapy and the evolution of neuronal damage in the hemodynamic penumbra.
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PMID:[New method for evaluating the effects of neuroprotective therapy in the hemodynamic penumbra]. 1087 1

1. We examined time- and cell-type-dependent changes in endothelin (ET)-1-like immunoreactivity, ET receptors binding and nitric oxide (NO) synthase (NOS) activity in CA1 subfields of the hippocampus of stroke-prone spontaneously hypertensive rats subjected to a 10-min bilateral carotid occlusion and reperfusion. 2. Microglia aggregated in accord with neuronal death and expressed a high density of ET(B) receptors and an intense NOS activity in the damaged CA1 pyramidal cell layer, 7 days after the induced transient forebrain ischemia. The increased NOS activity and ET(B) receptor in microglia disappeared 28 days after this transient ischemia. 3. In contrast to microglia, astrocytes presented a moderate level of ET-1-like immunoreactivity, ET(B) receptors, and NOS activity in all areas of the damaged CA1 subfields, 7 days after the ischemia. These events were further enhanced 28 days after the ischemia. 4. In light of these findings, the possibility that the microglial and the astrocytic ET(B)/NO system largely contributes to development of the neuronal death and to reconstitution of the damaged neuronal tissue, respectively, in the hippocampus subjected to a transient forebrain ischemia would have to be considered.
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PMID:Involvement of glial endothelin/nitric oxide in delayed neuronal death of rat hippocampus after transient forebrain ischemia. 1093 Jan 31

The objective of this study was to determine what roles the endothelial cell and inducible isoforms of nitric oxide synthase (eNOS, iNOS) play in ischemia and reperfusion (I/R)-induced liver injury in vivo in mice genetically deficient in each isoform of NOS. We found that 45 min of partial (70%) liver ischemia and 5 h of reperfusion induced substantial liver injury as assessed by the release of large and significant amounts of the liver-specific enzyme alanine aminotransferase (ALT) into the serum of wild-type (wt) mice. The enhanced ALT levels were not due to increased recruitment of potentially damaging PMNs, which could mediate hepatocyte injury, as neither histopathological inspection nor quantitative MPO determinations revealed the presence of PMNs in the liver at this time point. In addition, we observed a significant enhancement in liver injury in eNOS-deficient but not iNOS-deficient mice subjected to liver I/R compared to postischemic wt mice. Taken together, these data suggest that eNOS- but not iNOS-derived NO plays an important role in limiting or downregulating I/R-induced liver injury in vivo following 5 h of reperfusion.
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PMID:Nitric oxide synthase and postischemic liver injury. 1102 58

Because long-term pulmonary artery (PA) obstruction is associated with expansion of the systemic blood supply to the lung, chronic ischemia may not occur, and endothelium nitric oxide synthase (eNOS) function may be preserved in postobstructive pulmonary arteries. To test this hypothesis, we studied piglets 2 d or 5 wk after left PA ligation or a sham operation. We measured left lung ATP and lactate lung concentrations; calcium-dependent and calcium-independent NOS activities and eNOS protein; and left PA relaxations in response to acetylcholine, calcium ionophore, and sodium nitroprusside. Decreases in ATP and increases in lactate concentrations were significantly attenuated after 5 wk PA occlusion (p < 0.05 versus sham and 2-d ligation). Compared with sham and 2-d PA occlusion, calcium-dependent NOS activity and eNOS protein were lower in the long-term PA occlusion group. Calcium-independent NOS activity was unchanged. Acetylcholine and calcium ionophore relaxations were impaired after 5 wk, whereas only acetylcholine relaxation was impaired after 2-d PA occlusion. Relaxation to sodium nitroprusside remained unchanged. In conclusion, despite relative conservation of lung energy metabolism, prolonged PA occlusion decreased eNOS function and protein in postobstructive pulmonary arteries.
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PMID:Endothelial nitric oxide synthase function in pig lung after chronic pulmonary artery obstruction. 1102 57

Despite the emergence of therapies for hypoxic-ischemic injury to the mature nervous system, there have been no proven efficacious therapies for the developing nervous system. Recent studies have shown that pharmacological blockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate damage after ischemia in the mature rodent. We have previously shown that elimination of nNOS neurons, either by targeted disruption of the gene or by pharmacological depletion with intraparenchymal quisqualate, can decrease injury after hypoxia-ischemia. Using a simpler pharmacological approach, we studied the efficacy of a systemically administered NOS inhibitor, 7-nitroindazole, a relatively selective inhibitor of nNOS activity. Using multiple doses and concentrations administered after the insult, we found that there was only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cortex, and at 2 h and 18 h in the hippocampus after the hypoxia-ischemia. nNOS expression decreased and remained depressed for at least 18 h after the insult. When nNOS expression was normalized to MAP2 expression, a decrease was seen at 18 h in the cortex and at 2 and 18 h in the hippocampus. These data suggest that further inhibition of NOS activity at early timepoints may not provide substantial benefit. At 5 days after the insult, however, NOS activity and normalized nNOS expression returned to baseline or higher in the hippocampus, the region showing the most damage. These data suggest that delayed administration of nNOS inhibitor after hypoxic-ischemic injury might be beneficial.
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PMID:Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain. 1104 40

In conscious rabbits, a sequence of six 4-min coronary occlusion/4-min reperfusion cycles, which elicits late preconditioning (PC), caused rapid activation of calcium-dependent nitric oxide (NO) synthase (NOS) [cNOS; endothelial NOS (eNOS) and/or neuronal NOS (nNOS)], whereas calcium-independent NOS [inducible NOS (iNOS)] activity remained unchanged. The enhanced cNOS activity was associated with increased myocardial levels of NO(2) and/or NO(3) (NO(x)). Twenty-four hours after ischemic PC was induced, the opposite pattern was observed, i.e., there was a pronounced increase in cytosolic iNOS activity but no change in cNOS activity. The initial burst of ischemia-induced cNOS activity was not affected by pretreatment with the antioxidant N-2-mercaptopropionyl glycine (MPG), the protein kinase C (PKC) inhibitor chelerythrine, or the tyrosine kinase inhibitor lavendustin A, indicating that it is independent of the generation of oxidant species and the activation of PKC and tyrosine kinases. In contrast, the delayed upregulation of iNOS 24 h after PC was prevented by pretreatment with N(omega)-nitro-L-arginine, MPG, or chelerythrine before the PC ischemia, indicating that it is triggered by a signaling mechanism that involves the generation of NO, the formation of oxidant species, and the activation of PKC. Taken together, these results demonstrate that, in conscious animals, ischemic PC elicits a biphasic response in cardiac NOS activity, i. e., an immediate activation of cNOS (most likely eNOS) followed 24 h later by a delayed upregulation of iNOS. To our knowledge, this is the first study to directly measure NOS activity after brief myocardial ischemia in vivo. In conjunction with previous functional studies, the data support a distinctive role of NOS isoforms in late PC, with eNOS serving as the trigger on day 1 and iNOS as the mediator on day 2.
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PMID:Biphasic response of cardiac NO synthase isoforms to ischemic preconditioning in conscious rabbits. 1104 73


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