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 expression pattern of endothelial and inducible forms of nitric oxide synthase (e-NOS, i-NOS) in rat neurohypophysis after transient ischemia was investigated using post-embedding immunogold method. We demonstrate that ischemia induced an early (10 min) expression of e-NOS not only in endothelium but also in the mast cells. Expression of i-NOS was almost exclusively confined to glial cells (pituicytes) and perivascular macrophages of experimental animals, and peaked at 24 h after ischemia. This evidence indicates that NO plays a significant role in mechanisms of cerebral ischemia. Taking into account the known beneficial role of e-NOS in ischemia it is likely that mast cells protect against post-ischemic brain damage by producing vasodilatation via nitric oxide. In contrast, cerebral macrophages and pituicytes may mediate neuronal and endothelial damage in late period after ischemia in rat neurohypophysis.
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PMID:Immunocytochemical localization of endothelial nitric oxide synthase (e-NOS) and inducible nitric oxide synthase (i-NOS) in rat neurohypophysis after transient cerebral ischemia. 1033 59

With the use of immunohistochemical technique, nerve biopsy is more informative for the diagnosis of inflammatory neuropathies. In chronic inflammatory demyelinating neuropathy, an increased number of T cells are frequently present in endoneurium, which is in contrast to hereditary neuropathies. In active demyelinating lesions, macrophages adhering nerve fibers showed stainings with TNF-alpha. NOS and cyclooxygenase-2 (COX-2). These molecules may act in concert to promote nerve damage. The inhibitor of COX-2, nimesulide, was effective on experimental allergic neuritis, even if given after the onset of clinical signs. A COX-2 inhibitor may have potential as an additional therapeutic agent in human inflammatory neuropathies. In vasculitic neuropathies, cell-mediated cytotoxicity may be involved in the pathogenesis of small vessel injury. Axonal injury may be caused by focal ischemia. However, an immune attack might be involved in nerve damage, since T cells and IL-12 positive cells were found in endoneurium of some patients with active vasculitis.
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PMID:[Immunopathology of inflammatory neuropathies]. 1037 18

Recent studies implicate iNOS as the mediator of the late phase of ischemic preconditioning (PC). However, it is unknown whether induction of iNOS activity is mediated by transcriptional, post-transcriptional, translational, or post-translational mechanisms. To address this issue, we isolated and sequenced a partial iNOS cDNA expressed in preconditioned rabbit myocardium. Using a rabbit-specific probe generated from this sequence, we measured the steady state levels of the iNOS transcript after ischemic PC [six cycles of 4-min occlusion/4-min reperfusion (O/R)]. Three hours after ischemic PC, the iNOS mRNA levels in the ischemic/reperfused region were increased approximately three-fold relative to samples from the non-ischemic region and from control rabbits. This increase in mRNA levels was completely abolished by pretreatment with the NOS inhibitor Nomega -nitro- L-arginine. Conversely, administration of the NO donor nitroglycerin induced an increase in iNOS mRNA levels similar to that induced by ischemic PC. We conclude that in the conscious rabbit, ischemic PC induces an increase in iNOS mRNA levels, and that this induction is triggered by increased generation of NO during the PC stimulus. These results provide direct evidence that upregulation of iNOS is a natural response of the heart to a brief ischemic stress and that NO itself, in the absence of ischemia, upregulates myocardial iNOS transcript levels, a finding that may have implications for nitrate therapy. This previously unrecognized NO-dependent upregulation of iNOS mRNA is likely to play an important role in the development of late PC as well as in many other pathophysiological conditions in which NO is implicated.
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PMID:Ischemic preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism. 1042 45

In guinea-pig myocardial mitochondria preparation, lowering the Ca2+ concentration or pH level in the perfusate rapidly elevated the fura-2 Ca2+ signal ([Ca2+]m). Pretreatment with 10(-4) M L-Arg inhibited the rapid [Ca2+]m influx, whereas administration of 10(-4) M L-NAME did not, suggesting some association between nitric oxide (NO*) synthase (NOS) activation and Ca2+ kinetics in mitochondria. Immunoblotting analysis showed that endothelial (e)-NOS was present in mitochondria, but not inducible (i)-NOS or brain (b)-NOS. Electron microscopy observations revealed that the e-NOS antibody-reactive site in the mitochondria was the inner cristae. The production of reactive oxygen species and NO* in isolated mitochondria was detected by the spin trapping technique with electron paramagnetic resonance (EPR) spectrometry. Pretreatment with 10(-5) M S-nitroso-N-acetyl-DL-penicillamine (SNAP) and 10(-5) M 3-[2-Hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propananin e (NOC 5), which spontaneously generate NO*, completely inhibited the [Ca2+]m uptake. In addition, N-morpholino sydnonimine hydrochloride (SIN-1) (10(-5) M), which simultaneously generates NO* as well as *O2- and peroxynitrite anion (ONOO-), inhibited the increase in [Ca2+]m. ONOO- (3 x 10(-4) M) itself also inhibited this increase. Pretreatment with the *O2(-)-scavenger manganese superoxide dismutase or catalase (200 units/ml) completely inhibited the increase in [Ca2+]m caused by lowering of either the Ca2+ concentration or the pH in the perfusate. These results suggested that the formation of reactive oxygen species promoted the [Ca2+]m influx. The agents that inhibited the [Ca2+]m influx improved contractility even in Langendorff preparations after ischemia. Based on these findings, we concluded that e-NOS exists in mitochondria and that NO* may play an important protective role in reperfusion cardiac injury after ischemia, by inhibiting the Ca2+ influx into mitochondria which are otherwise damaged by *O2-.
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PMID:Protective role of nitric oxide synthase against ischemia-reperfusion injury in guinea pig myocardial mitochondria. 1051 58

Nitric oxide (NO) plays an important role in the pathogenesis of neuronal injury during cerebral ischemia. The endothelial and neuronal isoforms of nitric oxide synthase (eNOS, nNOS) generate NO, but NO generation from these two isoforms can have opposing roles in the process of ischemic injury. While increased NO production from nNOS in neurons can cause neuronal injury, endothelial NO production from eNOS can decrease ischemic injury by inducing vasodilation. However, the relative magnitude and time course of NO generation from each isoform during cerebral ischemia has not been previously determined. Therefore, electron paramagnetic resonance spectroscopy was applied to directly detect NO in the brain of mice in the basal state and following global cerebral ischemia induced by cardiac arrest. The relative amount of NO derived from eNOS and nNOS was accessed using transgenic eNOS(-/-) or nNOS(-/-) mice and matched wild-type control mice. NO was trapped using Fe(II)-diethyldithiocarbamate. In wild-type mice, only small NO signals were seen prior to ischemia, but after 10 to 20 min of ischemia the signals increased more than 4-fold. This NO generation was inhibited more than 70% by NOS inhibition. In either nNOS(-/-) or eNOS(-/-) mice before ischemia, NO generation was decreased about 50% compared to that in wild-type mice. Following the onset of ischemia a rapid increase in NO occurred in nNOS(-/-) mice peaking after only 10 min. The production of NO in the eNOS(-/-) mice paralleled that in the wild type with a progressive increase over 20 min, suggesting progressive accumulation of NO from nNOS following the onset of ischemia. NOS activity measurements demonstrated that eNOS(-/-) and nNOS(-/-) brains had 90% and < 10%, respectively, of the activity measured in wild type. Thus, while eNOS contributes only a fraction of total brain NOS activity, during the early minutes of cerebral ischemia prominent NO generation from this isoform occurs, confirming its importance in modulating the process of ischemic injury.
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PMID:Role of neuronal and endothelial nitric oxide synthase in nitric oxide generation in the brain following cerebral ischemia. 1052 26

The purpose of this study was to determine whether nitric oxide (NO) is present in clinically normal horses under basal conditions and if it increases secondary to naturally acquired small intestinal strangulation obstruction. Thirty-one horses were used; 20 horses with naturally acquired small intestinal strangulation obstruction and 11 clinically normal horses with no signs of gastrointestinal tract disease. Jugular venous blood, abdominal fluid, and urine were collected for NO quantification. Plasma, abdominal fluid, and urine were stored at -70 degrees C until analyzed for NO using a chemiluminescent method. Biopsy specimens collected from the affected jejunal segment, during anesthesia or after immediately after euthanasia, or from the midjejunum of control horses, were divided into subsections for fixation in zinc formalin and cryopreservation in OCT gel. Nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) diaphorase histochemical stains were performed on cryopreserved tissues and inducible nitric oxide synthase (iNOS) and nitrotyrosine immunohistochemical stains were performed on formalin-fixed, paraffin-embedded tissues. There were significantly greater plasma and abdominal fluid NO concentrations in affected horses as compared with controls, but there were no significant differences between horses for urine NO concentrations. There was a significant decrease in NADPH diaphorase stain in mucosal epithelium, vasculature, and leukocytes, and in submucosal plexi in affected horses compared with control horses. There was a significant increase in iNOS staining in mucosal and submucosal leukocytes and in mucosal leukocyte nitrotyrosine staining of the affected compared with control horses. Endothelial NOS and neuronal NOS are present under basal conditions in the jejunum of horses and probably mediate physiologic or cytoprotective effects. Plasma and abdominal fluid, but not urine, NO concentrations increase subsequent to small intestinal strangulation obstruction; this may be associated with increased mucosal and submucosal iNOS staining in leukocytes, which was likely due to increased expression subsequent to stimuli associated with ischemia. The increased nitrotyrosine staining in mucosal leukocytes of affected horses likely reflects the presence of peroxynitrite subsequent to increased NO and superoxide production and may reflect a cytotoxic role of NO in small intestinal strangulation obstruction in horses.
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PMID:Detection and comparison of nitric oxide in clinically normal horses and those with naturally acquired small intestinal strangulation obstruction. 1053 1

Several experimental studies have revealed that the administration of L-arginine can reduce ischemia/reperfusion injury to skeletal muscle, kidney, liver, heart and brain. Moreover, the administration of L-arginine can cause protective hemodynamic alterations. However, in situations with a stimulated inducible NOS, the administration of large amounts of L-arginine may be hazardous for the patients.
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PMID:The impact of L-arginine-nitric oxide metabolism on ischemia/reperfusion injury. 1056 37

KATP channels play an important role in physiology and pathophysiology of many tissues. As in the pancreatic beta cells, they couple the change of blood glucose with insulin release. The data coming from Baukrowitz et al. and Shyng and Nichols gave the possible answers to the two old enigmas of KATP channels, i.e., different ATP sensitivity reported in the same tissue and how the channel opened under intracellular millimolar ATP concentration, in which they showed the lipids and lipid metabolites are essential for KATP channel regulation by altering ATP sensitivity. This new information rises several further considerations. How does PIP2 reduce the sensitivity of the channel to ATP? In order to clarify the possibility of direct competing or allosteric effect on the ATP binding site, competitive binding assay should be performed. Since the PIP2 theory seems to be the key event to determine the ATP sensitivity and thus control the channel open probability, then what is the resting concentration of PIP2 in the cell membrane? Is it sufficient to account for the difference in the ATP sensitivity of the intact cell and excised patch from different tissues? Quantitative studies either immunoblotting by PIP2 antibody or fluorescence-labeled lipid assay-may obtain some basic but useful data for further studies to answer these questions. Furthermore, the ATPi mediated restoration of activity was inhibited by antibodies against PIP2. The dualistic behavior of KATP channels to intracellular NDPs should be reexamined with respect to PIP2. The vast majority of preconditioning studies has been performed in intact animals in which myocardial infarct size was used as the end point to define the cardio-protective effect of ischemic PC. These results suggest a key role for the KATP channel as both a trigger and as an end effector of both acute and delayed ischemic PC. The persistent activation of KATP channels during the early reperfusion phase is essential for a smooth and full recovery of contractile function, as well as for maintenance of electrical stability in heart that has been exposed to ischemia. Though activate adenosine A1 receptor coupled with Gi protein can open the KATP channels, adenosine is quickly released during ischemia and exerts potent coronary vasodilatation to maintain coronary blood flow through A2 receptors. This adenosine-induced coronary vasodilatation could be coupled with KATP channels based on the evidence of the augmentation effect of KCOs. Nitric oxide may also play some role in both first and second window of myocardial protection. It is possible that rapid and reversible phosphorylation and activation of constitutive expressed myocardial NOS or by direct KATP channel phosphorylation and activation leads to the first window of myocardial protection. This hypothesis can be further investigated either by using site direct mutagenesis of iNOS or KATP channel, or by applying the dominant negative iNOS in the cell ischemic model, or by building the adenosine or iNOS knock-out mice to study the relationship of these possible mechanisms. Recently, Kontos further showed that KCOs need L-lysine or L-arginine to dilate cerebral arterioles. This suggests that there may be an amino acid binding site inside the KATP channel and nitric oxide can open the KATP channel either by direct acting on the channel protein or by modulating the affinity of the amino acid binding site for L-lysine or L-arginine. Other KATP channel openers in need of additional characterization are the Type III KCOs (nicorandiol). They open the KATP channel only in the presence of elevated intracellular NDPs, which may make them specifically target to the ischemic region, because the intracellular NDP increases mostly in ischemic region. It is possible that type III KCOs can selectively improve blood flow to ischemic areas without diverting blood away to non-ischemic region, and prevents the "steal phenomenon". (ABSTRACT TRUNCATED)
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PMID:ATP sensitive potassium channel and myocardial preconditioning. 1060 45

Hyperbaric oxygen (HBO) is being studied as a therapeutic intervention for ischemia/reperfusion (I/R) injury. We have developed an in vitro endothelial cell model of I/R injury to study the impact of HBO on the expression of intercellular adhesion molecule-1 (ICAM-1) and polymorphonuclear leukocyte (PMN) adhesion. Human umbilical vein endothelial cell (HUVEC) and bovine aortic endothelial cell (BAEC) induction of ICAM-1 required simultaneous exposure to both hypoxia and hypoglycemia as determined by confocal laser scanning microscopy, ELISA, and Western blot. HBO treatment reduced the expression of ICAM-1 to control levels. Adhesion of PMNs to BAECs was increased following hypoxia/hypoglycemia exposure (3. 4-fold, P < 0.01) and was reduced to control levels with exposure to HBO (P = 0.67). Exposure of HUVECs and BAECs to HBO induced the synthesis of endothelial cell nitric oxide synthase (eNOS). The NOS inhibitor nitro-L-arginine methyl ester attenuated HBO-mediated inhibition of ICAM-1 expression. Our findings suggest that the beneficial effects of HBO in treating I/R injury may be mediated in part by inhibition of ICAM-1 expression through the induction of eNOS.
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PMID:Hyperbaric oxygen downregulates ICAM-1 expression induced by hypoxia and hypoglycemia: the role of NOS. 1066 24

The endothelium plays a critical role in maintaining vascular tone by releasing vasoconstrictor and vasodilator substances. Endothelium-derived nitric oxide (NO) is a vasodilator rapidly inactivated by superoxide and by Fe(II) and Fe(III), all found in significant quantities in biological systems. Thus due to the short life of NO in tissue (t1/2 = 3-6 s), in situ quantification of NO is a challenging problem. We designed the present study to perform direct measurements of nitric oxide using the electrochemical porphyrinic sensor. The most significant advantages of this sensor is small size (0.5-8 microm), rapid response time (0.1-1 ms), and low detection limit (10(-9) mol l(-1)). The porphyrinic sensor was used for in vitro and in vivo measurements of NO in an isolated single cell or tissue. Effects of hypertension, endotoxemia, and ischemia/reperfusion on the release of NO and/or its interaction with superoxide (O2-) were delineated. In the single endothelial cell (rabbit endocardium), NO concentration was highest at the cell membrane (950 +/- 50 nmol l(-1)), decreasing exponentially with distance from cell, and becoming undetectable at distances beyond 50 microm. The endothelium of spontaneously hypertensive rats (SHR) released 35% less NO (580 +/- 30 nmol l(-1)) than that of normotensive rats (920 +/- 50 nmol l(-1)), due to the higher production of O2- in SHR rats. Endothelial NO synthase (eNOS) generated NO (140 +/- 20 nmol l(-1)) in lung during the acute phase (first 10-15 min) of endotoxemia, followed by production of NO by inducible NOS. High production of O2- was observed during the entire period of endotoxemia. Ischemia (lower limb of rabbit) caused a significant increase of NO peaking at 15 min and decreasing thereafter, also due to O2- production.
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PMID:Direct electrochemical measurement of nitric oxide in vascular endothelium. 1069 75


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