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

We determined the functional role of nitric oxide (NO) and endothelins (ET), two potent vasoactive mediator systems in the liver, for the pathogenesis of sinusoidal perfusion failure and lethal hepatocyte injury after low-flow ischemia/reperfusion in the isolated perfused rat liver. NO synthase blockade with Nomega-nitro-L-arginine methyl ester (L-NAME) (10[-3] mol/L) before reperfusion prevented increased N02-/NO3- the final products of NO oxidation, which could be observed in the vehicle group. Epifluorescence microscopy revealed that the decrease in functional sinusoid density during reperfusion was much more profound compared with vehicle. This was associated with a lower surface PO2, a substantially higher number of nonviable hepatocytes, as assessed by in situ propidium iodide staining, and enhanced enzyme release into the perfusate compared with vehicle. In contrast, reperfusion in the presence of the endothelinA+B receptor antagonist bosentan (2 x 10(-4) mol/L) restored functional sinusoid density and surface PO2 to baseline values, resulted in a small reduction in the number of propidium iodide-positive hepatocytes, and caused similar increases in enzyme release as compared with vehicle. This indicates that hepatic generation of NO attenuates sinusoidal perfusion failure and improves liver tissue oxygenation, thus limiting hepatocyte injury during early reperfusion after hepatic low-flow ischemia. In contrast, endothelins counteract the microcirculatory effects of NO, i.e., mediate the no-reflow in hepatic sinusoids; however, the restoration of functional sinusoid density with bosentan resulted only in a small reduction in tissue damage, suggesting that additional components, which are independent of microcirculatory failure, contribute to hepatic reperfusion injury under these conditions.
 ...
PMID:Role of endothelins and nitric oxide in hepatic reperfusion injury in the rat. 950 Jul 4

Nitric oxide (NO) generation in the rat gastric mucosa during ischemia-reperfusion was measured using an NO-sensitive electrode. Under pentobarbital sodium anesthesia, an electrode was inserted into the submucosa from the serous membrane side in the fundus. After steady-state baseline recording, the celiac artery was clamped for 30 min, and then ischemia-reperfusion was achieved by removing the clamp. The clamping of the celiac artery caused a decrease in blood flow and an increase in NO level in the gastric tissue. Just after the removal of the clamp, the NO level rapidly fell and returned to the baseline level. Administration of NG-nitro-L-arginine methyl ester (an NO synthase inhibitor, 30 mg/kg i.p.) before ischemia significantly attenuated both the increase in NO level during ischemia and the formation of acute gastric mucosal lesions observed after 60 min reperfusion. Administration of superoxide dismutase (a superoxide radical scavenger, 10,000 U/kg i.v.) at the end of ischemia inhibited both the rapid decrease in NO level during the reperfusion and the gastric mucosal erosions. Because NO and superoxide radical produce a highly reactive peroxynitrite, it can be argued that NO has an important pathological role in acute gastric mucosal injury induced by ischemia-reperfusion. Our conclusion was strongly supported by immunohistochemical staining of nitrotyrosine residues, an indication of peroxynitrite formation.
 ...
PMID:Direct measurement of nitric oxide release in gastric mucosa during ischemia-reperfusion in rats. 953 Jan 46

We have previously reported that induction of nuclear factor-kappa B (NF-kappa B) occurs in a biphasic manner in postischemic myocardium. Because interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric-oxide synthase (iNOS) contain kappa B-response elements, and since transforming growth factor-beta 1 (TGF-beta 1) down-modulates both cytokine and iNOS expression, we studied their temporal expression during myocardial ischemia/reperfusion (I/R). Northern and Western analyses showed low levels of IL-6 and no signal for IL-1 beta, TNF-alpha and iNOS under basal conditions. Their expression rose significantly over sham-operated controls by 1 h reperfusion, and persisted high for various periods. Under basal conditions, low levels of TGF-beta 1 were detected, which rose significantly at 3 h reperfusion, and remained high until 24 h reperfusion. Administration of diethyldithiocarbamate (DDC) inhibited induction of NF-kappa B and concomitantly the expression of IL-1 beta, IL-6, TNF-alpha as well as iNOS. However, expression of TGF-beta was not altered. Our results indicate that ischemia/reperfusion induces NF-kappa B, and upregulates kappa B-response genes. Administration of DDC inhibits NF-kappa B levels, and attenuates expression of inflammatory cytokines and iNOS.
 ...
PMID:Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and inducible nitric-oxide synthase expression in postischemic myocardium. 954 47

Both endothelin and nitric oxide (NO) have been proposed to act as pathophysiological factors in ischemia-related neural damage. This review is concerned with the participation of the glial endothelin-NO system in ischemia-related neuronal cell death. In the rat brain with cerebral apoplexy, endothelin, endothelin receptors and NO synthase (NOS) were rich in the glial cells of damaged brain areas. The brain subjected to transient forebrain ischemia contained astrocytic endothelins and microglial expressions of the ETB-receptor and NOS aggregating in the damaged CA1 subfield of the hippocampus at 7 days after the ischemia. Astrocytic endothelin, ETB-receptor and NOS became more apparent at 28 days after the ischemia, corresponding to a time when neural tissue-repair/remodeling after damage occurs, whereas no activities of the endothelin-NO system are observed in microglia. In the in vitro experiment, endothelin was found to modulate the release of NO from the hippocampal slices subjected to transient forebrain ischemia. There may be a cross-talk between the endothelin system and NO in the astrocytes and microglia during the process of ischemia-related neuronal cell death and neural tissue-remodeling.
 ...
PMID:[The glial endothelin-nitric oxide system in ischemia-related neuronal cell death]. 955 70

We have already reported that the concentration of nitric oxide (NO) increases during and after cerebral ischemia and a selective inhibitor of neuronal NO synthase (nNOS) suppresses this increase and subsequently mitigates brain damage in rats. Although the selective inhibition of nNOS is a promising pharmacological strategy for the treatment of stroke, the role of inducible NOS (iNOS) remains to be clarified. Toward this end, we investigated temporal alterations in iNOS mRNA by the RT-PCR method in a rat model of middle cerebral artery (MCA) occlusion. We found that iNOS mRNA in the ischemic hemisphere began to increase at 3 hr and reached the maximum level at 24 hr of reperfusion following 3 hr of MCA occlusion. However, quantitative analysis revealed that no significant difference existed between 6 hr or 24 hr reperfusion group and their respective time-matched sham operation group. In addition, neither Western blotting nor immunocytochemical study disclosed an apparent induction of iNOS at any time points examined. Similar results were obtained at 24 hr of permanent MCA occlusion. Taken together, these data indicate that iNOS induction during and after MCA occlusion may be not a critical event for the development of infarction caused by ischemia itself.
 ...
PMID:[Lack of evidence that inducible nitric oxide synthase participates in the development of ischemic brain damage]. 955 72

Long-term potentiation (LTP) has been widely studied as a form of synaptic plasticity that represents a cellular mechanism of learning and memory. Among numerous processes and molecules that may be involved in LTP formation, a great many of them including neurotrophic and transcription factors have been described as those involved in neural death after ischemic insult. Nitric oxide (NO) is a molecule that is known to also exert double-edged effects on LTP formation. Here we will be describing recent advances with respect to the LTP mechanisms in the hippocampal synapses, a critical brain region for learning and memory function. In another context, we described our study elucidating the changes in hippocampal LTP as a functional response to transient cerebral ischemic insult, from the viewpoint of its relevance to NO production. As indices of NO production, nitrite and nitrate levels were determined by in vivo microdialysis. It was demonstrated that hippocampal LTP deficiency after transient cerebral ischemia was preceded by an increase in hippocampal NO production. Direct or indirect inhibition of an inducible NO synthase restored ischemia-induced LTP deficiency. These findings suggest that NO production, in part via inducible NO synthase, is responsible for LTP deficiency after transient cerebral ischemia in the rat hippocampus.
 ...
PMID:[Transient cerebral ischemia and long-term potentiation in the rat hippocampus]. 955 73

1. The functional role of the nitric oxide (NO)/guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway in experimental myocardial ischaemia and reperfusion was studied in rat isolated hearts. 2. Rat isolated hearts were perfused at constant pressure with Krebs-Henseleit buffer for 25 min (baseline), then made ischaemic by reducing coronary flow to 0.2 ml min(-1) for 25 or 40 min, and reperfused at constant pressure for 25 min. Drugs inhibiting or stimulating the NO/cyclic GMP pathway were infused during the ischaemic phase only. Ischaemic contracture, myocardial cyclic GMP and cyclic AMP levels during ischaemia, and recovery of reperfusion mechanical function were monitored. 3. At baseline, heart rate was 287+/-12 beats min(-1), coronary flow was 12.8+/-0.6 ml min(-1), left ventricular developed pressure (LVDevP) was 105+/-4 mmHg and left ventricular end-diastolic pressure 4.6+/-0.2 mmHg in vehicle-treated hearts (control; n=12). Baseline values were similar in all treatment groups (P>0.05). 4. In normoxic perfused hearts, 1 microM N(G)-nitro-L-arginine (L-NOARG) significantly reduced coronary flow from 13.5+/-0.2 to 12.1+/-0.1 ml min(-1) (10%) and LVDevP from 97+/-1 to 92+/-1 mmHg (5%; P<0.05, n=5). 5. Ischaemic contracture was 46+/-2 mmHg, i.e. 44% of LVDevP in control hearts (n=12), unaffected by low concentrations of nitroprusside (1 and 10 microM) but reduced to approximately 30 mmHg (approximately 25%) at higher concentrations (100 or 1000 microM; P<0.05 vs control, n=6). Conversely, the NO synthase inhibitor L-NOARG reduced contracture at 1 microM to 26+/-3 mmHg (23%), but increased it to 63+/-4 mmHg (59%) at 1000 microM (n=6). Dobutamine (10 microM) exacerbated ischaemic contracture (81+/-3 mmHg; n = 7) and the cyclic GMP analogue Sp-8-(4-p-chlorophenylthio)-3',5'-monophosphorothioate (Sp-8-pCPT-cGMPS; 10 microM) blocked this effect (63+/-11 mmHg; P<0.05 vs dobutamine alone, n=5). 6. At the end of reperfusion, LVDevP was 58+/-5 mmHg, i.e. 55% of pre-ischaemic value in control hearts, significantly increased to approximately 80% by high concentrations of nitroprusside (100 or 1000 microM) or L-NOARG at 1 microM, while a high concentration of L-NOARG (1000 microM) reduced LVDevP to approximately 35% (P<0.05 vs control; n=6). 7. Ischaemia increased tissue cyclic GMP levels 1.8 fold in control hearts (P<0.05; n=12); nitroprusside at 1 microM had no sustained effect, but increased cyclic GMP approximately 6 fold at 1000 microM; L-NOARG (1 or 1000 microM) was without effect (n=6). Nitroprusside (1 or 1000 microM) marginally increased cyclic AMP levels whereas NO synthase inhibitors had no effect (n=6). 8. In conclusion, the cardioprotective effect of NO donors, but not of low concentrations of NO synthase inhibitors may be due to their ability to elevate cyclic GMP levels. Because myocardial cyclic GMP levels were not affected by low concentrations of NO synthase inhibitors, their beneficial effect on ischaemic and reperfusion function is probably not accompanied by reduced formation of NO and peroxynitrite in this model.
 ...
PMID:Effect of nitrovasodilators and inhibitors of nitric oxide synthase on ischaemic and reperfusion function of rat isolated hearts. 955

The effects of agents which affect the action of nitric oxide (NO) were studied intracellularly on the ischemia-induced changes in membrane potential of single CA1 pyramidal neurons of the rat hippocampal slice preparations. The N-methyl-D-aspartate (NMDA) receptor antagonists, (+/-)-2-amino-5-phosphonopentanoic acid (AP5, 250 microM) or Co2 (2 mM) restored the membrane potential in more than 80% of the neurons. In about 60% of the neurons, the membrane potential was partially recovered as a result of exposure to the NO synthase inhibitor, NG-nitro-L-arginine (100 microM). The NO scavengers, carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO, 300 microM) and hemoglobin (10 microM) restored the membrane potential in all neurons examined. Superoxide dismutase (50 U/ml) protected about 75% of the neurons from irreversible membrane dysfunction. It is concluded that the release of NO induced by experimental ischemia may result in the irreversible membrane dysfunction, and that a NO scavenger, carboxy-PTIO, prevents the ischemic changes in membrane potential. With respect to ischemic brain damage, the neuroprotection provided by carboxy-PTIO may have clinical relevance in the management of a variety of neurological conditions.
 ...
PMID:Nitric oxide contributes to irreversible membrane dysfunction caused by experimental ischemia in rat hippocampal CA1 neurons. 957 75

Neutrophil activation and oxygen-derived free radical formation have been implicated in cardiac ischemia-reperfusion injury. To elucidate the mechanism of ischemia-reperfusion injury, we thus determined the effect of the nitric oxide (NO) precursor L-arginine on the free radical injury of cultured cardiomyocytes which were obtained from patients undergoing corrective surgery for tetralogy of Fallot. Free radicals were generated from hypoxanthine via xanthine oxidase, and the cellular changes were determined microscopically. All concentrations of L-arginine (0.5 to 3 mM) prolonged the myocyte survival time compared to the control group, with 0.5 mM L-arginine increasing the survival time to the greatest extent. Cellular susceptibility to free radical injury was the lowest with 0.5 mM L-arginine. Further experiments were performed with 0.5 mM L-arginine plus 100 mM or 1000 mM of the NO synthase (NOS) inhibitor NG-nitro-L-arginine methylester (L-NAME) to determine whether or not the effects of L-arginine are mediated through the NO pathway. The survival time for the cells treated with a concentration of L-NAME was shorter than for the cells treated with 0.5 mM L-arginine alone. These results suggest that L-arginine acts through the NO-dependent pathway. In conclusion, our findings thus confirmed the quenching effects of NO on free radical injury in cultured cardiomyocytes.
 ...
PMID:Quenching the effects of L-arginine on free radical injury in cultured cardiomyocytes. 959 Jul 1

Oxygen free radicals and nitric oxide (NO.) have been proposed to be involved in acute CNS injury produced by cerebral ischemia; however, controversy remains regarding how they cause injury. Because superoxide generation is triggered during reperfusion, the cytotoxic oxidant peroxynitrite could be formed, but it is not known if this occurs. Dot blot and immunohistochemistry studies were performed on the magnitude and time course of tyrosine nitration and inducible NO synthase (NOS2) in the postischemic rat pup brain. Neonatal ischemia was induced by permanent left middle cerebral artery occlusion in association with 1-h occlusion of the left common carotid artery in 7-day-old Wistar pups. Nitrotyrosine (NT) immunoreactivity was evident in the blood vessels close to the cortical infarct at 48-72 h of recovery, and T lymphocytes were involved with this production. NOS2 immunoreactivity was seen in neutrophils in the same vessels and in the parenchyma at 72 h of recirculation. Whereas NT staining decreased with time, NOS2-positive neutrophils could be still detected in arachnoid vessels at 14 days of recirculation. We conclude that perivascular reactions mediated by peroxynitrite are important in the cascade of events that lead to brain oxidative stress in neonatal ischemia. Moreover, NO-related species may serve as a signaling function instead of directly mediating toxicity.
 ...
PMID:Nitric oxide production and perivascular tyrosine nitration following focal ischemia in neonatal rat. 960 17


<< Previous 1 2 3 4 5 6 7 8 9 10