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)

Nitrite has emerged as an endogenous signaling molecule with potential therapeutic implications for cardiovascular disease. Steady-state levels of nitrite are derived in part from dietary sources; therefore, we investigated the effects of dietary nitrite and nitrate supplementation and deficiency on NO homeostasis and on the severity of myocardial ischemia-reperfusion (MI/R) injury. Mice fed a standard diet with supplementation of nitrite (50 mg/liter) in their drinking water for 7 days exhibited significantly higher plasma levels of nitrite, exhibited significantly higher myocardial levels of nitrite, nitroso, and nitrosyl-heme, and displayed a 48% reduction in infarct size (Inf) after MI/R. Supplemental nitrate (1 g/liter) in the drinking water for 7 days also increased blood and tissue NO products and significantly reduced Inf. A time course of ischemia-reperfusion revealed that nitrite was consumed during the ischemic phase, with an increase in nitroso/nitrosyl products in the heart. Mice fed a diet deficient in nitrite and nitrate for 7 days exhibited significantly diminished plasma and heart levels of nitrite and NO metabolites and a 59% increase in Inf after MI/R. Supplementation of nitrite in the drinking water for 7 days reversed the effects of nitrite deficiency. These data demonstrate the significant influence of dietary nitrite and nitrate intake on the maintenance of steady-state tissue nitrite/nitroso levels and illustrate the consequences of nitrite deficiency on the pathophysiology of MI/R injury. Therefore, nitrite and nitrate may serve as essential nutrients for optimal cardiovascular health and may provide a treatment modality for cardiovascular disease.
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PMID:Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury. 1802 68

The aim of this experimental study was to investigate whether dimethylsulfoxide (DMSO) has protective effects on spinal cord ischemia-reperfusion (I/R) injury. New Zealand rabbits were enrolled in the study. In addition to the control group, the study group received 0.1 mL/kg DMSO prior to ischemia. Blood samples were taken to obtain nitrite-nitrate levels during the surgical procedure. After neurological evaluation at 24 hr of reperfusion, lumbar spinal cords were removed for electron microscopic evaluation and malondialdehyde and myeloperoxidase measurements. The mean Tarlov score of the DMSO group was higher than that of the control group. Electron microscopic examination was carried out with tissue samples at 24 hr of reperfusion. The DMSO group had better preservation with the electron microscopic scoring compared to the control group. Malondialdehyde and myeloperoxidase levels were decreased in the DMSO group compared to the control group. Nitrite-nitrate levels were also lower in the DMSO group compared to control at 5 and 30 min of reperfusion. This study demonstrates a considerable neuroprotective effect of DMSO on neurological, biochemical, and histopathological analyses during periods of spinal cord I/R injury in rabbits. Although there was a difference between the DMSO and control groups in all measured parameters in our study, this was not statistically significant. DMSO deserves further investigation related with spinal cord ischemia and reperfusion. We should also consider the effect of DMSO when we use it as a solvent or vehicle during experimental I/R models.
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PMID:How DMSO, a widely used solvent, affects spinal cord injury. 1808 17

Nitrite plays an eminent role in cardiovascular physiology and pathology, mediating hypoxic vasodilation, reducing ischemia-reperfusion injury, and regulating cardiac energetics and function. The role of circulating nitrite in critically ill patients has not been examined so far. To investigate whether whole blood nitrite can be determined reproducibly in an intensive care setting, 30 patients from a cardiology intensive care unit were enrolled in this study, no matter what the underlying disease. Blood was drawn from an arterial catheter and whole blood nitrite was determined, using a tri-iodide/ozone-based chemiluminescence assay after incubation with a ferricyanide-containing stabilization solution. Whole blood nitrite levels ranged from 35 to 1193 nmol/L (mean+/-SEM: 220+/-20 nmol/L). Myocardial infarction was associated with lower whole blood nitrite levels (200+/-53 nmol/L for elevated serum CK MB levels vs 432+/-95 nmol/L in the normal CK MB range, p=0.039). Neither impaired kidney function nor an inflammatory state was associated with higher or lower whole blood nitrite levels. In conclusion, whole blood nitrite can be measured easily and reproducibly in critically ill patients, regardless of renal function and inflammation. The origin of decreased nitrite levels in myocardial infarction is currently unclear and needs to be further elucidated.
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PMID:Serial measurements of whole blood nitrite in an intensive care setting. 1837 62

Postoperative neurologic deficit is the most devastating complication after thoracoabdominal aortic aneurysm repair. Our aim was to investigate whether nebivolol has protective effects during ischemia or reperfusion and the most effective mechanism of protection via inhibiting nitric oxide (NO) release with an NO synthase inhibitor in an experimental model of spinal cord ischemia/reperfusion injury. Spinal cord ischemia was induced by occlusion of the infrarenal aorta for 30 min. Thirty-one rabbits were divided into five groups according to the administration period of nebivolol and/or N(G)-nitro-L-arginine methyl ester (L-NAME): control group; group NI, nebivolol during ischemic period; group NR, nebivolol during reperfusion period; group NILR, nebivolol during ischemic period and L-NAME during reperfusion period; and group LINR, L-NAME during ischemic period and nebivolol during reperfusion period. Blood samples were taken at both ischemia and reperfusion periods to obtain nitrite/nitrate levels. After neurologic evaluation at 24 hr of reperfusion, malondialdehyde (MDA) levels were measured. Neurologic impairment was significantly lower in group LINR (Tarlov score 3.4 +/- 0.6, p < 0.05). MDA levels were lower in nebivolol-treated animals, but the lowest value was achieved in the NR group, 35.6 +/- 2.7 nmol/g (p < 0.001). Nitrite levels were decreased significantly in all nebivolol-treated animals in the reperfusion period, but the lowest value was measured in the LINR group (455 +/- 137 vs. 1,760 +/- 522 nmol/mL, p < 0.001). Prophylactic use of nebivolol reduced neurologic injury, and combining with L-NAME provided the best clinical improvement by attenuating the inflammatory mileu in this experimental model. Combination of nebivolol and L-NAME appears to be an effective option for spinal cord protection against ischemia/reperfusion injury.
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PMID:Collaborative therapy with nebivalol and L-NAME for spinal cord ischemia/reperfusion injury. 1846 20

Chronic tissue ischemia due to defective vascular perfusion is a hallmark feature of peripheral artery disease for which minimal therapeutic options exist. We have reported that sodium nitrite therapy exerts cytoprotective effects against acute ischemia/reperfusion injury in both heart and liver, consistent with the model of bioactive NO formation from nitrite during ischemic stress. Here, we test the hypothesis that chronic sodium nitrite therapy can selectively augment angiogenic activity and tissue perfusion in the murine hind-limb ischemia model. Various therapeutic doses (8.25-3,300 mug/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a time-dependent manner, with low-dose sodium nitrite being most effective. Nitrite therapy significantly increased ischemic limb vascular density and stimulated endothelial cell proliferation. Remarkably, the effects of sodium nitrite therapy were evident within 3 days of the ischemic insult demonstrating the potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite therapy also increased ischemic tissue nitrite and NO metabolites compared to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic activity consistent with nitrite reduction to NO being the proangiogenic mechanism. These data demonstrate that chronic sodium nitrite therapy is a recently discovered therapeutic treatment for peripheral artery disease and critical limb ischemia.
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PMID:Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis. 1850 74

The nitrite anion is reduced to nitric oxide (NO*) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO* signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ((+/+)) and knockout ((-/-)) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO* generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO* generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO* by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin(+/+) but not in myoglobin(-/-) hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin(+/+) mice, whereas in myoglobin(-/-) mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation [corrected]
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PMID:Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. 1863 62

Small increases in physiological nitrite concentrations have now been shown to mediate a number of biological responses, including hypoxic vasodilation, cytoprotection after ischemia/reperfusion, and regulation of gene and protein expression. Thus, while nitrite was until recently believed to be biologically inert, it is now recognized as a potentially important hypoxic signaling molecule and therapeutic agent. Nitrite mediates signaling through its reduction to nitric oxide, via reactions with several heme-containing proteins. In this report, we show for the first time that the mitochondrial electron carrier cytochrome c can also effectively reduce nitrite to NO. This nitrite reductase activity is highly regulated as it is dependent on pentacoordination of the heme iron in the protein and occurs under anoxic and acidic conditions. Further, we demonstrate that in the presence of nitrite, pentacoordinate cytochrome c generates bioavailable NO that is able to inhibit mitochondrial respiration. These data suggest an additional role for cytochrome c as a nitrite reductase that may play an important role in regulating mitochondrial function and contributing to hypoxic, redox, and apoptotic signaling within the cell.
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PMID:Nitrite reductase activity of cytochrome c. 1882 Mar 38

Growing evidence indicates that nitrite, NO2-, serves as a circulating reservoir of nitric oxide (NO) bioactivity that is activated during physiological and pathological hypoxia. One of the intravascular mechanisms for nitrite conversion to NO is a chemical nitrite reductase activity of deoxyhemoglobin. The rate of NO production from this reaction is increased when hemoglobin is in the R conformation. Because the mammalian fetus exists in a low-oxygen environment compared with the adult and is exposed to episodes of severe ischemia during the normal birthing process, and because fetal hemoglobin assumes the R conformation more readily than adult hemoglobin, we hypothesized that nitrite reduction to NO may be enhanced in the fetal circulation. We found that the reaction was faster for fetal than maternal hemoglobin or blood and that the reactions were fastest at 50-80% oxygen saturation, consistent with an R-state catalysis that is predominant for fetal hemoglobin. Nitrite concentrations were similar in blood taken from chronically instrumented normoxic ewes and their fetuses but were elevated in response to chronic hypoxia. The findings suggest an augmented nitrite reductase activity of fetal hemoglobin and that the production of nitrite may participate in the regulation of vascular NO homeostasis in the fetus.
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PMID:Increased nitrite reductase activity of fetal versus adult ovine hemoglobin. 1902 97

Our recent work suggested that early infusion of nitrite might represent a novel therapeutic approach for acute ischemic stroke. In this study, we sought to examine the therapeutic time window of nitrite in an experimental stroke model, and to develop combined strategies for augmenting its protective effects. Nitrite was infused at various times after ischemia to rats subjected to transient or permanent focal ischemia. Nitrite was infused with memantine to prevent the potential toxicity. Infarct volumes, functional outcomes, microhypoxic areas, and oxidative stress were measured. Nitrite reduced the infarction volume and enhanced functional recovery when administered within 3 and 1.5h in the transient and permanent model, respectively. Combined therapy with nitrite and memantine prolonged the time window up to 4.5h. The potential oxidative toxicities of nitrite were significantly inhibited by memantine. The combination therapy of nitrite and memantine may be a feasible therapeutic approach for acute ischemic stroke.
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PMID:Augmentation of nitrite therapy in cerebral ischemia by NMDA receptor inhibition. 1905 43

The nitrite anion is an endogenous product of nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants and bacteria, and a constituent of many foods. Research over the past 6 years has revealed a surprising biological and cytoprotective activity of this anion. Its ability to restore NO homeostasis throughout the physiological oxygen gradient in vivo has transformed this once-thought to be inert anion into a critical molecule in health and disease. Ischemia-reperfusion (I/R) injury is a major clinical problem worldwide. NO has been shown to be one of the most important molecules for the prevention of injury from I/R. Paradoxically, however, enzymatic NO formation from NO synthase (NOS) is inactive during conditions of inadequate oxygen and substrate delivery, such as in ischemia. Nitrite has emerged as a viable alternative source of NO under ischemic conditions. As nitrite is known to be derived not only from the oxidation of NO but also through diet, understanding nitrite metabolism and mechanisms of cytoprotection may offer novel and natural means to prevent disease or at least limit injury from an I/R event. Here, we review the current body of knowledge regarding dietary sources of nitrite and its modulation of cytoprotection in an I/R injury.
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PMID:Dietary sources of nitrite as a modulator of ischemia/reperfusion injury. 1921 22


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