sodium-nitrite and Hypoxia

Cyanide is a potent and rapidly-acting asphyxiant which prevents tissue utilization of oxygen by inhibition of the cellular respiratory enzyme, cytochrome oxidase. Inhalation or ingestion of cyanide produces reactions within a few seconds and death within minutes. Cyanide toxicity of dietary origin has been implicated in acute animal deaths and as major etiologic factors in toxic ataxic neuropathy in man and as a cause of vision failure in humans suffering from tobacco amblyopia and leber's hereditary optic atrophy. Diagnosis of cyanide toxicity may be confirmed by a variety of laboratory procedures, but accurate assay is essential for proper conclusions from analysis of animal tissues several hours after death or from human samples in instances of chronic dietary exposure. Biological detoxification of cyanide is available through several routes, and the application of sodium nitrite with sodium thiosulfate or administration of methylene blue are effective treatment procedure. The environmental availability of cyanide in its various forms necessitates an understanding of its pathophysiology and responsible management of hazardous situations.

Topics: Absorption; Animal Husbandry; Animals; Chelating Agents; Chemical Phenomena; Chemistry; Cyanides; Electron Transport Complex IV; Environmental Pollutants; Humans; Hydroxocobalamin; Hypoxia; Inactivation, Metabolic; Poisoning; Postmortem Changes; Sodium Nitrite; Thiosulfates

The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models.. Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively.. Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH.. On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.

Topics: Administration, Inhalation; Adolescent; Adult; Biomarkers; Cohort Studies; Drug Interactions; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sodium Nitrite; Sulfonamides; Young Adult

Nitrites are commonly used in the chemical, pharmaceutical, and food industries. Recently, they have been identified in cases of voluntary intoxication. We report the case of a 13-year-old girl who was found lifeless on her bed next to a glass containing a white powder and a bottle containing a white powder with a moistened appearance. External examination and autopsy revealed a nonspecific asphyxia syndrome, which was confirmed by the pathological analysis. Analysis of the samples revealed metoclopramide in the peripheral blood at a concentration of 0.402 mg/L (LC-HRMS). An analysis of the gastric contents was carried out after sodium nitrite was detected in the powders found near the body (Raman spectrometry). Nitrites were found in the gastric fluid at a concentration of 30.9 mg/L. Death occurred secondary to anoxia, following ingestion of nitrites; suicide kits are available on the web and nitrites are relatively easy to source and inexpensive. Nitrites are delivered in powder form to be dissolved in liquid, which may then be consumed with metoclopramide (or an alternative anti-emetic drug) to maximize absorption and reduce emesis. The toxic effect of nitrites lies in their oxidizing power, causing the transformation of hemoglobin into methemoglobin, which, when it accumulates, induces tissue anoxia resulting in death. There has been an alarming increase in the number of cases linked to suicide using nitrites or a nitrite suicide kit. The fact that nitrites are readily available online underscores the importance of establishing effective preventive measures such as limiting the access and use of this chemical.

Topics: Adolescent; Female; Humans; Hypoxia; Internet; Metoclopramide; Nitrites; Powders; Sodium Nitrite; Suicide

Sodium nitrite (SN) is an inorganic salt that appears as a slightly yellowish crystalline solid, odorless, and highly soluble in water at room temperature. It is highly toxic to humans at specific doses because it can oxidize hemoglobin to methemoglobin, causing severe tissue hypoxia. A 20-year-old woman was unconscious in her bedroom and died shortly after that. Two days later, following the discovery of a jar of SN and a paper in which were written instructions on how to take it (and the website from which the procedure was learned) in the same room were death occurred, the Judicial Authority ordered the execution of the autopsy on the exhumed body of the young woman. The autopsy procedure was performed ∼ 2h after exhumation. It showed greyish-purple hypostasis, labial cyanosis, stomach distension and greenish color but empty, subpleural petechiae, brownish fluid in the pleural cavities (∼300 ml), congested and edematous lungs and diffuse visceral congestion. At autopsy, foamy liquid was observed at the lung section and subsequent squeezing. In addition, the autopsy showed edema and hemorrhagic petechiae of the laryngeal, glottal, and tracheal submucosa and green-brownish foamy liquid in the tracheal lumen. The cause of death was attributed tocardiac arrest induced by anoxia resulting from acute methemoglobinemia caused by sodium nitrite poisoning, intensified by severe malnutrition. Manner of death was suicidal.

Topics: Adult; Autopsy; Eating; Exhumation; Female; Humans; Hypoxia; Sodium Nitrite; Suicidal Ideation; Young Adult

Sodium nitrite (NaNO

Topics: Eating; Fertilizers; Food Additives; Forensic Pathology; Heme; Hemoglobins; Humans; Hypoxia; Iron; Methemoglobin; Methemoglobinemia; Sodium Nitrite; Suicidal Ideation

We present two patients who were treated for an intentional overdose of sodium nitrite. When ingested sodium nitrite leads to severe methaemoglobinaemia, resulting in severe hypoxia (as methaemoglobin does not transport oxygen), vasodilation and hypotension. Symptoms include cyanosis, headache, nausea, convulsions, coma and death. When measured by pulse oximetry, patients with a sodium nitrite intoxication and severe methaemoglobinaemia generally have an oxygen saturation of around 85%. This value is unreliable as the oxygen content of the blood is often extremely low - this can be confirmed by arterial blood gas analysis. Treatment of sodium nitrite intoxication consists of intravenous administration of methylthioninium chloride 1-2 mg/kg. Methylthioninium chloride converts the methaemoglobin back to haemoglobin. Due to the pharmacokinetics of methylthioninium chloride and sodium nitrite, a rebound effect is not to be expected. The only contra-indication for methylthioninium chloride is glucose-6-phosphate dehydrogenase deficiency, which is extremely rare in the Netherlands.

Topics: Adult; Drug Overdose; Enzyme Inhibitors; Food Preservatives; Humans; Hypoxia; Male; Methemoglobinemia; Methylene Blue; Oxygen; Poisoning; Sodium Nitrite; Suicide, Attempted

Dysfunction in the nitric oxide (NO) signaling pathway can lead to the development of pulmonary hypertension (PH) in mammals. Discovery of an alternative pathway to NO generation involving reduction from nitrate to nitrite and to NO has motivated the evaluation of nitrite as an alternative to inhaled NO for PH. In contrast, inhaled nitrate has not been evaluated to date, and potential benefits include a prolonged half-life and decreased risk of methemoglobinemia. In a canine model of acute hypoxia-induced PH we evaluated the effects of inhaled nitrate to reduce pulmonary arterial pressure (PAP). In a randomized controlled trial, inhaled nitrate was compared to inhaled nitrite and inhaled saline. Exhaled NO, PAP and systemic blood pressures were continuously monitored. Inhaled nitrite significantly decreased PAP and increased exhaled NO. In contrast, inhaled nitrate and inhaled saline did not decrease PAP or increase exhaled NO. Unexpectedly, we found that inhaled nitrite resulted in prolonged (>5 h) exhaled NO release, increase in nitrate venous/arterial levels and a late surge in venous nitrite levels. These findings do not support a therapeutic role for inhaled nitrate in PH but may have therapeutic implications for inhaled nitrite in various disease states.

Topics: Administration, Inhalation; Animals; Dogs; Hypertension, Pulmonary; Hypoxia; Nitrates; Nitric Oxide; Rats; Sodium Nitrite

Adequate perfusion of the placental vasculature is essential to meet the metabolic demands of fetal growth and development. Lacking neural control, local tissue metabolites, circulating and physical factors contribute significantly to blood flow regulation. Nitric oxide (NO) is a key regulator of fetoplacental vascular tone. Nitrite, previously considered an inert end-product of NO oxidation, has been shown to provide an important source of NO. Reduction of nitrite to NO may be particularly relevant in tissue when the oxygen-dependent NO synthase (NOS) activity is compromised, e.g. in hypoxia. The contribution of this pathway in the placenta is currently unknown. We hypothesised that nitrite vasodilates human placental blood vessels, with enhanced efficacy under hypoxia. Placentas were collected from uncomplicated pregnancies and the vasorelaxant effect of nitrite (10

Topics: Adult; Arteries; Benzoates; Chorion; Cyclic GMP; Dose-Response Relationship, Drug; Female; Humans; Hypoxia; Imidazoles; Nitrites; Placenta; Pregnancy; Sodium Nitrite; Vasodilation; Veins

Extracellular vesicles (EVs) are small, spherical particles enclosed by a phospholipid bilayer (∼30-1000 nm) released from multiple cell types, and have been shown to have pathophysiological roles in a plethora of disease states. The transcription factor hypoxia-inducible factor-1 (HIF-1) allows for adaptation of cellular physiology in hypoxia and may permit the enhanced release of EVs under such conditions. Nitric oxide (NO) plays a pivotal role in vascular homeostasis, and can modulate the cellular response to hypoxia by preventing HIF-1 accumulation. We aimed to selectively target HIF-1 via sodium nitrite (NaNO. Endothelial (HECV) cells were exposed to hypoxic conditions (1% O. Endothelial (HECV) cells exposed to hypoxia (1% O. These data provide evidence that hypoxia enhances the release of EVs in endothelial cells, and that this is mediated by HIF-1α, but not HIF-2α. Furthermore, the reduction of NO

Topics: Allopurinol; Basic Helix-Loop-Helix Transcription Factors; Deferoxamine; Endothelial Cells; Enzyme Inhibitors; Extracellular Vesicles; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Nitric Oxide; Particle Size; Sodium Nitrite; Xanthine Dehydrogenase

The study aims to compare, through histological and biochemical studies, the effects of quercetin, melatonin and their combination in regulation of immuno-inflammatory mediators and heat shock protein expressions in sodium nitrite induced hypoxia in rat lungs. The results revealed that NaNO2 injection caused a significant decrease in Hb in rats, while serum levels of TNF-α, IL-6 and CRP, VEGF and HSP70 were elevated compared to the control group. Administration of melatonin, quercetin or their combination before NaNO2 injection markedly reduced these parameters. Histopathological examination of the lung tissue supported these biochemical findings. The study suggests that melatonin and/or quercetin are responsible for lung tissue protection in hypoxia by downregulation of immuno-inflammatory mediators and heat shock protein expressions. Pre-treatment of hypoxic animals with a combination of melatonin and quercetin was effective in modulating most of the studied parameters to near-normal levels.

Topics: Animals; Anti-Inflammatory Agents; Carrier Proteins; Cytoprotection; Disease Models, Animal; Drug Therapy, Combination; HSP70 Heat-Shock Proteins; Hypoxia; Inflammation Mediators; Interleukin-6; Lung; Lung Injury; Male; Melatonin; Pneumonia; Quercetin; Rats, Wistar; Sodium Nitrite; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

This study was aimed at determining the influence of cytoflavin on the morphological features of contractile cardiomyocytes in female rats after gestation and in newborn rats exposed to hemic hypoxia induced by sodium nitrite (NaNO(2)). The experiment was performed on 28 three-month-old female Wistar albino rats and their offspring (24 seven-day-old newborns). Throughout pregnancy and during 7 days of suckling period, all animals divided into two groups were daily injected intraperitoneally with NaNO(2) at a dose of 5 mg/100 g body weight. Animals in the second test group were additionally injected intraperitoneally with. cytoflavin at a dose of 0.5 mL/100 g body weight. It was found that hemid hypoxia had a strong pathogenic effect on the contractile cardiomyocytes and hemomicrocirculatory bed vessels, which was manifested by the hypoxic and ischernic damage involving violation of the integrity of cellular and mitochondrial membranes. Histological and morphometric studies in animals of the first group showed a significant decrease in the length and area of contractile cardiomyocytes: up to 16.9 and 36.04%, respectively (p = 0.05). In the second group of animals (treated with cytoflavin), these changes were less pronounced: reduction in length and area on the average was 8.2 and 18.6%, respectively (p = 0.05). The administration of cytoflavin reduces the degree of cardiomyocyte damage in female rats after gestation and in newborns, presumably due to the antioxidant and membrane-protective properties of this drug.

Topics: Animals; Dose-Response Relationship, Drug; Drug Combinations; Female; Flavin Mononucleotide; Hypoxia; Inosine Diphosphate; Myocardium; Myocytes, Cardiac; Niacinamide; Rats; Sodium Nitrite; Succinates

The carotid body (CB) is a small neural crest-derived chemosensory organ that detects the chemical composition of the arterial blood and responds to its changes by regulating breathing. The effects of acute nitrite treatment on the CB morphology in rats were examined by morphometry. We found that 1h after administrating a single dose of sodium nitrite, the CB underwent structural changes characterized by a prominent increase in its size with a marked, several-fold dilation of the blood vessels. The obvious CB enlargement mostly due to apparent vasodilation and glomus cell hypertrophy was at its highest one day later and persisted until the fifth day. 20 days after the treatment, the CB regained its size to the normoxic control state. Morphometric analysis revealed that the CB size increase in treated animals is statistically significant when compared to that of untreated controls. It can be inferred that the nitrite-exposed CB displays remarkable structural plasticity and enlarges its size mostly through vascular expansion.

Topics: Animals; Blood Vessels; Carotid Body; Hypoxia; Indicators and Reagents; Male; Rats; Rats, Wistar; Sodium Nitrite; Time Factors

Acute mountain sickness, one of the most common altitude diseases, causes lung and brain injury. The present study aimed to investigate the anti‑hypoxic effect of purified polysaccharides extracted from Cordyceps militaris. The aqueous extract of Cordyceps militaris was purified progressively through a DEAE‑52 cellulose anion exchange column and a Sepharose G‑100 column. The fraction CMN1, with a molecular weight of 37842 Da, was the main fraction obtained and its chemical composition and structural characteristics were determined. CMN1 was found to have a monosaccharide composition of L‑rhamnose, L‑arabinose, D‑mannose, D‑galactose. The backbone of CMN1 comprised (1→2) and (1→3) linkages, with branched (1→6) and (1→4) linkages. The anti‑hypoxic effects of CMN1 were determined using a sodium nitrite toxicosis test, acute cerebral ischemic/hypoxic test and normobarie hypoxia test. CMN1 (0.5 g/kg) possessed a similar anti‑hypoxic effect to rhodiola oral liquid. Overall, the Cordyceps militaris polysaccharide, CMN1, was identified as an effective agent against hypoxia.

Topics: Animals; Apoptosis; Chromatography, Gel; Chromatography, Ion Exchange; Cordyceps; Female; Hypoxia; Male; Methemoglobinemia; Mice; Molecular Weight; Polysaccharides; Sodium Nitrite; Spectroscopy, Fourier Transform Infrared; Survival Rate

Hypoxia injury (HI) with its long-term neurological complications is one of the leading causes of morbidity and mortality in the world. Currently, the treatment regimens for hypoxia are aimed only at ameliorating the damage without complete cure. The need, therefore, for novel therapeutic drugs to treat HI continues.. This study investigates the protective effects of the ethanol extract of Cyperus rotundus L. (Cyperaceae) (EECR), a medicinal plant used in Ayurvedic traditional medicine against sodium nitrite-induced hypoxia in rats.. We have evaluated the protective effect of 200 and 400 mg/kg of EECR against sodium nitrite-induced hypoxia injury in rats by assessing the cognitive functions, motor, and behavioral effects of EECR treatment along with the histological changes in the brain. By comparing the protective effects of standard drugs galantamine, a reversible cholinesterase inhibitor and pyritinol, an antioxidant nootropic drug against sodium nitrite-induced hypoxia in rats, we have tested the protective ability of EECR.. EECR at doses of 200 and 400 mg/kg was able to protect against the cognitive impairments, and the locomotor activity and muscular coordination defects, which are affected by sodium nitrite-induced hypoxia injury in rats.. Based on our results, we suggest that the medicinal herb C. rotundus possesses a protective effect against sodium nitrite-induced hypoxia in rats. Further studies on these protective effects of EECR may help in designing better therapeutic regimes for hypoxia injury.

Topics: Animals; Behavior, Animal; Cognition Disorders; Cyperus; Disease Models, Animal; Dose-Response Relationship, Drug; Galantamine; Hypoxia; Male; Medicine, Ayurvedic; Motor Activity; Plant Extracts; Pyrithioxin; Rats; Rats, Wistar; Sodium Nitrite

It was investigated the features of microcirculation and mechanisms it's conditioned, under acute administration of sodium nitrite in 5 mg of dry substance per 100 g of body weight. It was shown that acute administration of sodium nitrite leads to the development of methemoglobinemia, arterial and venous hypoxemia, and severe tissue hypoxia. Increase in the diffusion path O2 at methemoglobinemia is caused due to significant hyperhydratation of lung air-blood barrier and its individual layers, and is accompanied by a decrease in both components of the diffusion capacity of the lungs for oxygen: its membrane and blood components. It was revealed that the administration of sodium nitrite has a double effect, leading to inactivation of hemoglobin, as well as to microcirculatory disturbances associated primarily with changes in the regulation of vascular tone. In this initial perfusion per unit volume of tissue per time unit intrinsic for the organism defines a set of mechanisms which are responsible for changes in tissue blood flow under methemoglobinemia.

Topics: Animals; Blood Vessels; Blood-Air Barrier; Diffusion; Hypoxia; Lung; Male; Methemoglobinemia; Microcirculation; Oxygen; Rats; Sodium Nitrite; Water

Comparative study of antihypoxic activity of glutamic and N-acetylglutamic acid in doses of 1, 10, 50 and 100 mg/kg was realized. It was experimentally ascertained that the most apparent antihypoxic action of study objects occurs in conditions of hypobaric hypoxia of acetylated derivative of glutamic acid considerably exceeds glutamic acid.

Topics: Animals; Dose-Response Relationship, Drug; Glutamates; Glutamic Acid; Hypercapnia; Hypoxia; Injections, Intraperitoneal; Longevity; Mice; Mice, Inbred CBA; Nitroprusside; Sodium Nitrite

The present study aims to clarify the protective effect of supplementation with some antioxidants, such as idebenone (200 mg/kg, ip), melatonin (10 mg/kg, ip) and arginine (200 mg/kg, ip) and their combination, on liver function (T. protein, albumin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase), energetic parameters (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, inorganic phosphate, total adenylate, adenylate energy charge and potential phosphate). The effect on glycolytic and glycogenolytic enzymes (glucose, glycogen, glycogen phosphorylase, pyruvate kinase and phosphofructokinase against hypoxia) was also studied. The drugs were administered 24 and 1 h prior sodium nitrite intoxication. All biochemical parameters were estimated 1 h after sodium nitrite injection. Injection of sodium nitrite (75 mg/kg, sc) produced a significant disturbance in all biochemical parameters of liver function, energetic parameters and glycolytic and glycogenolytic enzymes. Hepatic damage was confirmed by histopathological examination of the liver as compared to controls. The marked changes in hepatic cells induced by sodium nitrite were completely abolished by pretreatment with the drug combination, suggesting potential protection against sodium nitrite-induced hypoxia. It could be concluded that a combination of both idebenone and melatonin or idebenone and arginine provides potential protection against sodium nitrite-induced hypoxia by improving biochemical parameters and preserving liver histology.

Topics: Animals; Antioxidants; Arginine; Chemical and Drug Induced Liver Injury; Cytoprotection; Dietary Supplements; Disease Models, Animal; Drug Therapy, Combination; Energy Metabolism; Hypoxia; Liver; Male; Melatonin; Oxidative Stress; Rats; Reactive Oxygen Species; Sodium Nitrite; Time Factors; Ubiquinone

Endogenous H(2)S has been proposed to transduce the effects of hypoxia in the carotid bodies (CB). To test this hypothesis, we created a sink for endogenously produced H(2)S by inducing ∼10% methemoglobinemia via the injection of 250 mg of sodium nitrite in spontaneously breathing anaesthetized sheep. Methemoglobinemia has been shown to catalyze the oxidation of large quantities of sulfide in the blood and tissues. We found that the presence of metHb completely abolished the ventilatory stimulation induced by 10 mg NaHS (i.v.), which in control conditions mimicked the effects of breathing 6-7 tidal volumes of nitrogen, confirming the dramatic increase in the oxidative power of the blood for sulfide. The ventilatory responses to hypoxia (10% O(2)), nitrogen and hyperoxia were in no way depressed by the metHb. Our results demonstrate that the ventilatory chemoreflex is not depressed in the presence of a high oxidative capacity for sulfide and challenge the view that H(2)S transduces the effects of hypoxia in the CB.

Topics: Animals; Blood Gas Analysis; Blood Pressure; Carotid Arteries; Hydrogen Sulfide; Hyperoxia; Hypoxia; Methemoglobin; Models, Biological; Nitrogen; Oxidation-Reduction; Pneumoradiography; Reflex; Sheep; Sodium Nitrite; Sulfides; Tidal Volume

A water-soluble polysaccharide, named as SNP, was extracted and fractioned from the body wall of Sipunculus nudus L. by DEAE-Sepharose anion exchange and Sepharose CL-6B column chromatography. The evaluation for anti-hypoxia activity demonstrated that SNP had significant anti-hypoxic activity on normobarie hypoxia, chemical intoxicant hypoxia and acute cerebral ischemia hypoxia models in mice. SNP also enhanced the number of red blood cell count (RBC) and the concentration of hemoglobin (HGB). The structural characteristics of SNP investigated by high performance size exclusion chromatography, Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry indicated that SNP was a homogeneous polysaccharide with a molecular mass of 350 kD and was composed of rhamnose (28%), fucose (16%) and galactose (56%). The results suggested that SNP could be explored as a novel potential anti-hypoxia agent.

Topics: Animals; Annelida; Brain Ischemia; Hypoxia; Methylation; Mice; Polysaccharides; Sodium Nitrite; Spectrophotometry, Infrared; Survival Analysis; Toxicity Tests

Methemoglobin in the blood cannot be detected by conventional pulse oximetry, although it can bias the oximeter's estimate (Spo2) of the true arterial functional oxygen saturation (Sao2). A recently introduced "Pulse CO-Oximeter" (Masimo Rainbow SET(R) Radical-7 Pulse CO-Oximeter, Masimo Corp., Irvine, CA) is intended to additionally monitor noninvasively the fractional carboxyhemoglobin and methemoglobin content in blood. The purpose of our study was to determine whether hypoxia affects the new device's estimated methemoglobin reading accuracy, and whether the presence of methemoglobin impairs the ability of the Radical-7 and a conventional pulse oximeter (Nonin 9700, Nonin Medical Inc., Plymouth, MN) to detect decreases in Sao2.. Eight and 6 healthy adults were included in 2 study groups, respectively, each fitted with multiple sensors and a radial arterial catheter for blood sampling. In the first group, IV administration of approximately 300 mg sodium nitrite increased subjects' methemoglobin level to a 7% to 8% target and hypoxia was induced to different levels of Sao2 (70%-100%) by varying fractional inspired oxygen. In the second group, 15% methemoglobin at room air and 80% Sao2 were targeted. Pulse CO-oximeter readings were compared with arterial blood values measured using a Radiometer multiwavelength hemoximeter. Pulse CO-oximeter methemoglobin reading performance was analyzed by observing the incidence of meaningful reading errors at the various hypoxia levels. This was used to determine the impact on predictive values for detecting methemoglobinemia. Spo2 reading bias, precision, and root mean square error were evaluated during conditions of elevated methemoglobin.. Observations spanned 66.2% to 99% Sao2 and 0.6% to 14.4% methemoglobin over the 2 groups (170 blood draws). Masimo methemoglobin reading bias and precision over the full Sao2 span was 7.7% +/- 13.0%. Best accuracy was found in the 95% to 100% Sao2 range (1.9% +/- 2.5%), progressing to its worst in the 70% to 80% range (24.8% +/- 15.6%). Occurrence of methemoglobin readings in error >5% increased over each 5-point decrease in Sao2 (P < 0.05). Masimo Spo2 readings were biased -6.3% +/- 3.0% in the 95% to 100% Sao2 range with 4% to 8.3% methemoglobin. Both the Radical-7 and Nonin 9700 pulse oximeters accurately detected decreases in Sao(2) <90% with 4% to 15% methemoglobin, despite displaying low Spo2 readings when Sao2 was >95%.. The Radical-7's methemoglobin readings become progressively more inaccurate as Sao2 decreases <95%, at times overestimating true values by 10% to 40%. Elevated methemoglobin causes the Spo2 readings to underestimate Sao2 similar to conventional 2-wavelength pulse oximeters at high saturation. Spo2 readings from both types of instruments continue to trend downward during the development of hypoxemia (Sao2 <90%) with methemoglobin levels up to 15%.

Topics: Adult; Blood Gas Analysis; Carbon Monoxide; Carboxyhemoglobin; Data Interpretation, Statistical; Female; Hemoglobinometry; Humans; Hypoxia; Male; Methemoglobin; Methemoglobinemia; Oximetry; Oxygen; Predictive Value of Tests; Reproducibility of Results; Sodium Nitrite

Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension.. We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide-dependent induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well.. These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension.

Topics: Administration, Inhalation; Animals; Cell Division; Cells, Cultured; Chronic Disease; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocrotaline; Myocytes, Smooth Muscle; Nitric Oxide; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Xanthine Dehydrogenase

Generalized hypoxic pulmonary vasoconstriction (HPV) occurring during exposure to hypoxia is a detrimental process resulting in an increase in lung vascular resistance. Nebulization of sodium nitrite has been shown to inhibit HPV. The aim of this project was to investigate and compare the effects of nebulization of nitrite and different formulations of acidified sodium nitrite on acute HPV.. Ex vivo isolated rabbit lungs perfused with erythrocytes in Krebs-Henseleit buffer (adjusted to 10% hematocrit) and in vivo anesthetized catheterized rabbits were challenged with periods of hypoxic ventilation alternating with periods of normoxic ventilation. After baseline hypoxic challenges, vehicle, sodium nitrite or acidified sodium nitrite was delivered via nebulization. In the ex vivo model, pulmonary arterial pressure and nitric oxide concentrations in exhaled gas were monitored. Nitrite and nitrite/nitrate were measured in samples of perfusion buffer. Pulmonary arterial pressure, systemic arterial pressure, cardiac output and blood gases were monitored in the in vivo model.. In the ex vivo model, nitrite nebulization attenuated HPV and increased nitric oxide concentrations in exhaled gas and nitrite concentrations in the perfusate. The acidified forms of sodium nitrite induced higher levels of nitric oxide in exhaled gas and had longer vasodilating effects compared to nitrite alone. All nitrite formulations increased concentrations of circulating nitrite to the same degree. In the in vivo model, inhaled nitrite inhibited HPV, while pulmonary arterial pressure, cardiac output and blood gases were not affected. All nitrite formulations had similar potency to inhibit HPV. The tested concentration of appeared tolerable.. Nitrite alone and in acidified forms effectively and similarly attenuates HPV. However, acidified nitrite formulations induce a more pronounced increase in nitric oxide exhalation.

Topics: Acute Disease; Administration, Inhalation; Animals; Blood Pressure; Cardiac Output; Chemistry, Pharmaceutical; Disease Models, Animal; Dose-Response Relationship, Drug; Exhalation; Hydrogen-Ion Concentration; Hypoxia; Male; Nebulizers and Vaporizers; Nitrates; Nitric Oxide; Perfusion; Pulmonary Artery; Rabbits; Sodium Nitrite; Time Factors; Vasoconstriction; Vasodilator Agents

Crude water-soluble polysaccharides (BRP) were extracted from the root of Brassica rapa L. using boiling-water. The polysaccharides were successively purified by chromatography on DEAE-cellulose and Sephadex G-100 column, giving three major polysaccharide fractions termed BRP1-1, BRP2-1, BRP3-1. The gel permeation chromatography (GPC) analysis showed that the average molecular weight (Mw) of polysaccharides (BRP1-1, BRP2-1, BRP3-1) were approximately 5.53×10(3) Da, 3.35×10(4) Da and 3.37×10(4) Da, respectively. Monosaccharide components analysis indicated that BRP1-1 was composed of arabinose and glucose in a molar ratio of 1.66:98.34. BRP2-1 was composed of arabinose, galactose and glucose in a molar ratio of 9.3:14.63:76.07. BRP3-1 was composed of arabinose, rhamnose, galactose and glucose in a molar ratio of 24.98:24.10:44.09:6.83. The evaluation of anti-hypoxia activity in vivo revealed that BRP is a novel potential anti-hypoxia agent.

Topics: Acute Disease; Animals; Brain Ischemia; Brassica rapa; Chemical Fractionation; Chromatography; Erythrocyte Count; Hemodynamics; Hemoglobins; Hypoxia; Male; Mice; Molecular Weight; Monosaccharides; Polysaccharides; Sodium Nitrite; Spectroscopy, Fourier Transform Infrared; Survival Analysis; Time Factors; Toxicity Tests

Methemoglobin in the blood cannot be detected by conventional pulse oximetry and may bias the oximeter's estimate (Spo(2)) of the true arterial functional oxygen saturation (Sao(2)). A recently introduced "pulse CO-oximeter" (Masimo Rainbow SET® Radical-7) that measures SpMet, a noninvasive measurement of the percentage of methemoglobin in arterial blood (%MetHb), was shown to read spuriously high values during hypoxia. In this study we sought to determine whether the manufacturer's modifications have improved the device's ability to detect and accurately measure methemoglobin and deoxyhemoglobin simultaneously.. Twelve healthy adult volunteer subjects were fitted with sensors on the middle finger of each hand, and a radial arterial catheter was placed for blood sampling. Intravenous administration of ∼300 mg of sodium nitrite elevated subjects' methemoglobin levels to a 7% to 11% target level, and hypoxia was induced to different levels of Sao(2) (70% to 100%) by varying fractional inspired oxygen. Pulse CO-oximeter readings were compared with arterial blood values measured with a Radiometer ABL800 FLEX multi-wavelength oximeter. Pulse CO-oximeter methemoglobin reading performance was analyzed by the bias (SpMet-%MetHb), and by observing the incidence of meaningful reading errors and predictive value at the various hypoxia levels. Spo(2) bias (Spo(2)--Sao(2)), precision, and root-mean-square error were evaluated during conditions of elevated methemoglobin.. Observations spanned 74% to 100% Sao(2) and 0.4% to 14.4% methemoglobin with 307 blood draws and 602 values from the 2 oximeters. Masimo methemoglobin reading bias and precision over the full Sao(2) span was 0.16% and 0.83%, respectively, and was similar across the span. Masimo Spo(2) readings were biased -1.93% across the 70% to 100% Sao(2) range.. The Rainbow's methemoglobin readings are acceptably accurate over an oxygen saturation range of 74%-100% and a methemoglobin range of 0%-14%.

Topics: Administration, Inhalation; Biomarkers; Carboxyhemoglobin; Female; Fingers; Hemoglobins; Humans; Hypoxia; Injections, Intravenous; Male; Materials Testing; Methemoglobin; Oximetry; Oxygen; Predictive Value of Tests; Reproducibility of Results; San Francisco; Sodium Nitrite

Recent studies show that pulmonary vasodilator responses to nitrite are enhanced by hypoxia. However, the mechanism by which nitrite is converted to vasoactive nitric oxide (NO) is uncertain. In the present study, intravenous injections of sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure were enhanced when tone in the pulmonary vascular bed was increased with U-46619. Under elevated tone conditions, decreases in pulmonary and systemic arterial pressures in response to nitrite were attenuated by allopurinol in a dose that did not alter responses to the NO donors, sodium nitroprusside and diethylamine/NO, suggesting that xanthine oxidoreductase is the major enzyme-reducing nitrite to NO. Ventilation with a 10% O(2) gas mixture increased pulmonary arterial pressure, and the response to hypoxia was enhanced by N(G)-nitro-l-arginine methyl ester and not altered by allopurinol. This suggests that NO formed by the endothelium and not from the reduction of plasma nitrite modulates the hypoxic pulmonary vasoconstrictor response. Although intravenous injections of sodium nitrite reversed pulmonary hypertensive responses to U-46619, hypoxia, and N(G)-nitro-l-arginine methyl ester, the pulmonary vasodilator response to nitrite was not altered by ventilation with 10% O(2) when baseline pulmonary arterial pressure was increased to similar values in animals breathing room air or the hypoxic gas. These data provide evidence that xanthine oxidoreductase is the major enzyme-reducing nitrite to vasoactive NO, and that this mechanism is not modified by hypoxia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Allopurinol; Animals; Blood Pressure; Cardiac Output; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hydrazines; Hypoxia; Injections, Intravenous; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Oxypurinol; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Time Factors; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Xanthine Oxidase

To investigate the effects of the ethanol extract from Portulaca oleracea (EEPO) on hypoxia models mice and to find the possible mechanism of its anti-hypoxic actions so as to elucidate the anti-hypoxia activity and provide scientific basis for the clinical use of Portulaca oleracea.. EEPO was evaluated on anti-hypoxic activity in several hypoxia mice models, including closed normobaric hypoxia and sodium nitrite or potassium cyanide toxicosis. To verify the possible mechanism(s), we detected the activities of pyruvate kinase (PK), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and the level of adenosine triphosphate (ATP) in mice cortices.. Given orally, the EEPO at doses of 100, 200, 400 mg/kg could dose-dependently enhance the survival time of mice in both of the normobaric and chemical hypoxia models. The activity of the glycolysis enzymes and the level of ATP were higher than those of the control. In the pentobarbital sodium-induced sleeping time test and the open-field test, EEPO neither significantly enhanced the pentobarbital sodium-induced sleeping time nor impaired the motor performance, indicating that the observed anti-hypoxic activity was unlikely due to sedation or motor abnormality.. These results demonstrated that the EEPO possessed notable anti-hypoxic activity, which might be related to promoting the activity of the key enzymes in glycolysis and improving the level of ATP in hypoxic mice.

Topics: Adenosine Triphosphate; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Glycolysis; Hypoxia; L-Lactate Dehydrogenase; Mice; Mice, Inbred ICR; Panax; Phosphofructokinases; Phytotherapy; Plant Components, Aerial; Plant Extracts; Portulaca; Potassium Cyanide; Pyruvate Kinase; Sleep; Sodium Nitrite

The brain insulin receptor and ERK I/II are known to play an important role in memory formation and neuroprotection. A series of experiments was designed to explore if Liriopsis tuber (LT) extracts could exhibit neuroprotection and memory enhancing actions. LT was extracted with 70% methanol and subsequently fractionated into chloroform (fraction C), chloroform/methanol-(3:1) (fraction CM), methanol-soluble (fraction M) and methanol-insoluble, water-soluble fractions (fraction A). The LT fractions (T, C, M, A) significantly inhibited the cortical depolarization induced by AMPA in cortical slices of rats. In addition, these fractions were also effective in promoting memory in the passive avoidance test in mice. To gain insight into the mechanism of memory enhancing effects by Liriopsis tuber extracts, the activities of hippocampal insulin receptors and ERK I/II were tested in rats. Extract of LT (T) dramatically stimulated tyrosine phosphorylation of the insulin receptor, while fraction C of LT also significantly stimulated the same. In addition, ERK I/II were stimulated and cholinesterase activities were inhibited by fractions T, C, M and A in the rat hippocampus. These results suggest that Liriopsis tuber extracts may exert neuroprotection and memory enhancing effects via activation of the insulin receptor and ERK I/II as well as inhibiting cholinesterase.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Avoidance Learning; Brain Injuries; Electrophysiology; Hippocampus; Hypoxia; Magnoliopsida; Male; Memory; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuroprotective Agents; Phosphorylation; Phytotherapy; Plant Extracts; Plant Tubers; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Sodium Nitrite

Alert Wistar rats were subcutaneously injected with sodium nitrite (3 mg/100 g body weight), the control group rats were injected with saline. The blood was taken in 30, 60 and 90 minutes after the injection. Total leucocyte quantity and their subpopulations, the oxygen-dependent and oxygen-independent phagocytosis by neutrophils, functional activity of T-lymphocytes and their responsiveness to neurotransmitters and sodium nitrite and sodium nitrite and basal cell activity mobility were studied. It was shown that a more obvious alteration of the lymphocyte number, an increase of migratory and cytokine-productive activity, as well as augmentation of the cell sensitivity response to sodium nitrite and acetylcholine occurred in 30 minutes after the nitric oxide donor injection. At the same time, the neutrophil radical-productive activity and quantity of cationic peptides in neutrophils remained unchanged during nitric intoxication. At a later time, the leucocyte state did not change as compared with the control parameters.

Topics: Animals; Antimicrobial Cationic Peptides; Cell Movement; Food Preservatives; Hypoxia; Leukocytes; Lymphocyte Count; Male; Neurotransmitter Agents; Phagocytosis; Rats; Rats, Wistar; Sodium Nitrite; Time Factors

It has been proposed that under hypoxic conditions, nitrite may release nitric oxide, which causes potent vasodilation. We hypothesized that nitrite would have a greater dilator effect in capacitance than in resistance vessels because of lower oxygen tension and that resistance-vessel dilation should become more pronounced during hypoxemia. The effect of intra-arterial infusion of nitrite on forearm blood flow and forearm venous volumes was assessed during normoxia and hypoxia.. Forty healthy volunteers were studied. After baseline infusion of 0.9% saline, sodium nitrite was infused at incremental doses from 40 nmol/min to 7.84 mumol/min. At each stage, forearm blood flow was measured by strain-gauge plethysmography. Forearm venous volume was assessed by radionuclide plethysmography. Changes in forearm blood flow and forearm venous volume in the infused arm were corrected for those in the control arm. The peak percentage of venodilation during normoxia was 35.8+/-3.4% (mean+/-SEM) at 7.84 micromol/min (P<0.001) and was similar during hypoxia. In normoxia, arterial blood flow, assessed by the forearm blood flow ratio, increased from 1.04+/-0.09 (baseline) to 1.62+/-0.18 (nitrite; P<0.05) versus 1.07+/-0.09 (baseline) to 2.37+/-0.15 (nitrite; P<0.005) during hypoxia. This result was recapitulated in vitro in vascular rings.. Nitrite is a potent venodilator in normoxia and hypoxia. Arteries are modestly affected in normoxia but potently dilated in hypoxia, which suggests the important phenomenon of hypoxic augmentation of nitrite-mediated vasodilation in vivo. The use of nitrite as a selective arterial vasodilator in ischemic territories and as a potent venodilator in heart failure has therapeutic implications.

Topics: Animals; Aorta, Abdominal; Electrocardiography; Forearm; Heart Rate; Humans; Hypoxia; Infusions, Intravenous; Male; Plethysmography; Rabbits; Reference Values; Sodium Nitrite; Supine Position; Vasodilation; Vasodilator Agents; Veins; Vena Cava, Inferior

Nitrite reduction to nitric oxide (NO) may be potentiated by a nitrite reductase activity of deoxyHb and contribute to systemic hypoxic vasodilation. The effect of nitrite on the pulmonary circulation has not been well characterized. We explored the effect of nitrite on hypoxic pulmonary vasoconstriction (HPV) and the role of the red blood cell (RBC) in nitrite reduction and nitrite-mediated vasodilation. As to method, isolated rat lungs were perfused with buffer, or buffer with RBCs, and subjected to repeated hypoxic challenges, with or without nitrite. As a result, in buffer-perfused lungs, HPV was reduced at nitrite concentrations of 7 muM and above. Nitrite inhibition of HPV was prevented by excess free Hb and RBCs, suggesting that vasodilation was mediated by free NO. Nitrite-inhibition of HPV was not potentiated by mild acidosis (pH = 7.2) or xanthine oxidase activity. RBCs at 15% but not 1% hematocrit prevented inhibition of HPV by nitrite (maximum nitrite concentration of approximately 35 muM) independent of perfusate Po(2). Degradation of nitrite was accelerated by hypoxia in the presence of RBCs but not during buffer perfusion. In conclusion, low micromolar concentrations of nitrite inhibit HPV in buffer-perfused lungs and when RBC concentration is subphysiological. This effect is lost when RBC concentration approaches physiological levels, despite enhanced nitrite degradation in the presence of RBCs. These data suggest that, although deoxyHb may generate NO from nitrite, insufficient NO escapes the RBC to cause vasodilation in the pulmonary circulation under the dynamic conditions of blood flow through the lungs and that RBCs are net scavengers of NO.

Topics: Acidosis; Animals; Breath Tests; Dose-Response Relationship, Drug; Erythrocytes; Hemoglobins; Hypoxia; Lung; Nitric Oxide; Perfusion; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Time Factors; Vasoconstriction; Xanthine Oxidase

Growing evidence suggests that nitrite, acting via reduction to nitric oxide by deoxyhemoglobin, may play an important role in local control of blood flow during hypoxia. To investigate the effect of hypoxia (65 Torr arterial Po(2)) on the kinetic properties of nitrite, a bolus injection of sodium nitrite (10 mg/kg iv) was given to normoxic or hypoxic newborn lambs, and the time course of plasma nitrite and methemoglobin (MetHb) concentrations was measured. The in vivo kinetics of nitrite disappearance from plasma were biphasic and were not affected by hypoxia. Changes in MetHb, a product of the nitrite-hemoglobin reaction, also did not differ with the level of oxygenation. Hypoxia potentiated the hypotensive effects of nitrite on pulmonary and systemic arterial pressures. The disappearance of nitrite from plasma was equivalent to the increase in MetHb on a molar basis. In contrast, nitrite metabolism in sheep blood in vitro resulted in more than one MetHb per nitrite equivalent under mid- and high-oxygenation conditions: oxyhemoglobin (HbO(2)) saturation = 50.3 +/- 1.7% and 97.0 +/- 1.3%, respectively. Under the low-oxygenation condition (HbO(2) saturation = 5.2 +/- 0.9%), significantly less than 1 mol of MetHb was produced per nitrite equivalent, indicating that a significant portion of nitrite is metabolized through pathways that do not produce MetHb. These data support the idea that the vasodilating effects of nitrite are potentiated under hypoxic conditions due to the reduction of nitrite to nitric oxide by deoxyhemoglobin.

Topics: Animals; Hemoglobins; Hypoxia; Injections; Methemoglobin; Nitrites; Oxyhemoglobins; Sheep; Sodium Nitrite; Time Factors; Vasodilation

Free radical homeostasis parameters of rat's brain mitochondria under conditions of sodium nitrite administration at the peak of hypoxia had been studied. Prior to study experimental animals have been divided into two groups depending on resistance to hypobaric hypoxia. In brain mitochondria of high-resistant to hypoxia rats increase of the nitrites-ions contents and also intensification of pro- and antioxidative processes were registered in comparison with the control group. Decrease of all investgated free radical homeostasis parameters in brain mitochondria of low-resistant to hypoxia animals in comparison with the control group was determined. Administration of pro-hypoxic factor in toxic dose allowed us to reveal specific peculiarities of redox processes development in the brain mitochondria of experimental animals with different resistance to hypoxia.

Topics: Adaptation, Physiological; Animals; Antioxidants; Brain; Free Radicals; Hypoxia; Male; Mitochondria; Rats; Sodium Nitrite

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

Topics: Anesthesia; Animals; Blood Pressure; Hypoxia; Male; Nitrates; Peroxynitrous Acid; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Vascular Resistance; Vasoconstriction; Vasodilation

The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction ( approximately 65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Aerosols; Animals; Animals, Newborn; Blood Pressure; Cardiac Output; Disease Models, Animal; Hemoglobins; Humans; Hydrogen-Ion Concentration; Hypoxia; Infant, Newborn; Methemoglobin; Nitric Oxide; Oxygen; Persistent Fetal Circulation Syndrome; Sheep; Sodium Nitrite; Vasodilator Agents

Rundown of ionic gradients is a central feature of white matter anoxic injury; however, little is known about the contribution of anions such as Cl-. We used the in vitro rat optic nerve to study the role of aberrant Cl- transport in anoxia/ischemia. After 30 min of anoxia (NaN3, 2 mm), axonal membrane potential (V(m)) decreased to 42 +/- 11% of control and to 73 +/- 11% in the presence of tetrodotoxin (TTX) (1 microm). TTX + 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid disodium salt (500 microm), a broad spectrum anion transport blocker, abolished anoxic depolarization (95 +/- 8%). Inhibition of the K-Cl cotransporter (KCC) (furosemide 100 microm) together with TTX was also more effective than TTX alone (84 +/- 14%). The compound action potential (CAP) area recovered to 26 +/- 6% of control after 1 hr anoxia. KCC blockade (10 microm furosemide) improved outcome (40 +/- 4%), and TTX (100 nm) was even more effective (74 +/- 12%). In contrast, the Cl- channel blocker niflumic acid (50 microm) worsened injury (6 +/- 1%). Coapplication of TTX (100 nm) + furosemide (10 microm) was more effective than either agent alone (91 +/- 9%). Furosemide was also very effective at normalizing the shape of the CAPs. The KCC3a isoform was localized to astrocytes. KCC3 and weaker KCC3a was detected in myelin of larger axons. KCC2 was seen in oligodendrocytes and within axon cylinders. Cl- gradients contribute to resting optic nerve membrane potential, and transporter and channel-mediated Cl- fluxes during anoxia contribute to injury, possibly because of cellular volume changes and disruption of axo-glial integrity, leading to propagation failure and distortion of fiber conduction velocities.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Action Potentials; Animals; Astrocytes; Axons; Chloride Channels; Chlorides; Hypoxia; In Vitro Techniques; Ion Transport; K Cl- Cotransporters; Membrane Potentials; Myelin Sheath; Neural Conduction; Niflumic Acid; Oligodendroglia; Optic Neuropathy, Ischemic; Protein Isoforms; Rats; Rats, Long-Evans; Sodium Nitrite; Symporters; Tetrodotoxin

The fundamental, yet poorly understood, physiological mechanism known as 'acidic-metabolic' vasodilation, contributes to local blood flow regulation during hypoxia/ischaemia and increased metabolic activity. The vasodilator nitric oxide (NO) has been suggested to be involved in this event. Besides enzymatic production by NO synthases, a novel mechanism for generation of this gas in vivo was recently described. This involves non-enzymatic reduction of inorganic nitrite to NO, a reaction that takes place predominantly during acidic/reducing conditions. We have studied the effects of physiological amounts of nitrite on NO generation and relaxation of rat aorta in vitro in a situation where environmental pH was reduced to levels seen in tissues during hypoxia/ischaemia. The relaxatory effect of nitrite was increased in an acidic buffer solution (pH 6.6) compared with neutral pH; EC50 for nitrite was reduced from 200 to 40 microM. Nitrite-evoked relaxation was effectively prevented by coadministration of an inhibitor of soluble guanylyl cyclase. The relaxation was further potentiated by the addition of ascorbic acid. In parallel, NO was generated from nitrite in a pH dependent manner with even larger amounts seen after addition of ascorbic acid. NO generation from nitrite correlated to the the degree of relaxation of rat aorta. These results illustrate non-enzymatic release of NO from nitrite at physiological concentrations. This may be an important auto-regulated physiological mechanism involved in the regulation of vascular tone during hypoxia/ischaemia.

Topics: Acidosis; Animals; Aorta; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hypoxia; In Vitro Techniques; Indicators and Reagents; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Oxadiazoles; Penicillamine; Quinoxalines; Rats; Rats, Wistar; Regional Blood Flow; Sodium Nitrite; Vasodilation

Topics: Animals; Brain; Carbon Dioxide; Chromatography, Thin Layer; Gangliosides; Hypoxia; Rats; Sodium Nitrite

Concentration of blood proteins, alpha-amino nitrogen, cGMP and endothelin-1,2 was studied in rat's blood at nitric hypoxia. The injection of NaNO2 (5 mg/100 g body weight) was followed by decrease in total protein, albumin and hemoglobin content and by sharp increase in methemoglobin and Hb-NO complexes concentration in rat's blood. Simultaneously, the elevation of free amino acids and peptides with m.w. 2500 D in blood was discovered. One of these peptides was the endothelin-1,2, whose concentration increased twice in plasma at nitric hypoxia. The increase in endothelin and cGMP concentrations is mostly linked with activation of compensative mechanisms, arising as a response to high concentrations of nitro compounds and NO in rats.

Topics: Adaptation, Physiological; Animals; Blood Proteins; Chromatography, High Pressure Liquid; Cyclic GMP; Electron Spin Resonance Spectroscopy; Endothelins; Hypoxia; Male; Rats; Rats, Wistar; Sodium Nitrite

The EPR spectrum was optimally recorded at 20 degrees C in the blood sample. The rotatory ability of the probe, expressing the microviscosity of the blood, was shown to depend on the dose of administered solution of the sodium nitrite and to correlate with the degree of hypoxic state. An analysis of probable causes of the changes in the blood microviscosity in acute hypoxia was carried out.

Topics: Acute Disease; Animals; Blood Viscosity; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Hypoxia; Rats; Rats, Wistar; Sodium Nitrite; Temperature

The anti-anoxic experiments have indicated that the petroleum ether extract of Rhizoma Zingiberis can prolong the survival time in mice poisoned by KCN or under the condition of normobaric hypoxia, as well as decapitation-induced gasping duration in mice, but can not prolong the survival time in mice poisoned by NaNO4. The anti-anoxic action might be related to the reduction rate of O2 consumption of the body. The aqueous extract of Rhizoma Zingiberis does not possess the above-mentioned anti-anoxic action. Both extracts do not affect the survival time in cooled mice.

Topics: Animals; Cold Temperature; Drugs, Chinese Herbal; Female; Hypoxia; Male; Mice; Oxygen Consumption; Poisoning; Potassium Cyanide; Sodium Nitrite

The effects of a reversible activator of adenylate cyclase sclareol glycol (SG), a semisynthetic diterpene of the labdane family, on acute hypoxia (asphyctic, hemic-induced by 300 mg/kg of sodium nitrite injected subcutaneously, and histotoxic-induced by 20 mg/kg sodium nitroprusside injected intraperitoneally) in mice were studied. SG was applied at doses well below the lethal dose. SG increased the latency to convulsions and the survival time to death. It is suggested that the antihypoxic effects of SG on these three models of acute hypoxia are induced mainly via its effects on adenylate cyclase and perhaps its involvement in synaptic transmitter action.

Topics: Animals; Diterpenes; Hypoxia; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Nitroprusside; Seizures; Sodium Nitrite; Time Factors

The antihypoxic effect of the newly-synthesized hydroxylamine barbiturate HB-7, compared with the effects of phenobarbital and pentobarbital, was studied in experiments on albino mice, using the following models of hypoxia: hypobaric, anoxic, asphyctic and haemic. A dose-effect dependence was established when the survival of the mice was prolonged under the effects of the barbiturates tested, applying the asphyctic and haemic hypoxy tests. The latter two tests were also used to determine the average effective doses (ED60) of the barbiturates. HB-7 was superior in its action to phenobarbital and pentobarbital, manifesting higher protective indices (PI-LD50: ED50): for HB-7 PI is 4.2, for phenobarbital--3.2 and for pentobarbital--2.5, using the haemic hypoxy test. It is concluded that HB-7, i.e. 2-hydroxylamine-5-ethyl-5-sec, pentylbarbituric acid, manifests a marked protective effect in the hypoxy tests used, exceeding in some cases the effects of phenobarbital and pentobarbital.

Topics: Animals; Anticonvulsants; Asphyxia; Atmospheric Pressure; Hydroxylamines; Hypoxia; Mice; Pentobarbital; Phenobarbital; Sodium Nitrite

Topics: Animals; Exploratory Behavior; Hypoxia; Male; Motor Activity; Nitrites; Rats; Rats, Inbred Strains; Sodium Nitrite

Topics: Animals; Brain; Hypoxia; Male; Membrane Lipids; Rats; Sodium Nitrite; Subcellular Fractions; Time Factors

Topics: Animal Feed; Animals; Food, Fortified; Hypoxia; Nitrites; Protein Hydrolysates; Rats; Sodium Nitrite

Topics: Animals; China; Cyanides; Female; Hypoxia; Male; Mice; Oxygen Consumption; Plants, Medicinal; Sodium Nitrite

Topics: Animals; Convulsants; Dogs; Drug Synergism; Fever; Hypercapnia; Hypoxia; Male; Mice; Mice, Inbred ICR; Phencyclidine; Potassium Cyanide; Rats; Sodium Nitrite

Topics: Acetylcholine; Animals; Brain; Cyclic AMP; Cyclic GMP; Glucose; Hypoxia; Male; Mice; Potassium Cyanide; Sodium Nitrite

The administration of sodium nitrite (60 mg/kg, s.c.) 30 min prior to carbon tetrachloride intoxication (2 ml/kg, p.o.) significantly enhanced the rise in serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and isocitrate dehydrogenase. Sodium nitrite pretreatment also enhanced the carbon tetrachloride-induced decrease in hepatic microsomal glucose-6-phosphatase activity. Microsomal diene conjugation absorption indicative of microsomal lipid peroxidation was observed following carbon tetrachloride intoxication, but was not altered by sodium nitrite pretreatment. The data indicate a potentially toxic interaction between sodium nitrite-induced methemoglobinemia and carbon tetrachloride-induced hepatic injury.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Drug Synergism; Hypoxia; Lipid Metabolism; Male; Methemoglobinemia; Nitrites; Peroxides; Rats; Sodium Nitrite; Time Factors

Topics: Animals; Blood Chemical Analysis; Hypoxia; Injections; Injections, Intraperitoneal; Injections, Intravenous; Metabolism; Methemoglobin; Methylene Blue; Mice; Nitrites; Oxygen; Radiation Injuries; Radiation Injuries, Experimental; Radiation-Protective Agents; Research; Sodium Nitrite; Spleen; Vena Cava, Inferior

Topics: Blood Chemical Analysis; Hypoxia; Injections, Intravenous; Metabolism; Methemoglobin; Mice; Nitrites; Oximetry; Pharmacology; Radiation Injuries; Radiation Protection; Radiation-Protective Agents; Research; Sodium Nitrite; Spleen

Topics: Arsenic Poisoning; Glucosephosphate Dehydrogenase; Hypoxia; Nitrites; Oxidation-Reduction; Oxidoreductases; Phosphogluconate Dehydrogenase; Sodium Nitrite