sodium-nitrite and Disease-Models--Animal

Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO-based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a "2-hit" murine model. Methods and Results Nine-week-old male C57BL/6 N mice (n=15 per group) were treated concurrently with high-fat diet and N(ω)-nitro-L-arginine methyl ester (L-NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L-NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of "two-hit" HFpEF. Conclusions Our data demonstrate that nitrite, a well-established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the "2-hit" mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the "2-hit" cardiometabolic HFpEF. These data suggest that supplementing NO-based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.

Topics: Animals; Disease Models, Animal; Drinking Water; Heart Failure; Hydralazine; Male; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Sodium Nitrite; Stroke Volume

Topics: Animals; Anti-Bacterial Agents; Bacteria; Biofilms; Disease Models, Animal; Down-Regulation; Drug Resistance, Bacterial; Edetic Acid; Lung Diseases; Metabolic Networks and Pathways; Mice; Nitrites; Pseudomonas aeruginosa; Sodium Nitrite

Proton pump inhibitors (PPI) are suppressors of gastric acid secretion (SGAS) that decrease gastric nitric oxide (NO) formation from nitrite and increase the cardiovascular risk. However, H2 receptor antagonists (H2RA) are considered safer than PPIs. We challenged this notion and hypothesized that both omeprazole (PPI) and ranitidine (H2RA) attenuate the responses to oral nitrite because both drugs increase gastric pH and therefore could decrease nitrite-derived NO formation in the stomach. We examined the blood pressure responses to oral nitrite in hypertensive rats treated with omeprazole, ranitidine, or vehicle. Chemiluminensce-based assays were used to measure gastric NO formation, plasma and gastric concentrations of nitrite, nitrate, and nitrosylated species (RXNO) to clarify the mechanism involved in the effects of SGAS on the responses to oral nitrite. Both drugs increased gastric pH, impaired oral nitrite-induced hypotensive responses, gastric NO formation, and blunted the increases in circulating RXNO concentrations, but not in circulating nitrite and nitrate concentrations. These findings were reproduced in a second study using sodium acetate buffers at pH 3.5, 4.5, and 5.5 to mimic gastric pH found with vehicle, ranitidine, and omeprazole, respectively. Increasing gastric pH impaired oral nitrite-induced hypotensive responses, gastric NO formation, and blunted the increases in circulating RXNO concentrations, but not in circulating nitrite and nitrate concentrations. Our results clearly indicate that SGAS impair nitrite-induced gastric formation of NO and vasoactive RXNO in a pH-dependent manner, thus resulting in impaired responses to oral nitrite. These findings may have several clinical implications, particularly to patients with cardiovascular diseases.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hypertension; Male; Nitrates; Nitric Oxide; Nitrites; Omeprazole; Proton Pump Inhibitors; Ranitidine; Rats; Rats, Wistar; Sodium Nitrite; Treatment Outcome

Mental retardation is a progressive condition in Down syndrome: intelligence starts to decline linearly within the first year. This phenomenon could be related to the overproduction of a toxic compound, hydrogen sulfide. Indeed, a gene located on chromosome 21 controls the production of cystathionine-β-synthase, an enzyme involved in hydrogen sulfide production in the central nervous system. It has recently been demonstrated that excess cystathionine-β-synthase levels are needed and sufficient to induce cognitive phenotypes in mouse models of Down syndrome. Thus, two therapeutic options might be used in Down syndrome patients: the use of a specific cystathionine β-synthase inhibitor and the use of an effective antidote to reduce hydrogen sulfide toxicity. Prenatal treatment of Down syndrome fetuses is also suggested.

Topics: Aminooxyacetic Acid; Animals; Benserazide; Brain; Chromosomes, Human, Pair 21; Cobamides; Cystathionine beta-Synthase; Disease Models, Animal; Disease Progression; Disulfiram; Down Syndrome; Enzyme Inhibitors; Gene Dosage; Humans; Hydrogen Sulfide; Infant, Newborn; Intellectual Disability; Mice; Mitochondria; Rats; Sodium Nitrite; Species Specificity; Thiosulfates

Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in Lmna

Topics: Animals; Disease Models, Animal; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Progeria; Sodium Nitrite; Vascular Stiffness

Continuous exposure to preservatives such as nitrite salts has deleterious effects on different organs. Meanwhile, Nigella sativa oil can remediate such organ dysfunction. Here, we studied the effect of consumption of thymoquinone (TQ); the main component of Nigella sativa oil on the brain damage induced by sodium nitrite. Forty adult male rats were daily given oral gavage of sodium nitrite (80 mg/kg) with or without thymoquinone (50 mg/kg). Oxidative stress, cytokines of inflammation, fibrotic elements and apoptotic markers in brain tissue were measured. Exposure to sodium nitrite (SN) resulted in increased levels of malondialdehyde, TGF-β, c-reactive protein, NF-κB, TNF-α, IL-1β and caspase-3 associated with reduced levels of glutathione, cytochrome c oxidase, Nrf2 and IL-10. However, exposure of rats' brain tissues to thymoquinone resulted ameliorated all these effects. In conclusion, thymoquinone remediates sodium nitrite-induced brain impairment through several mechanisms including attenuation of oxidative stress, retrieving the reduced concentration of glutathione, blocks elevated levels of pro-inflammatory cytokines, restores cytochrome c oxidase activity, and reducing the apoptosis markers in the brain tissues of rats.

Topics: Animals; Benzoquinones; Cytokines; Disease Models, Animal; Electron Transport Complex IV; Encephalitis; Food Preservatives; Gene Expression Regulation; Glutathione; Male; Mice; Oxidative Stress; Plant Oils; Sodium Nitrite

Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators.. Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points. In addition, sGC expression was detected by immunohistochemistry.. At 1 day after injury, acidified sodium nitrite-induced relaxation was attenuated in the injured artery, whereas BAY 60-2770-induced relaxation was augmented. Similar attenuation of response to acidified sodium nitrite was seen at 7 and 14 days after injury. On the other hand, the augmentation of response to BAY 60-2770 disappeared at 7 and 14 days after injury. At 1 day after injury, the immunohistochemical expression pattern of sGC in the smooth muscle layer of the injured artery was not different from that of the uninjured artery. However, in the injured artery, the intensity of sGC staining was weak at 7 and 14 days after injury.. Balloon injury alters vascular responsiveness to cGMP generators, which seems to be associated with the form and/or expression of sGC.

Topics: Angioplasty, Balloon; Animals; Benzoates; Biphenyl Compounds; Carotid Arteries; Carotid Artery Injuries; Cyclic GMP; Disease Models, Animal; Enzyme Activation; Enzyme Activators; Hydrocarbons, Fluorinated; Male; Muscle, Smooth, Vascular; Nitric Oxide Donors; Rats, Sprague-Dawley; Second Messenger Systems; Sodium Nitrite; Soluble Guanylyl Cyclase; Time Factors; Vasodilation

Endothelial dysfunction accompanied by an increase in oxidative stress is a key event leading to hypertension. As dietary nitrite has been reported to exert antihypertensive effect, the present study investigated whether chronic oral administration of sodium nitrite improves vascular function in conduit and resistance arteries of hypertensive animals with elevated oxidative stress.. Sodium nitrite (50mg/L) was given to angiotensin II-infused hypertensive C57BL/6J (eight to ten weeks old) mice for two weeks in the drinking water. Arterial systolic blood pressure was measured using the tail-cuff method. Vascular responsiveness of isolated aortae and renal arteries was studied in wire myographs. The level of nitrite in the plasma and the cyclic guanosine monophosphate (cGMP) content in the arterial wall were determined using commercially available kits. The production of reactive oxygen species (ROS) and the presence of proteins (nitrotyrosine, NOx-2 and NOx-4) involved in ROS generation were evaluated with dihydroethidium (DHE) fluorescence and by Western blotting, respectively.. Chronic administration of sodium nitrite for two weeks to mice with angiotensin II-induced hypertension decreased systolic arterial blood pressure, reversed endothelial dysfunction, increased plasma nitrite level as well as vascular cGMP content. In addition, sodium nitrite treatment also decreased the elevated nitrotyrosine and NOx-4 protein level in angiotensin II-infused hypertensive mice.. The present study demonstrates that chronic treatment of hypertensive mice with sodium nitrite improves impaired endothelium function in conduit and resistance vessels in addition to its antihypertensive effect, partly through inhibition of ROS production.

Topics: Administration, Oral; Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Aorta, Thoracic; Arterial Pressure; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Hypertension; Male; Mice, Inbred C57BL; NADPH Oxidase 2; NADPH Oxidase 4; Nitric Oxide; Oxidative Stress; Renal Artery; Sodium Nitrite; Tyrosine; Vasodilation

In this study, spherical shaped chiral mesoporous silica nanoparticles (CMS) was biomimetic synthesized using histidine derivatives (C

Topics: Administration, Oral; Animals; Biological Availability; Biomimetic Materials; Biomimetics; Calcium Channel Blockers; Calorimetry, Differential Scanning; Crystallography, X-Ray; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Liberation; Histidine; Hydrogen Bonding; Hypoxia, Brain; Male; Mice; Molecular Structure; Nimodipine; Porosity; Rats, Sprague-Dawley; Silicon Dioxide; Sodium Nitrite; Solubility; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical; Tissue Distribution; Water

Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.

Topics: Administration, Oral; Aging; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Fasting; Homeostasis; Humans; Hyperlipidemias; Hypertension; Male; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Signal Transduction; Sodium Nitrite; Time Factors; Treatment Outcome

S-nitrosocaptopril (CapNO) possesses dual capacities of both Captopril and an NO donor with enhanced efficacy and reduced side effects. CapNO crystals are difficult to make due to its unstable S-NO bond. Here, we report a novel stable S-nitrosocaptopril monohydrate (CapNO·H

Topics: Animals; Antihypertensive Agents; Aorta; Captopril; Crystallization; Disease Models, Animal; Endothelium, Vascular; Heart Ventricles; Humans; Hypertension, Pulmonary; Male; Nitric Oxide Donors; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Stomach; Tissue Culture Techniques; Vascular Resistance; Vasodilation; Vasodilator Agents

Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated.. The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice.. Chronic treatment of large dose of D-gal/NaNO. PAAs as the bioactive principles of P. oleracea attenuated oxidative stress, improved survival rate, and enhanced cognitive function in D-gal/NaNO

Topics: Aging; Amides; Animals; Antioxidants; Cognitive Dysfunction; Disease Models, Animal; Galactose; Indoles; Male; Maze Learning; Memory; Mice; Nootropic Agents; Oxidative Stress; Phenols; Piracetam; Plant Extracts; Portulaca; Sodium Nitrite; Survival Rate

RRx-001, a clinical macrophage-stimulating anti-cancer agent that also produces nitric oxide (NO) was studied in a model of ischemia-reperfusion injury.. The results demonstrated that, compared to control, RRx-001 preconditioning increased blood flow and functional capillary density, and preserved tissue viability in the absence of side effects over a sustained time period.. Thus, RRx-001 may serve as a long-lived protective agent during postsurgical restoration of flow and other ischemia-reperfusion associated conditions, increasing blood flow and functional capillary density as well as preserving tissue viability in the absence of side effects.

Topics: Animals; Azetidines; Blood Flow Velocity; Capillaries; Cricetinae; Disease Models, Animal; Male; Mesocricetus; Microcirculation; Nitro Compounds; Reperfusion Injury; Sodium Nitrite

Staphylococcus aureus is frequently isolated in the setting of infections of indwelling medical devices, which are mediated by the microbe's ability to form biofilms on a variety of surfaces. Biofilm-embedded bacteria are more resistant to antimicrobial agents than their planktonic counterparts and often cause chronic infections and sepsis, particularly in patients with prolonged hospitalizations. In this study, we demonstrate that sustained nitric oxide-releasing nanoparticles (NO-np) interfere with S. aureus adhesion and prevent biofilm formation on a rat central venous catheter (CVC) model of infection. Confocal and scanning electron microscopy showed that NO-np-treated staphylococcal biofilms displayed considerably reduced thicknesses and bacterial numbers compared to those of control biofilms in vitro and in vivo, respectively. Although both phenotypes, planktonic and biofilm-associated staphylococci, of multiple clinical strains were susceptible to NO-np, bacteria within biofilms were more resistant to killing than their planktonic counterparts. Furthermore, chitosan, a biopolymer found in the exoskeleton of crustaceans and structurally integrated into the nanoparticles, seems to add considerable antimicrobial activity to the technology. Our findings suggest promising development and translational potential of NO-np for use as a prophylactic or therapeutic against bacterial biofilms on CVCs and other medical devices.

Topics: Animals; Anti-Bacterial Agents; Bacterial Adhesion; Biofilms; Catheter-Related Infections; Central Venous Catheters; Chitosan; Delayed-Action Preparations; Disease Models, Animal; Female; Glucose; Humans; Methicillin-Resistant Staphylococcus aureus; Nanoparticles; Nitric Oxide; Oxidation-Reduction; Plankton; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Staphylococcal Infections

The 2 antidotes for acute cyanide poisoning in the United States must be administered by intravenous injection. In the out-of-hospital setting, intravenous injection is not practical, particularly for mass casualties, and intramuscular injection would be preferred. The purpose of this study is to determine whether sodium nitrite and sodium thiosulfate are effective cyanide antidotes when administered by intramuscular injection.. We used a randomized, nonblinded, parallel-group study design in 3 mammalian models: cyanide gas inhalation in mice, with treatment postexposure; intravenous sodium cyanide infusion in rabbits, with severe hypotension as the trigger for treatment; and intravenous potassium cyanide infusion in pigs, with apnea as the trigger for treatment. The drugs were administered by intramuscular injection, and all 3 models were lethal in the absence of therapy.. We found that sodium nitrite and sodium thiosulfate individually rescued 100% of the mice, and that the combination of the 2 drugs rescued 73% of the rabbits and 80% of the pigs. In all 3 species, survival in treated animals was significantly better than in control animals (log rank test, P<.05). In the pigs, the drugs attenuated an increase in the plasma lactate concentration within 5 minutes postantidote injection (difference: plasma lactate, saline solution-treated versus nitrite- or thiosulfate-treated 1.76 [95% confidence interval 1.25 to 2.27]).. We conclude that sodium nitrite and sodium thiosulfate administered by intramuscular injection are effective against severe cyanide poisoning in 3 clinically relevant animal models of out-of-hospital emergency care.

Topics: Animals; Antidotes; Cyanides; Disease Models, Animal; Injections, Intramuscular; Male; Mice; Rabbits; Random Allocation; Sodium Nitrite; Sus scrofa; Thiosulfates

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

Candida albicansis a leading nosocomial pathogen. Today, candidal biofilms are a significant cause of catheter infections, and such infections are becoming increasingly responsible for the failure of medical-implanted devices.C. albicansforms biofilms in which fungal cells are encased in an autoproduced extracellular polysaccharide matrix. Consequently, the enclosed fungi are protected from antimicrobial agents and host cells, providing a unique niche conducive to robust microbial growth and a harbor for recurring infections. Here we demonstrate that a recently developed platform comprised of nanoparticles that release therapeutic levels of nitric oxide (NO-np) inhibits candidal biofilm formation, destroys the extracellular polysaccharide matrices of mature fungal biofilms, and hinders biofilm development on surface biomaterials such as the lumen of catheters. We found NO-np to decrease both the metabolic activity of biofilms and the cell viability ofC. albicansin vitroandin vivo Furthermore, flow cytometric analysis found NO-np to induce apoptosis in biofilm yeast cellsin vitro Moreover, NO-np behave synergistically when used in combination with established antifungal drug therapies. Here we propose NO-np as a novel treatment modality, especially in combination with standard antifungals, for the prevention and/or remediation of fungal biofilms on central venous catheters and other medical devices.

Topics: Animals; Antifungal Agents; Apoptosis; Biofilms; Candida albicans; Candidiasis; Catheter-Related Infections; Catheterization, Central Venous; Chitosan; Disease Models, Animal; Drug Therapy, Combination; Female; Fluconazole; Fungal Polysaccharides; Hyphae; Microbial Sensitivity Tests; Microbial Viability; Nanoparticles; Nitric Oxide; Nitric Oxide Donors; Organosilicon Compounds; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Voriconazole

Cardiovascular health is influenced by dietary composition and the western diet is composed of varying types/amounts of fat. Conjugated linoleic acid (cLA) is an abundant dietary unsaturated fatty acid associated with health benefits but its biological signaling is not well understood. Nitrite is enriched in vegetables within the diet and can impact signaling of unsaturated fatty acids; however, its role on cLA signaling is not well understood. Elucidating how nitrite may impact the biological signaling of cLA is important due to the dietary consumption of both cLA and nitrite in the western diet. Since co-administration of cLA and nitrite results in cardioprotection during myocardial infarction (MI), it was hypothesized that cLA and nitrite may affect cardiac mitochondrial respiratory function and complex activity in MI. C57BL/6J mice were treated with cLA and nitrite for either 10 or 13days, where MI was induced on day 3. Following treatment, respiration and complex activity were measured. Among the major findings of this study, cLA treatment (10days) decreases state 3 respiration in vivo. Following MI, nitrite alone and in combination with cLA attenuates increased state 3 respiration and decreases hydrogen peroxide levels. Further, nitrite and cLA co-treatment attenuates increased complex III activity after MI. These results suggest that cLA, nitrite and the combination significantly alter cardiac mitochondrial respiratory and electron transport chain activity in vivo and following MI. Overall, the daily consumption of cLA and nitrite in the diet can have diverse cardiovascular implications, some of which occur at the mitochondrial level.

Topics: Animals; Cardiotonic Agents; Dietary Supplements; Disease Models, Animal; Echocardiography; Electron Transport; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Electron Transport Complex IV; Heart; Hydrogen Peroxide; Linoleic Acids, Conjugated; Male; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Proton-Translocating ATPases; Myocardial Reperfusion Injury; Oxidative Phosphorylation Coupling Factors; Oxidative Stress; Sodium Nitrite

Nitrite-derived NO protects against middle cerebral artery occlusion in mice. We developed a new mouse model of global cerebral ischemia and reperfusion (GCI/R) involving reversible occlusion of the major vessels from the aortic arch supplying the brain, and investigated neuroprotection with dietary sodium nitrite supplementation against GCI/R injury.. Mice received drinking water with (nitrite group) or without (control group) sodium nitrite (2 mM) for 5 days and underwent 3-min GCI/R by reversible occlusion of major vessels from the aortic arch (i.e., brachiocephalic, left common carotid, and left subclavian artery). Survival rates and neurological function scores were evaluated for up to 5 days after GCI/R. Histopathological studies were performed to detect neurological degeneration and caspase-3 activation in serial hippocampal sections.. In the control group, 17/30 mice (57 %) survived 5 days after 3-min GCI/R, whereas in the nitrite group 25/30 mice (83 %) survived (p < 0.05). The neurological score at 5 days after GCI in control group was significantly higher than in the nitrite group. Cerebral blood flow (CBF) during GCI was significantly higher in the nitrite group than in the control group, while MABP did not differ significantly between groups. Degenerative changes and caspase-3 activation in hippocampal sections after GCI were observed in the control group but not in the nitrite group. Pretreatment with the NO scavenger c-PTIO abolished the neuroprotective effects of sodium nitrite.. Sodium nitrite supplementation attenuated mortality and neurological impairment after 3-min GCI in mice; an effect likely mediated via vascular mechanisms involving NO.

Topics: Animals; Brain; Brain Ischemia; Caspase 3; Cerebrovascular Circulation; Dietary Supplements; Disease Models, Animal; Hippocampus; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Reperfusion Injury; Sodium Nitrite

To investigate whether nitrite administered prior to ischemia/reperfusion (I/R) reduces liver injury.. Thirty-six male Sprague-Dawley rats were randomized to 3 groups, including sham operated (n = 8), 45-min segmental ischemia of the left liver lobe (IR, n = 14) and ischemia/reperfusion (I/R) preceded by the administration of 480 nmol of nitrite (n = 14). Serum transaminases were measured after 4 h of reperfusion. Liver microdialysate (MD) was sampled in 30-min intervals and analyzed for glucose, lactate, pyruvate and glycerol as well as the total nitrite and nitrate (NOx). The NOx was measured in serum.. Aspartate aminotransferase (AST) at the end of reperfusion was higher in the IR group than in the nitrite group (40 ± 6.8 μkat/L vs 22 ± 2.6 μkat/L, P = 0.022). Similarly, alanine aminotransferase (ALT) was also higher in the I/R group than in the nitrite group (34 ± 6 μkat vs 14 ± 1.5 μkat, P = 0.0045). The NOx in MD was significantly higher in the nitrite group than in the I/R group (10.1 ± 2.9 μmol/L vs 3.2 ± 0.9 μmol/L, P = 0.031) after the administration of nitrite. During ischemia, the levels decreased in both groups and then increased again during reperfusion. At the end of reperfusion, there was a tendency towards a higher NOx in the I/R group than in the nitrite group (11.6 ± 0.7 μmol/L vs 9.2 ± 1.1 μmol/L, P = 0.067). Lactate in MD was significantly higher in the IR group than in the nitrite group (3.37 ± 0.18 mmol/L vs 2.8 ± 0.12 mmol/L, P = 0.01) during ischemia and the first 30 min of reperfusion. During the same period, glycerol was also higher in the IRI group than in the nitrite group (464 ± 38 μmol/L vs 367 ± 31 μmol/L, P = 0.049). With respect to histology, there were more signs of tissue damage in the I/R group than in the nitrite group, and 29% of the animals in the I/R group exhibited necrosis compared with none in the nitrite group. Inducible nitric oxide synthase transcription increased between early ischemia (t = 15) and the end of reperfusion in both groups.. Nitrite administered before liver ischemia in the rat liver reduces anaerobic metabolism and cell necrosis, which could be important in the clinical setting.

Topics: Animals; Biomarkers; Cytoprotection; Disease Models, Animal; Energy Metabolism; Injections, Intravenous; Liver; Male; Necrosis; Rats, Sprague-Dawley; Reperfusion Injury; Sodium Nitrite; Time Factors

We tested the hypothesis that short-term oral sodium nitrite supplementation would improve vascular dysfunction in obese, diabetic mice.. Vascular function was determined in control mice and in db/db mice receiving drinking water with or without sodium nitrite (50 mg/L) for 5 weeks. Nitrite supplementation increased plasma nitrite concentrations in db/db mice (0.19±0.02 µM vs 0.80±0.26 µM; p < 0.05). Db/db mice had lower endothelium-dependent dilation (EDD) in response to increasing doses of acetylcholine versus heterozygous control mice (71.2% ± 14.3% vs 93% ± 7.0%; p < 0.05), and sodium nitrite supplementation restored endothelium-dependent dilation to control levels (92.9% ± 2.3% vs 93% ± 7.0%; p < 0.05). The improvement in endothelial function was accompanied by a reduction in intrinsic stiffness, but not by alterations in plasma or vascular markers of inflammation.. These data suggest that sodium nitrite may be a novel therapy for treating diabetes-related vascular dysfunction; however, the mechanisms of improvement are unknown.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Heterozygote; Homozygote; Mice, Inbred C57BL; Mice, Mutant Strains; Point Mutation; Receptors, Leptin; Sodium Nitrite; Vascular Stiffness; Vasodilation; Vasodilator Agents

In Iranian traditional medicine, asafoetida is introduced as a valuable remedy for nervous disorders. Dementia was induced by injection of d-galactose and NaNO2 for 60 consecutive days. Animals were divided into normal control (NC), dementia control (DC), dementia prophylactic (DP), and dementia treated (DT). The learning and memory functions were examined by 1-way active and passive avoidance tests, using a shuttle box device. Avoidance response in training tests and 1 and 3 weeks later was significantly increased in NC, DP, and DT groups compared to the DC group. Step through latency in all groups was significantly greater than the DC group. Total time spent in light room, which shows the memory retention ability, in DP, NC, and DT was significantly greater than the DC group. Our findings indicate that asafoetida could prevent and treat amnesia. These beneficial effects maybe related to some constituent's effectiveness such as ferulic acid and umbelliferone.

Topics: Animals; Behavior, Animal; Dementia; Disease Models, Animal; Ferula; Food Preservatives; Galactose; Iran; Memory Disorders; Mice; Phytotherapy; Plant Preparations; Sodium Nitrite

To provide evidence for the protective role of inorganic nitrite against acute ischaemia and reperfusion-induced ventricular arrhythmias in a large animal model.. Dogs, anaesthetized with chloralose and urethane, were administered intravenously with sodium nitrite (0.2 µmol kg(-1) min(-1)) in two protocols. In protocol 1 nitrite was infused 10 min prior to and during a 25 min occlusion of the left anterior descending (LAD) coronary artery (NaNO2-PO; n = 14), whereas in protocol 2 the infusion was started 10 min prior to reperfusion of the occluded vessel (NaNO2-PR; n = 12). Control dogs (n = 15) were infused with saline and subjected to the same period of ischaemia and reperfusion. Severities of ischaemia and ventricular arrhythmias, as well as changes in plasma nitrate/nitrite (NOx) levels in the coronary sinus blood, were assessed throughout the experiment. Myocardial superoxide and nitrotyrosine (NT) levels were determined during reperfusion. Changes in protein S-nitrosylation (SNO) and S-glutathionylation were also examined.. Compared with controls, sodium nitrite administered either pre-occlusion or pre-reperfusion markedly suppressed the number and severity of ventricular arrhythmias during occlusion and increased survival (0% vs. 50 and 92%) upon reperfusion. There were also significant decreases in superoxide and NT levels in the nitrite treated dogs. Compared with controls, increased SNO was found only in NaNO2-PR dogs, whereas S-glutathionylation occurred primarily in NaNO2-PO dogs.. Intravenous infusion of nitrite profoundly reduced the severity of ventricular arrhythmias resulting from acute ischaemia and reperfusion in anaesthetized dogs. This effect, among several others, may result from an NO-mediated reduction in oxidative stress, perhaps through protein SNO and/or S-glutathionylation.

Topics: Administration, Intravenous; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Hemodynamics; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitrates; Nitric Oxide; Nitrites; Protein Processing, Post-Translational; Sodium Nitrite; Superoxides; Tyrosine

Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprotective and proangiogenic actions of a novel, sustained-release formulation of nitrite (SR-nitrite) in a clinically relevant in vivo swine model of critical limb ischemia (CLI) involving central obesity and metabolic syndrome. CLI was induced in obese Ossabaw swine (n = 18) by unilateral external iliac artery deployment of a full cross-sectional vessel occlusion device positioned within an endovascular expanded polytetrafluoroethylene-lined nitinol stent-graft. At post-CLI day 14, pigs were randomized to placebo (n = 9) or SR-nitrite (80 mg, n = 9) twice daily by mouth for 21 days. SR-nitrite therapy increased nitrite, nitrate, and S-nitrosothiol in plasma and ischemic skeletal muscle. Oxidative stress was reduced in ischemic limb tissue of SR-nitrite- compared with placebo-treated pigs. Ischemic limb tissue levels of proangiogenic growth factors were increased following SR-nitrite therapy compared with placebo. Despite the increases in cytoprotective and angiogenic signals with SR-nitrite therapy, new arterial vessel formation and enhancement of blood flow to the ischemic limb were not different from placebo. Our data clearly demonstrate cytoprotective and proangiogenic signaling in ischemic tissues following SR-nitrite therapy in a very severe model of CLI. Further studies evaluating longer-duration nitrite therapy and/or additional nitrite dosing strategies are warranted to more fully evaluate the therapeutic potential of nitrite therapy in peripheral vascular disease.

Topics: Angiogenesis Inducing Agents; Animals; Delayed-Action Preparations; Disease Models, Animal; Hindlimb; Iliac Artery; Ischemia; Metabolic Syndrome; Muscle, Skeletal; Neovascularization, Physiologic; Nitrates; Nitrites; Peripheral Arterial Disease; S-Nitrosothiols; Sodium Nitrite; Swine

Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg · kg(-1) · day(-1) bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.

Topics: Animals; Coronary Vessels; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Female; Heart Diseases; Male; Metabolic Syndrome; Myocardium; Nitric Oxide Synthase Type III; Obesity; Oxidation-Reduction; Oxidative Stress; Peripheral Vascular Diseases; Severity of Illness Index; Sodium Nitrite; Swine; Vasodilation

Hypertension is a common disease that includes oxidative stress as a major feature, and oxidative stress impairs physiological nitric oxide (NO) activity promoting cardiovascular pathophysiological mechanisms. While inorganic nitrite and nitrate are now recognized as relevant sources of NO after their bioactivation by enzymatic and non-enzymatic pathways, thus lowering blood pressure, mounting evidence suggests that sodium nitrite also exerts antioxidant effects. Here we show for the first time that sodium nitrite exerts consistent systemic and vascular antioxidant and antihypertensive effects in the deoxycorticosterone-salt (DOCA-salt) hypertension model. This is particularly important because increased oxidative stress plays a major role in the DOCA-salt hypertension model, which is less dependent on activation of the renin-angiotensin system than other hypertension models. Indeed, antihypertensive effects of oral nitrite were associated with increased plasma nitrite and nitrate concentrations, and completely blunted hypertension-induced increases in plasma 8-isoprostane and lipid peroxide levels, in vascular reactive oxygen species, in vascular NADPH oxidase activity, and in vascular xanthine oxidoreductase activity. Together, these findings provide evidence that the oral administration of sodium nitrite consistently decreases the blood pressure in association with major antioxidant effects in experimental hypertension.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Desoxycorticosterone; Dinoprost; Disease Models, Animal; Hypertension; Lipid Peroxides; Male; NADPH Oxidases; Nitrites; Nitrogen Oxides; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Sodium Nitrite; Xanthine Oxidase

Many effects of nitrite and nitrate are attributed to increased circulating concentrations of nitrite, ultimately converted into nitric oxide (NO(•)) in the circulation or in tissues by mechanisms associated with nitrite reductase activity. However, nitrite generates NO(•) , nitrous anhydride, and other nitrosating species at low pH, and these reactions promote S-nitrosothiol formation when nitrites are in the stomach. We hypothesized that the antihypertensive effects of orally administered nitrite or nitrate involve the formation of S-nitrosothiols, and that those effects depend on gastric pH. The chronic effects of oral nitrite or nitrate were studied in two-kidney, one-clip (2K1C) hypertensive rats treated with omeprazole (or vehicle). Oral nitrite lowered blood pressure and increased plasma S-nitrosothiol concentrations independently of circulating nitrite levels. Increasing gastric pH with omeprazole did not affect the increases in plasma nitrite and nitrate levels found after treatment with nitrite. However, treatment with omeprazole severely attenuated the increases in plasma S-nitrosothiol concentrations and completely blunted the antihypertensive effects of nitrite. Confirming these findings, very similar results were found with oral nitrate. To further confirm the role of gastric S-nitrosothiol formation, we studied the effects of oral nitrite in hypertensive rats treated with the glutathione synthase inhibitor buthionine sulfoximine (BSO) to induce partial thiol depletion. BSO treatment attenuated the increases in S-nitrosothiol concentrations and antihypertensive effects of oral nitrite. These data show that gastric S-nitrosothiol formation drives the antihypertensive effects of oral nitrite or nitrate and has major implications, particularly to patients taking proton pump inhibitors.

Topics: Animals; Antihypertensive Agents; Antioxidants; Disease Models, Animal; Free Radicals; Gastric Mucosa; Humans; Hypertension, Renovascular; Nitrites; Rats; S-Nitrosothiols; Sodium Nitrite

Chronic heart failure (CHF) reduces nitric oxide (NO) bioavailability and impairs skeletal muscle vascular control during exercise. Reduction of NO2 (-) to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O2 delivery. We tested the hypothesis that NO2 (-) infusion would increase exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats with a preferential effect in muscles composed primarily of type IIb + IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a >21-day recovery, mean arterial pressure (MAP; carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% incline) with and without NO2 (-) infusion. The myocardial infarct size (35 ± 3%) indicated moderate CHF. NO2 (-) infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1) and CHF + NO2 (-): 0.93 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1), P < 0.05) without changing MAP (CHF: 123 ± 4 mmHg and CHF + NO2 (-): 120 ± 4 mmHg, P = 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 ± 7 and CHF + NO2 (-): 109 ± 7 ml·min(-1)·100 g(-1) ml·min(-1)·100 g(-1), P > 0.05). BF increased in 6 (∼21%) and VC in 8 (∼29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO2 (-) infusion comprised ≥63% type IIb + IId/x muscle fibers. These data demonstrate that NO2 (-) infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO2 (-)-based therapy may provide an attractive "needs-based" approach for treatment of the vascular dysfunction in CHF.

Topics: Animals; Chronic Disease; Disease Models, Animal; Exercise Tolerance; Heart Failure; Hemodynamics; Hindlimb; Infusions, Intra-Arterial; Male; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Myocardial Infarction; Nitric Oxide; Physical Exertion; Rats, Sprague-Dawley; Regional Blood Flow; Sodium Nitrite; Time Factors

The cellular injury that occurs in the setting of hemorrhagic shock and resuscitation (HS/R) affects all tissue types and can drive altered inflammatory responses. Resuscitative adjuncts hold the promise of decreasing such injury. Here we test the hypothesis that sodium nitrite (NaNO2), delivered as a nebulized solution via an inhalational route, protects against injury and inflammation from HS/R.. Mice underwent HS/R to a mean arterial pressure (MAP) of 20 or 25 mmHg. Mice were resuscitated with Lactated Ringers after 90-120 min of hypotension. Mice were randomized to receive nebulized NaNO2 via a flow through chamber (30 mg in 5 mL PBS). Pigs (30-35 kg) were anesthetized and bled to a MAP of 30-40 mmHg for 90 min, randomized to receive NaNO2 (11 mg in 2.5 mL PBS) nebulized into the ventilator circuit starting 60 min into the hypotensive period, followed by initial resuscitation with Hextend. Pigs had ongoing resuscitation and support for up to four hours. Hemodynamic data were collected continuously.. NaNO2 limited organ injury and inflammation in murine hemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO2 significantly reversed this effect. Furthermore, NaNO2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO2 had no significant influence on shock induced hemodynamics. NaNO2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion.. NaNO2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury.

Topics: Administration, Inhalation; Animals; Blotting, Western; Disease Models, Animal; Mice; Mitochondria; Nebulizers and Vaporizers; Nitrites; Resuscitation; Shock, Hemorrhagic; Sodium Nitrite; Swine

Diabetes mellitus type 2 is a syndrome of disordered metabolism with inappropriate hyperglycemia owing to a reduction in the biological effectiveness of insulin. Type 2 diabetes is associated with an impaired nitric oxide (NO) pathway that probably serves as the key link between metabolic disorders and cardiovascular disease. Insulin-mediated translocation of GLUT4 involves the PI3K/Akt kinase signal cascade that results in activation of endothelial NO synthase (eNOS). eNOS is dysfunctional during diabetes. We hypothesize that loss of eNOS-derived NO terminates the signaling cascade and therefore cannot activate GLUT4 translocation and that dietary nitrite may repair this pathway. In this study, we administered 50mg/L sodium nitrite to db/db diabetic mice for 4 weeks. After 4 weeks treatment, the db/db mice experienced less weight gain, improved fasting glucose levels, and reduced insulin levels. Cell culture experiments using CHO-HIRc-myc-GLUT4eGFP cell lines stably expressing insulin receptor and myc-GLUT4eGFP protein, as well as L6 skeletal muscle cells stably expressing rat GLUT4 with a Myc epitope (L6-GLUT4myc), showed that NO, nitrite, and GSNO stimulate GLUT4 translocation independent of insulin, which is inhibited by NEM. Collectively our data suggest that nitrite improves insulin signaling through restoration of NO-dependent nitrosation of GLUT4 signaling translocation. These data suggest that NO-mediated nitrosation of GLUT4 by nitrite or other nitrosating agents is necessary and sufficient for GLUT4 translocation in target tissue. Description of this pathway may justify a high-nitrate/nitrite diet along with the glycemic index to provide a safe and nutritional regimen for the management and treatment of diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Ethylmaleimide; Gene Expression Regulation; Glucose Transporter Type 4; Humans; Male; Mice; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase Type III; Protein Transport; Proto-Oncogene Proteins c-myc; Rats; Receptor, Insulin; Signal Transduction; Sodium Nitrite

Nitrite has become a topic of interest in the field of medical research because of its potential therapeutic role as an alternative source of nitric oxide (NO). While the bioconversion of nitrite to NO occurs via either nonenzymatic or enzymatic reduction under acidic or hypoxic conditions, little is known about its conversion to NO under normoxic conditions. Because of a recent report of aldehyde dehydrogenase 2 (ALDH2)-catalyzed glyceryl trinitrate (GTN) vasorelaxation by denitration of GTN to 1,2-glyceryl dinitrate (1,2-GDN) and nitrite, we therefore investigated a catalytic activity of ALDH2 for nitrite reduction and subsequent effect on N(ω)-nitro-l-arginine methyl ester (l-NAME)-induced hypertension in normoxic rat. Male Sprague-Dawley rats treated with l-NAME in drinking water for 3 weeks developed hypertension with significantly reduced plasma levels of nitrite and nitrate. The intravenous injection of sodium nitrite lowered the arterial pressure in a dose-dependent manner (17, 50 and 150 μmol/kg). Pretreatment with ALDH2 inhibitors (cyanamide and chloral hydrate) partially inhibited the hypotensive responses to sodium nitrite. In addition, cyanamide significantly delayed the nitrite clearance from plasma and most of the organs examined during the experimental period. These results suggest that ALDH2 may be at least in part involved in nitrite-mediated hypotensive effects and nitrite catalysis in many organs of normoxic rats.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hydrazines; Hypertension; Male; Mitochondrial Proteins; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitroglycerin; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Time Factors

Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.. No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.. Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.. These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.

Topics: Aged; Animals; Biological Availability; Cyclic GMP; Cytoprotection; Disease Models, Animal; Female; Heart Failure; Hemodynamics; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Middle Aged; Nitric Oxide; Signal Transduction; Sodium Nitrite; Stroke Volume; Ventricular Dysfunction, Left

Nitrite-derived nitric oxide (NO) formation exerts antihypertensive effects. Because NO inhibits angiotensin converting enzyme (ACE) activity, we carried a comprehensive series of experiments in rats to test the hypothesis that sodium nitrite exerts antihypertensive effects by inhibiting ACE. We examined whether sodium nitrite (15 mg/kg; or vehicle; by gavage): (I) attenuates the pressor responses to angiotensin I at doses of 0.03, 0.1, 0.3, 1, 3, and 10 μg/kg intravenously; (II) attenuates the acute hypertension induced by L-NAME (100 mg/kg; or vehicle; by gavage); (III) attenuates the chronic hypertension induced by L-NAME (1 g/L in drinking water; or vehicle) administered for 6 weeks; (IV) attenuates the hypertension in the 2 kidney-1 clip (2K1C) chronic hypertension model. Blood samples were collected at the end of each study and plasma angiotensin converting enzyme (ACE) activity was measured with a fluorimetric assay using Hippuryl-His-Leu as substrate. ACE inhibitors were used as positive controls. Plasma nitrite concentrations were measured by ozone-based reductive chemiluminescence. The in vitro effects of sodium nitrite (0, 1, 3, 10, 30, 100 μmol/L) on plasma ACE activity were also determined. We found that sodium nitrite did not affect the pressor responses to angiotensin I. Moreover, while sodium nitrite exerted significant antihypertensive effects in acute and chronic hypertension models, no significant effects on plasma ACE activity were found. In vitro experiments showed no effects of sodium nitrite on plasma ACE activity. This is the first study to demonstrate that the acute and chronic antihypertensive effects of sodium nitrite are not associated with significant inhibition of circulating ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Male; NG-Nitroarginine Methyl Ester; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Sodium Nitrite; Structure-Activity Relationship

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

Glycine, pyruvate, resveratrol, and nitrite are well-known protective compounds among others in ischemic tissue injury. Here, we compared their effects in acute lipopolysaccharide (LPS)-induced shock in rats to assess whether inhibition of the proinflammatory cytokine response is a prerequisite for their protective actions.. Rats (six or eight per group) were anesthetized, received LPS as an intravenous bolus (2.5 mg/kg), and were observed for 5 h. Glycine, sodium pyruvate, resveratrol, and sodium nitrite were continuously infused starting 30 min before LPS administration. Parameters included histopathologic changes, organ-specific cytokine levels, plasma nitrite and nitrate concentrations, and time courses of biomonitoring parameters, marker enzyme activities, and plasma cytokine concentrations.. Glycine, pyruvate, resveratrol, and nitrite enhanced arterial blood pressure after LPS-induced shock. Also, parameters reflecting tissue ischemia were significantly improved and plasma markers of organ injury ameliorated by all substances. Of the plasma cytokine concentrations increased by LPS, some were differently decreased or even further increased by the substances. None of them reduced the elevated plasma nitrite and nitrate concentration. Glycine diminished the increases in tissue cytokine levels organ specifically, pyruvate decreased some cytokine concentrations in all organs, and nitrite significantly affected only a few cytokine concentrations in some organs, whereas the levels of many cytokines were raised by resveratrol. All substances except resveratrol decreased granulocyte infiltrates in the liver.. The present results demonstrate that glycine, pyruvate, resveratrol, and nitrite protect against LPS-induced shock and tissue injury (cell death) in rats and suggest that inhibition of the proinflammatory cytokine response is not mandatory for their protective actions.

Topics: Animals; Blood Gas Analysis; Blood Pressure; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Electrolytes; Endotoxemia; Glycine; Hematocrit; Hemoglobins; Lipopolysaccharides; Male; Pyruvic Acid; Rats; Rats, Wistar; Resveratrol; Sodium Nitrite; Stilbenes

Red and processed meat consumption is associated with the risk of colorectal cancer. Three hypotheses are proposed to explain this association, via heme-induced oxidation of fat, heterocyclic amines, or N-nitroso compounds. Rats have often been used to study these hypotheses, but the lack of enterosalivary cycle of nitrate in rats casts doubt on the relevance of this animal model to predict nitroso- and heme-associated human colon carcinogenesis. The present study was thus designed to clarify whether a nitrite intake that mimics the enterosalivary cycle can modulate heme-induced nitrosation and fat peroxidation. This study shows that, in contrast with the starting hypothesis, drinking water added with nitrite to mimic the salivary nitrite content did not change the effect of hemoglobin on biochemical markers linked to colon carcinogenesis, notably lipid peroxidation and cytotoxic activity in the colon of rat. However, ingested sodium nitrite increased fecal nitroso-compounds level, but their fecal concentration and their nature (iron-nitrosyl) would probably not be associated with an increased risk of cancer. We thus suggest that the rat model could be relevant for study the effect of red meat on colon carcinogenesis, in spite of the lack of nitrite in the saliva of rats.

Topics: Acetylcysteine; Animals; Biomarkers; Body Weight; Colonic Neoplasms; Disease Models, Animal; Drinking Water; Eating; Feces; Heme; Lipid Peroxidation; Male; Meat; Nitrites; Nitroso Compounds; Rats, Inbred F344; Saliva; Sodium Nitrite; Thiobarbituric Acid Reactive Substances

Exposure to high levels of nitrites for a prolonged time have adverse health effects on several organs especially the liver due to oxidative properties. Meanwhile, cod liver oil has been reported to ameliorate organ dysfunction in animal models that involve oxidative stress.. Examine the impact of dietary cod liver oil on sodium nitrite-induced liver damage.. Thirty-two adult male Sprague-Dawely rats were daily treated with sodium nitrite (80 mg/kg) in presence or absence of cod liver oil (5 ml/kg). Morphological changes were assessed in liver sections. Oxidative stress and antioxidant markers were measured in serum and liver homogenates. Liver samples were used for measurements of MCP-1, DNA fragmentation and mitochondrial function.. The hepatoprotective effect of cod liver oil was proved by significant reduction of elevated liver enzymes and normal appearance of hepatocytes. Cod liver oil significantly reduced hepatic malondialdehyde, hydrogen peroxide and superoxide anion (224.3 ± 18.9 nmol/g, 59.3 ± 5.1 and 62.5 ± 5.1 µmol/g, respectively) compared with sodium nitrite (332.5 ± 25.5 nmol/g, 83.1 ± 8.1 and 93.9 ± 6.5 µmol/g, respectively). Cod liver oil restored hepatic cytochrome c oxidase activity after 38% reduction by sodium nitrite. Furthermore, cod liver oil significantly reduced hepatic MCP-1 (79.8 pg/mg) and DNA fragmentation (13.8%) compared with sodium nitrite (168.7 pg/mg and 41.3%, respectively).. Cod liver oil ameliorates sodium nitrite induced hepatic impairment through several mechanisms including attenuation of oxidative stress, blocking MCP-1, reactivation of mitochondrial function and reduction of DNA fragmentation.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Chemokine CCL2; Cod Liver Oil; Cytochromes c; Cytoprotection; Disease Models, Animal; DNA Fragmentation; Hydrogen Peroxide; Liver; Male; Malondialdehyde; Mitochondria, Liver; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Superoxides

The aim of the study was to isolate the harmine alkaloids from the seeds of Peganum harmala (TAPH) and its cerebroprotective effect on cognitive deficit mice. The tested doses of TAPH were screened for Sodium nitrite induced hypoxia and Ethanol induced neurodegeneration using behavioral models. The TAPH was found to be non-neurotoxic and Psychoactive by preventing the motor impairment and increasing the locomotion activity of animals in Rota rod and Actophotometer respectively. TAPH (5, 2.5 and 1.25 mg kg(-1) p.o.) significantly (p < 0.001) protected the Sodium nitrite induced memory impairment by decreasing the time require to find the water bottle in special water bottle case model. In Elevated Plus Maze (EPM) and Passive Shock Avoidance paradigm (PSA) the TAPH shown improved acquisition and retention memory significantly (p < 0.001) by decreasing the Transverse Latency Time (TLT) and increasing the Step Down Latency (SDL), respectively in dose dependent manner. The results were well supported by biochemical parameters, by inhibiting the Acetylcholinestrase (p < 0.01) activity, increasing the GSH (p < 0.001) level and decreasing the TBARS (p < 0.001) level of whole brain. Moreover TAPH has shown the significant Monoamine oxidase-A (MAO-A) inhibition action (p < 0.001), hence it reduces the metabolism of epinephrine, 5-HT and other monoamines and enhances the action of these neurotransmitters indirectly; this adrenergic system plays an important role in learning and memory. Further, TAPH (5 mg kg(-1)) protect the DNA fragmentation of frontotemporal cortex of the brain from hypoxic effect induced by Sodium nitrite in Gel Electrophoresis studies. The results were comparable to their respective standards. Hence, harmine alkaloids are potential enough to utilize in the management of Neurodegenerative disorders of the type Alzheimer's diseases.

Topics: Acetylcholinesterase; Animals; Apoptosis; Behavior, Animal; Brain; Cognition; Cognition Disorders; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Glutathione; GPI-Linked Proteins; Harmine; Hypoxia, Brain; Male; Mice; Monoamine Oxidase; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Peganum; Phytotherapy; Plant Extracts; Plants, Medicinal; Reaction Time; Seeds; Sodium Nitrite; Thiobarbituric Acid Reactive Substances; Time Factors

There is a strong male predominance of oesophageal adenocarcinoma, which might be related to the higher prevalence of precursor lesions such as erosive reflux oesophagitis in men compared with women. This experiment investigated the gender difference in a reflux oesophagitis model of rats and explored the potential role of oestrogen in controlling oesophageal tissue damage.. An acid-reflux oesophagitis model was surgically produced in male and female rats, and ascorbic acid in the diet and sodium nitrite in the drinking water were administered to half of either group to provoke luminal exogenous nitric oxide (NO) as an exacerbating agent. Seven days after the surgery, the oesophagus was excised, and the injury area, myeloperoxidase activity and pro-inflammatory cytokine levels were measured. Furthermore, 17β-oestradiol was administered to ovariectomised female rats or male rats, which then underwent reflux oesophagitis surgery.. While there was no gender difference in oesophageal damage in the baseline model, oesophageal damage was more intensively observed in males than in females in the presence of exogenous NO administration. While oesophageal damage was increased in ovariectomised rats compared with sham ovariectomised, exacerbated oesophageal damage was attenuated by the replacement of 17β-oestradiol. In addition, exacerbated oesophageal damage in male rats was suppressed by 17β-oestradiol.. This is the first study showing the prominent gender difference in the severity of oesophageal tissue damage in a gastro-oesophageal reflux disease-related animal model, highlighting the critical involvement of oestrogen in controlling gastro-oesophageal reflux disease-related oesophageal epithelial injury.

Topics: Animals; Ascorbic Acid; Biomarkers; Chronic Disease; Cytokines; Disease Models, Animal; Esophagitis, Peptic; Esophagus; Estradiol; Estrogens; Female; Gastroesophageal Reflux; Male; Mucous Membrane; Nitric Oxide; Ovariectomy; Peroxidase; Random Allocation; Rats; Rats, Wistar; Severity of Illness Index; Sex Factors; Sodium Nitrite; Stomach

Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N(2)O(3); harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO(2)) with HBOC-201 were investigated.. Swine underwent uncontrolled liver haemorrhage before receiving up to three 10min 10ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO(2) (5.4μmol/kg [LD NaNO(2)] or 10.8μmol/kg [HD NaNO(2)]) or 6% Hetastarch (HEX) with or without HD NaNO(2) during "prehospital" resuscitation (15, 30 and 45min after injury). Definitive surgical care occurred at 75min; anaesthetic recovery at 120min. Animals were euthanised at 72h.. NaNO(2) temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC+HD NaNO(2) (3 of 4 pigs) and HBOC+LD NaNO(2) (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO(2) combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX+NaNO(2). Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC+HD NaNO(2) pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder.. A significant interaction between NaNO(2) and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO(2) was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO(2) in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO(2) and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.

Topics: Animals; Blood Substitutes; Disease Models, Animal; Dose-Response Relationship, Drug; Hemoglobins; Hemostasis; Resuscitation; Shock, Hemorrhagic; Sodium Nitrite; Swine; Time Factors; Vasoconstriction

Dietary nitrite and nitrate have been reported as alternative sources of nitric oxide (NO). In this regard, we reported previously that sodium nitrite added to drinking water was able to exert antihypertensive effects in an experimental model of hypertension in a dose-dependent manner. Taking into consideration that nitrite is continuously converted to nitrate in the bloodstream, here we expanded our previous report and evaluate whether a single daily dose of sodium nitrite could exert antihypertensive effects in 2 kidney-1 clip (2K1C) hypertensive rats. Sham-operated and 2K1C rats were treated with vehicle or sodium nitrite (15 mg/kg/day) for 4 weeks. We evaluated the effects induced by sodium nitrite treatment on systolic blood pressure (SBP) and NO markers such as plasma nitrite, nitrite + nitrate (NOx), cGMP, and blood levels of nitrosyl-hemoglobin. In addition, we also evaluated effects of nitrite on oxidative stress and antioxidant enzymes. Dihydroethidium (DHE) was used to evaluate aortic reactive oxygen species (ROS) production by fluorescence microscopy, and plasma levels of thiobarbituric acid-reactive species (TBARS) were measured in plasma samples from all experimental groups. Red blood cell superoxide dismutase (SOD) and catalase activity were evaluated with commercial kits. Sodium nitrite treatment reduced SBP in 2K1C rats (P < 0.05). We found lower plasma nitrite and NOx levels in 2K1C rats compared with normotensive controls (both P < 0.05). Nitrite treatment restored the lower levels of nitrite and NOx. While no change was found in the blood levels of nitrosyl-hemoglobin (P > 0.05), nitrite treatment increased the plasma levels of cGMP in 2K1C rats (P < 0.05). Higher plasma TBARS levels and aortic ROS levels were found in hypertensive rats compared with controls (P < 0.05), and nitrite blunted these alterations. Lower SOD and catalase activities were found in 2K1C hypertensive rats compared with controls (both P < 0.05). Nitrite treatment restored SOD activity (P < 0.05), whereas catalase was not affected. These data suggest that even a single daily oral dose of sodium nitrite is able to lower SBP and exert antioxidant effects in renovascular hypertension.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Catalase; Cyclic GMP; Disease Models, Animal; Hemoglobins; Hypertension, Renovascular; Male; Nitrates; Nitrites; Oxidative Stress; Rats; Rats, Wistar; Sodium Nitrite; Superoxide Dismutase

The aim of this study was to investigate the protective effects of N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide (FLZ), a synthetic squamosamide cyclic derivative, on senescent mice induced by D: -galactose/NaNO(2) (120/90 mg/kg, i.p.) once daily for 60 days. FLZ (75 and 150 mg/kg) was orally administered once daily for 30 days after D: -galactose/NaNO(2) treatment for 30 days. The cognitive function of mice was evaluated with step-down task. The brain biomarkers including monoamine oxidase B (MAO-B), glutathione peroxidase (GSH-px), and malondialdehyde (MDA) were determined according to the manufacturer's instructions. The expression of acetylcholinesterase (ACh-E) and choline acetyltransferase (ChAT) protein in the CA1 region of hippocampus were counted by immunohistochemical staining. The results showed that the cognitive function, GSH-px activity in the brain, and the expression of ACh-E and ChAT in the CA1 region of hippocampus were significantly decreased, while MAO-B activity and MDA level in the brain were increased in senescent mice compared with the control mice. FLZ treatment prolonged the step-down latency and decreased the number of step-down errors in the senescent mice. In addition, FLZ treatment increased the GSH-px activity and the expression of ACh-E and ChAT in the hippocampus and decreased the MDA level and MAO-B activity compared with the senescent mice without drug administration. These findings suggested that FLZ improves the performance in the step-down task and the pathological alternations in senescent mice.

Topics: Aging; Animals; Avoidance Learning; Benzeneacetamides; Brain; Disease Models, Animal; Galactose; Glutathione Peroxidase; Male; Malondialdehyde; Memory Disorders; Mice; Mice, Inbred ICR; Monoamine Oxidase; Neurons; Neuroprotective Agents; Phenols; 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

Sodium nitrite (NaNO(2)) was evaluated in a 55% EBV hemorrhage swine model to mitigate the increased blood pressure due to HBOC-201. Animals were resuscitated by three 10 ml/kg infusions of either HBOC-201 or Hextend with and without NaNO(2). All vital signs, coagulation and blood chemistry were measured for 2 hr. HBOC-201-vasoconstriction was attenuated only after the first 10.8 μmol/kg NaNO(2) infusion. Complete abolition was obtained with the highest 3 NaNO(2) dose, but side effects were observed. There was no reduction in platelet function due to NaNO(2). NaNO(2) ability to reduce HBOC-201 vasoactivity was transient and 10.8 μmol/kg NaNO(2) seems an acceptable dose for further investigation.

Topics: Animals; Blood Pressure; Blood Vessels; Blood Volume; Disease Models, Animal; Dose-Response Relationship, Drug; Hemoglobins; Hemorrhage; Hemostasis; Resuscitation; Sodium Nitrite; Swine; Vital Signs

Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO(2)) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO(2) can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established.. Subarachnoid hemorrhage-induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO(2) infusion at 300 μg/kg/hr for 3 hours [7 monkeys] or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF.. Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% ± 8.8% [mean ± SD]; treatment, 45.5% ± 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO(2) infusion significantly reduced the degree of vasospasm (26.9% ± 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 ± 2.1 μmol/L), nitrate (18.2 ± 5.3 μmol/L), and S-nitrosothiols (33.4 ± 11.4 nmol/L) increased significantly in whole blood, and nitrite increased significantly in CSF.. These findings indicate that the intravenous infusion of NaNO(2) can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH.

Topics: Animals; Cerebral Angiography; Disease Models, Animal; Infusions, Intravenous; Macaca fascicularis; Middle Cerebral Artery; Nitrates; Nitric Oxide; Nitrites; S-Nitrosothiols; Sodium Nitrite; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Cyanide can cause severe hypotension with acute toxicity. To our knowledge, no study has directly compared hydroxocobalamin and sodium nitrite with sodium thiosulfate in an acute cyanide toxicity model. Our objective is to compare the return to baseline of mean arterial blood pressure between 2 groups of swine with acute cyanide toxicity and treated with hydroxocobalamin with sodium thiosulfate or sodium nitrite with sodium thiosulfate.. Twenty-four swine were intubated, anesthetized, and instrumented (continuous arterial and cardiac output monitoring) and then intoxicated with a continuous cyanide infusion until severe hypotension. The animals were divided into 2 arms of 12 each and then randomly assigned to intravenous hydroxocobalamin (150 mg/kg)+sodium thiosulfate (413 mg/kg) or sodium nitrite (10 mg/kg)+sodium thiosulfate (413 mg/kg) and monitored for 40 minutes after start of antidotal infusion. Twenty animals were needed for 80% power to detect a significant difference in outcomes (alpha 0.05). Repeated measures of analysis of covariance and post hoc t test were used for determining significance.. Baseline mean weights, time to hypotension (31 minutes 3 seconds versus 28 minutes 6 seconds), and cyanide dose at hypotension (5.6 versus 5.9 mg/kg) were similar. One animal in the hydroxocobalamin group and 2 animals in the sodium nitrite group died during antidote infusion and were excluded from analysis. Hydroxocobalamin resulted in a faster return to baseline mean arterial pressure, with improvement beginning at 5 minutes and lasting through the conclusion of the study (P<.05). No statistically significant difference was detected between groups for cardiac output, pulse rate, systemic vascular resistance, or mortality at 40 minutes post intoxication. Mean cyanide blood levels (4.03 versus 4.05 microg/mL) and lactate levels (peak 7.9 versus 8.1 mmol/L) at hypotension were similar. Lactate levels (5.1 versus 4.48 mmol/L), pH (7.40 versus 7.37), and base excess (-0.75 versus 1.27) at 40 minutes were also similar.. Hydroxocobalamin with sodium thiosulfate led to a faster return to baseline mean arterial pressure compared with sodium nitrite with sodium thiosulfate; however, there was no difference between the antidote combinations in mortality, serum acidosis, or serum lactate.

Topics: Acidosis; Animals; Antidotes; Blood Pressure; Cyanides; Disease Models, Animal; Drug Therapy, Combination; Female; Hydroxocobalamin; Hypotension; Lactates; Male; Monitoring, Physiologic; Sodium Nitrite; Sus scrofa; Thiosulfates; Time Factors

Sodium nitrite is widely recognized to be a highly effective NO donor for the treatment of several ischemic tissue disorders. However, mechanisms by which nitrite confers cytoprotection during ischemic disorders remain largely unknown. In this study, we used genome expression profiling approaches to evaluate changes in gene expression in the hind-limb ischemia model using vehicle or sodium nitrite therapy. Sodium nitrite significantly restored ischemic tissue perfusion by day 3 post-ligation which returned to normal by day 7. Genesifter analysis of Affymetrix GeneChip data revealed a significant down-regulation of gene expression profiles at day 3, whereas gene expression profiles were predominantly up-regulated at day 7. Ingenuity network analysis of gene expression profiles at day 3 showed a strong decrease in gene expression from networks associated with immune functions such as acute inflammatory responses, antigen presentation, and humoral immune responses while networks containing increased gene expression profiles were associated with cardiovascular, skeletal, and muscle system development and function. Network analysis of day 7 gene array data revealed predominant up-regulation of genes associated with cell survival, tissue morphology, connective tissue function, skeletal and muscular system development, and lymphoid tissue structure and development. These data suggest that sodium nitrite elicits potent anti-inflammatory and pro-angiogenic gene responses at early time points which is later followed by up-regulation of genes associated with tissue repair and homeostasis.

Topics: Animals; Chronic Disease; Disease Models, Animal; Gene Expression Profiling; Gene Regulatory Networks; Ischemia; Male; Mice; Mice, Inbred C57BL; 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

Exposure of the esophageal mucosa to refluxed gastroduodenal contents is recognized to be an important risk factor for Barrett's esophagus (BE). At the human gastroesophageal junction, nitric oxide is generated luminally through the enterosalivary recirculation of dietary nitrate, and in cases with gastroesophageal reflux, the site of luminal nitric oxide generation could shift to the distal esophagus. The aim of this study is to investigate whether exogenous luminal nitric oxide could promote the development of BE in rats. Sodium nitrite plus ascorbic acid were administered to a rat surgical model of BE, in which the gastroduodenal contents were refluxed into the esophagus to generate exogenous luminal nitric oxide in the esophagus by the acid-catalyzed chemical reaction between the 2 reagents. The emergence of BE was evaluated histologically in the early phase (several weeks) after the surgery with or without exogenous nitric oxide administration. To elucidate the histogenesis of BE, CDX2, MUC2 and MUC6 expressions were investigated immunohistochemically. Coadministration of sodium nitrite plus ascorbic acid significantly accelerated the timing of emergence and increased the area of BE compared with controls. Administration of either reagent alone did not show any promotive effects on BE formation. Immunohistochemically, the columnar epithelium thus induced was similar to the specialized intestinal metaplasia in human BE. The results of this animal model study suggest that exogenous luminal nitric oxide could be involved in the pathogenesis of the columnar transformation of the esophagus. Further studies in human are warranted.

Topics: Animals; Ascorbic Acid; Barrett Esophagus; Disease Models, Animal; Esophagitis; Gastroesophageal Reflux; Nitric Oxide; Random Allocation; Rats; Sodium Nitrite

Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the intestinal tract with excessive production of cytokines, adhesion molecules, and reactive oxygen species. Although nitric oxide (NO) is reported to be involved in the onset and progression of IBDs, it remains controversial as to whether NO is toxic or protective in experimental colitis. We investigated the effects of oral nitrite as a NO donor on dextran sulfate sodium (DSS)-induced acute colitis in mice. Mice were fed DSS in their drinking water with or without nitrite for up to 7days. The severity of colitis was assessed by disease activity index (DAI) observed over the experimental period, as well as by the other parameters, including colon lengths, hematocrit levels, and histological scores at day 7. DSS treatment induced severe colitis by day 7 with exacerbation in DAI and histological scores. We first observed a significant decrease in colonic nitrite levels and increase in colonic TNF-alpha expression at day 3 after DSS treatment, followed by increased colonic myeloperoxidase (MPO) activity and increased colonic expressions of both inducible NO synthase (iNOS) and heme oxygenase-1 (HO-1) at day 7. Oral nitrite supplementation to colitis mice reversed colonic nitrite levels and TNF-alpha expression to that of normal control mice at day 3, resulting in the reduction of MPO activity as well as iNOS and HO-1 expressions in colonic tissues with clinical and histological improvements at day 7. These results suggest that oral nitrite inhibits inflammatory process of DSS-induced experimental colitis by supplying nitrite-derived NO instead of impaired colonic NOS activity.

Topics: Analysis of Variance; Animals; Blood Pressure; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Heart Rate; Hematocrit; Heme Oxygenase-1; Histocytochemistry; Male; Methemoglobin; Mice; Mice, Inbred ICR; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Sodium Nitrite; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha

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

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.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Male; Memantine; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sodium Nitrite; Stroke

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

The nitrite anion is an endogenous product of mammalian nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants, and a constituent of many foods. Research over the past 6 years has revealed surprising biological and cytoprotective activity of this anion. Hypercholesterolemia causes a proinflammatory phenotype in the microcirculation. This phenotype appears to result from a decline in NO bioavailability that results from a reduction in NO biosynthesis, inactivation of NO by superoxide, or both. Since nitrite has been shown to be potently cytoprotective and restore NO biochemical homeostasis, we investigated if supplemental nitrite could attenuate microvascular inflammation caused by a high cholesterol diet. C57Bl/6J mice were fed either a normal diet or a high cholesterol diet for 3 wk to induce microvascular inflammation. Mice on the high cholesterol diet received either nitrite-free drinking water or supplemental nitrite at 33 or 99 mg/l ad libitum in their drinking water. The results from this investigation reveal that mice fed a cholesterol-enriched diet exhibited significantly elevated leukocyte adhesion to and emigration through the venular endothelium as well as impaired endothelium-dependent relaxation in arterioles. Administration of nitrite in the drinking water inhibited the leukocyte adhesion and emigration and prevented the arteriolar dysfunction. This was associated with sparing of reduced tetrahydrobiopterin and decreased levels of C-reactive protein. These data reveal novel anti-inflammatory properties of nitrite and implicate the use of nitrite as a new natural therapy for microvascular inflammation and endothelial dysfunction associated with hypercholesterolemia.

Topics: Animals; Anti-Inflammatory Agents; Biopterins; Blood Pressure; C-Reactive Protein; Cholesterol, Dietary; Diet; Disease Models, Animal; Endothelium, Vascular; Hypercholesterolemia; Inflammation; Leukocyte Rolling; Liver; Male; Mice; Mice, Inbred C57BL; Microvessels; Myocardium; Nitric Oxide; Sodium Nitrite; Triglycerides; Vasodilation; Vasodilator Agents

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

Hypertension secondary to scavenging of NO remains a limitation in the use of HBOCs (haemoglobin-based oxygen carriers). Recent studies suggest that nitrite reduction to NO by deoxyhaemoglobin supports NO signalling. In the present study we tested whether nitrite would attenuate HBOC-mediated hypertension using HBOC-201 (Biopure), a bovine cross-linked, low-oxygen-affinity haemoglobin. In a similar way to unmodified haemoglobin, deoxygenated HBOC-201 reduced nitrite to NO with rates directly proportional to the extent of deoxygenation. The functional importance of HBOC-201-dependent nitrite reduction was demonstrated using isolated aortic rings and a murine model of trauma, haemorrhage and resuscitation. In the former, HBOC-201 inhibited NO-donor and nitrite-dependent vasodilation when oxygenated. However, deoxygenated HBOC-201 failed to affect nitrite-dependent vasodilation but still inhibited NO-donor dependent vasodilation, consistent with a model in which nitrite-reduction by deoxyHBOC-201 counters NO scavenging. Finally, resuscitation using HBOC-201, after trauma and haemorrhage, resulted in mild hypertension ( approximately 5-10 mmHg). Administration of a single bolus nitrite (30-100 nmol) at the onset of HBOC-201 resuscitation prevented hypertension. Nitrite had no effect on mean arterial pressure during resuscitation with LR (lactated Ringer's solution), suggesting a role for nitrite-HBOC reactions in attenuating HBOC-mediated hypertension. Taken together these data support the concept that nitrite can be used as an adjunct therapy to prevent HBOC-dependent hypertension.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Substitutes; Disease Models, Animal; Hemoglobins; Hypertension; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Donors; Nitrite Reductases; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Vasodilation

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.

Topics: Animals; Arteries; Cyclic N-Oxides; Cytoprotection; Disease Models, Animal; Endothelium, Vascular; Free Radical Scavengers; Hindlimb; Imidazoles; Ischemia; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nitric Oxide; Peripheral Vascular Diseases; Sodium Nitrite

Acute pulmonary embolism produces acute pulmonary hypertension, which can be counteracted by activating the nitric oxide-cyclic guanosine 3',5'-monophosphate (cGMP) pathway. While previous studies have shown that sildenafil (an inhibitor of cGMP-specific phosphodiesterase type 5) or nitrite (a storage molecule for nitric oxide) produces beneficial effects during acute pulmonary embolism, no previous study has examined whether the combination of these drugs can produce additive effects. Here, we expand previous findings and examine whether sildenafil enhances the beneficial haemodynamic effects produced by a low-dose infusion of nitrite in a dog model of acute pulmonary embolism. Haemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with saline (n = 4), and in embolized dogs (intravenous injections of microspheres) that received nitrite (6.75 micromol/kg intravenously over 15 min. followed by 0.28 micromol/kg/min.) and sildenafil (0.25 mg/kg over 30 min.; n = 8), or nitrite followed by saline (n = 8), or saline followed by sildenafil (n = 7), or only saline (n = 8). Plasma thiobarbituric acid-reactive substances (TBARS) concentrations were determined using a fluorometric method. Acute pulmonary embolism increased pulmonary artery pressure by approximately 24 mmHg. While the infusion of nitrite or sildenafil infusions reversed this increase by approximately 42% (both P < 0.05), the combined infusion of both drugs reversed this increase by approximately 58% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance index. Nitrite or sildenafil alone produced no significant hypotension. However, the combined infusion of both drugs caused transient hypotension (P < 0.05). Both drugs, either alone or combined, blunted the increase in TBARS concentrations caused by acute pulmonary embolism (all P < 0.05). These results suggest that sildenafil improves the beneficial haemodynamic effects of nitrite during acute pulmonary embolism.

Topics: Acute Disease; Animals; Blood Pressure; Disease Models, Animal; Dogs; Drug Synergism; Drug Therapy, Combination; Female; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Lipid Peroxides; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sodium Nitrite; Sulfones; Vascular Resistance

To investigate the mechanisms of Naoyikang (Traditional Chinese Medicine) on the Alzheimer's Disease (AD) model mice induced by D-galactose (D-gal) and NaNO2.. The mouse model was established by intraperitoneal injection of D-gal and NaNO2. The capacity of learning and memory was tested on mice with electrical maze; the content of nitric oxide (NO) and the activity of monoamine oxidase-B (MAO-B), glutathione peroxidase (GSH-PX), Na(+) -K(+) -ATP enzyme and Ca(2+) -ATP enzyme in cerebral cortex and hippocampus were assayed by biochemical methods; expression of Bax and Bcl-2 mRNA was detested by RT-PCR.. Naoyikang could ameliorate the capacity of learning and memory of AD model mice and reduce MAO-B activity in the brain tissue and activate the activity of Na(+) -K(+) -ATP enzyme and Ca(2+) -ATP enzyme in the brain tissue and decrease the expression of Bax mRNA, but increase the expression of Bcl-2 mRNA in the model brain tissue.. Naoyikang could protect AD model mice induced by D-gal and NaNO2. It could modify the metabolism of monoamine neurotransmitter in brain through reducing MAO-B activity and protect neurons by activating the activity of Na(+) -K(+) -ATP enzyme and Ca(2+) -ATP enzyme and decrease Bax expression and increase Bcl-2 expression in the model brain tissue.

Topics: Alzheimer Disease; Animals; bcl-2-Associated X Protein; Disease Models, Animal; Drugs, Chinese Herbal; Female; Galactose; Male; Maze Learning; Mice; Mice, Inbred ICR; Neuroprotective Agents; Phytotherapy; Random Allocation; RNA, Messenger; Sodium Nitrite; Sodium-Potassium-Exchanging ATPase

Combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) has already been shown to promote rat forestomach carcinogenesis, possibly due to nitric oxide generation under acidic conditions. We hypothesized that a similar effect might occur in the esophagus when the luminal pH is decreased by acid reflux. To clarify this possibility, reflux esophagitis model rats (F344 male) were coadministered 0.2% NaNO2 in the drinking water and 1% AsA in the diet. After 32 weeks of the combined treatment, a significant increase in the incidence of epithelial hyperplasias of the lower-middle and lowest parts of the esophagus were observed compared with the basal-diet group, along with exacerbation of dysplasia and extension of the lesions. Additionally, one squamous cell papilloma was found only in the combined-treatment group. Subsequently, we confirmed the enhancing effects of NaNO2 and AsA cotreatment in the rat N-bis(2-hydroxypropyl)nitrosamine-initiated esophageal tumorigenesis model. The incidence of hyperplasia was enhanced in all segments, along with the incidence and multiplicity of squamous cell papillomas in the lowest segment of the esophagus. Thus, the data demonstrate that combined treatment with NaNO2 and AsA exerts promoting effects on rat esophageal carcinogenesis under acid reflux conditions, as in the forestomach. These findings suggest that the risk of excessive intake of a combination of nitrite and antioxidants for esophageal carcinogenesis is appreciable, particularly in patients with reflux esophagitis.

Topics: Animals; Antioxidants; Ascorbic Acid; Carcinoma, Squamous Cell; Cocarcinogenesis; Disease Models, Animal; Esophageal Neoplasms; Esophagitis, Peptic; Food Preservatives; Male; Rats; Rats, Inbred F344; Sodium Nitrite

Combination treatment with sodium nitrite (NaNO(2)) and ascorbic acid (AsA) is well known to promote forestomach carcinogenesis in rats and weakly enhance esophageal carcinogenesis under acid reflux conditions. Nitric oxide generation and oxidative DNA damage are considered to be related to the enhancement of carcinogenesis. The purpose of the present study was to investigate whether oxidative DNA damage-associated genotoxicity and tumor initiating potential are involved in the carcinogenesis. In the bacterial reverse mutation assay using Escherichia coli deficient in the mutM gene encoding 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase, the combination with NaNO(2) and AsA increased the mutation frequency dramatically, slight increase being evident in the parental strain. In vivo, a significant increase in 8-OHdG levels in the rat forestomach epithelium occurred at 24 h after combined treatment. Six-week-old F344 male rats were given drinking water containing 0.2% NaNO(2) and a diet supplemented with 1% AsA in combination, or the chemicals individually or basal diet alone for 12 weeks. After an interval of 2 weeks, they received 1% butylated hydroxyanisole in the diet for promotion until the end of weeks 52 and 78. Although one squamous cell carcinoma was observed in the combined group, there was no significant variation in tumor development among the groups. The study indicated that the combination of NaNO(2) with AsA induces genotoxicity due to oxidative DNA damage in vitro, and elevates 8-OHdG levels in the forestomach epithelium, but lacks initiating activity in the rat two-stage carcinogenesis model.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Carcinogens; Cocarcinogenesis; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA, Bacterial; Drug Therapy, Combination; Escherichia coli; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Mutagens; Organisms, Genetically Modified; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

A full-thickness burn wound model was used to evaluate the effects of a topically applied gel-based nitric oxide donor on wound healing in rats. The histological study demonstrated that the nitric oxide (NO) application significantly promoted re-epithelization that resulted in a fast recovery of burn wound. The histological sections further revealed that inflammatory cell infiltration in the NO-treated group was significantly increased in comparison to the control group. The enhanced accumulation of inflammatory cells resulted in a higher expression of myeloperoxidase (MPO) that was detected with imunoblotting. An immunohistochemistry study with CD31, a specific marker for endothelial cells, indicated that NO treatment markedly stimulated angiogenesis. Evaluation of collagen synthesis by immunohistochemistry with procollagen antibody demonstrated a significantly increased collagen synthesis in NO-treated wound bed. We concluded that NO treatment promoted re-epithelialization and wound closure by means of enhanced inflammatory cell infiltration, and that it promoted angiogenesis and facilitated collagen synthesis in the wound bed.

Topics: Administration, Topical; Animals; Blotting, Western; Burns; Disease Models, Animal; Gels; Immunoenzyme Techniques; Male; Neovascularization, Physiologic; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Wound Healing

We present noninvasive, quantitative in vivo measurements of methemoglobin formation and reduction in a rabbit model using broadband diffuse optical spectroscopy (DOS). Broadband DOS combines multifrequency frequency-domain photon migration (FDPM) with time-independent near infrared (NIR) spectroscopy to quantitatively measure bulk tissue absorption and scattering spectra between 600 nm and 1,000 nm. Tissue concentrations (denoted by brackets) of methemoglobin ([MetHb]), deoxyhemoglobin ([Hb-R]), and oxyhemoglobin ([HbO2]) were determined from absorption spectra acquired in "real time" during nitrite infusions in nine pathogen-free New Zealand White rabbits. As little as 30 nM [MetHb] changes were detected for levels of [MetHb] that ranged from 0.80 to 5.72 microM, representing 2.2 to 14.9% of the total hemoglobin content (%MetHb). These values agreed well with on-site ex vivo cooximetry data (r2= 0.902, P < 0.0001, n = 4). The reduction of MetHb to functional hemoglobins was also carried out with intravenous injections of methylene blue (MB). As little as 10 nM changes in [MB] were detectable at levels of up to 150 nM in tissue. Our results demonstrate, for the first time, the ability of broadband DOS to noninvasively quantify real-time changes in [MetHb] and four additional chromophore concentrations ([Hb-R], [HbO2], [H2O], and [MB]) despite significant overlapping spectral features. These techniques are expected to be useful in evaluating dynamics of drug delivery and therapeutic efficacy in blood chemistry, human, and preclinical animal models.

Topics: Animals; Disease Models, Animal; Hemoglobins; Kinetics; Methemoglobin; Methemoglobinemia; Methylene Blue; Oxidation-Reduction; Oxyhemoglobins; Photons; Rabbits; Scattering, Radiation; Sodium Nitrite; Spectroscopy, Near-Infrared

The cholinergic system undergoes changes with aging and in Alzheimer's disease. The effects of the anticholinesterase drugs galantamine and donepezil were studied in a model with sodium nitrite-induced hypoxia in rats. The animals were trained in the shuttle-box active avoidance test and in step-through and step-down passive avoidance tests. In the active avoidance test, hypoxic rats showed a decrease in the number of avoidances in the learning session and in retention. The hypoxic rats receiving galantamine showed an increase in the number of avoidances during the learning session. The groups in hypoxia treated with donepezil had an increased number of avoidances in the learning session. In memory retention tests, significant differences were not observed in the hypoxic animals treated with galantamine or donepezil. In the step-through passive avoidance test, rats treated with galantamine had no change in the latency of reactions during the learning session and memory retention tests. In the step-down passive avoidance test, the animals treated with galantamine had increase latency of reactions during the learning and short- or long-memory retention tests. The hypoxic rats receiving donepezil had increased latency of reactions in the step-down short memory retention test. Our results suggest that galantamine and donepezil improve cognitive functions in a model of hypoxia.

Topics: Animals; Avoidance Learning; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Galantamine; Hypoxia, Brain; Indans; Male; Memory; Memory Disorders; Piperidines; Rats; Rats, Wistar; Sodium Nitrite; Time Factors

Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.. To determine whether infusions of nitrite will prevent delayed cerebral vasospasm.. A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004.. A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days.. Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm.. In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) micromol/L to 0.4 (0.1) micromol/L at day 7 and to 0.4 (0.4) micromol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity.. Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.

Topics: Animals; Cerebral Angiography; Disease Models, Animal; Infarction, Middle Cerebral Artery; Infusions, Intravenous; Macaca fascicularis; Methemoglobin; Nitrites; S-Nitrosothiols; Sodium Nitrite; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Topics: Animals; Disease Models, Animal; Haplorhini; Randomized Controlled Trials as Topic; Research Design; Sodium Nitrite; Subarachnoid Hemorrhage; Vasospasm, Intracranial

To study the anti-aging effects of Coeloglossum. viride (L) Hartm. var. bracteatum (Willd) Richter extract (CE) on senescent model mice induced by D-galactose and sodium nitrite.. After one week of accommodation, 60 female NIH mice were divided into six groups with 10 mice in each group: normal control group, aging model group, Piracetam (positive control) group [300 mg/ (kg x d)], and CE reatment groups [2.5, 5, and 10 mg/ (kg x d)]. Mice in aging model group, Piracetam group, and CE treatment group were consecutively intraperitoneally injected with D-galactose [120 mg/ (kg x d)] and sodium nitrite [90 mg/ (kg x d)] for 60 days. From day 47, mice in Piracetam group and CE treatment group were po given Piracetam 300 mg/ (kg x d) or CE 2.5, 5, and 10 mg/ (kg x d). Mice in normal control group and aging model group were po given saline. The drug administration lasted for 14 days. Water maze test was performed to evaluate the learning and memory function in the mice. The activity of superoxide dismutase (SOD), the content of malondialdehyde (MDA), and the activities of adenosinetriphosphatase (ATPase), and monoamine-oxidase (MAO) in brain tissue were measured.. The latencies in water maze test in aging model group mice were significantly longer than in normal control group (P < 0.01, P < 0.05), and the number of errors increased (P < 0.05). In aging model group mice, the activities of SOD, Na+K(+)-ATPase, and Ca2+Mg(2+)-ATPase decreased (P < 0.01, P < 0.05), while the content of MDA and the activities of MAO-A and MAO-B increased (P < 0.01). Piracetam [300 mg/ (kg x d), po] and CE [2.5, 5, 10 mg/ (kg x d), po] ameliorated the above changes in aging model mice.. CE may improve the memory dysfunction induced by consecutive injection of D-galactose and sodium nitrite,and has nootropic and antiaging effects.

Topics: Aging; Animals; Brain; Disease Models, Animal; Female; Galactose; Learning Disabilities; Malondialdehyde; Memory Disorders; Mice; Mice, Inbred Strains; Monoamine Oxidase; Orchidaceae; Oxidative Stress; Plant Extracts; Sodium Nitrite; Superoxide Dismutase

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

Salmonella enterica serovar Enteritidis is a major cause of food-borne diseases associated with consumption of shell eggs. Clinical isolates of S. enterica serovar Enteritidis exhibit a wide spectrum of virulence in mice. A highly virulent isolate (SE2472) was previously shown to be more resistant in vitro than other clinical isolates to acidified sodium nitrite (ASN), a generator of reactive nitrogen and oxygen intermediates (RNI/ROI). SE2472 is also more resistant to S-nitrosoglutathione (GSNO) and hydrogen peroxide (H(2)O(2)) than an ASN-susceptible isolate of S. enterica serovar Enteritidis (SE8743). To investigate the molecular basis for the RNI/ROI resistance of S. enterica serovar Enteritidis, we transformed a genomic DNA library of SE2472 into SE8743. A plasmid clone conferred upon SE8743 enhanced resistance to ASN, GSNO, and H(2)O(2). The DNA insert in the clone encoded ArcA, a global regulator. An arcA mutant of SE2472 was constructed and was found to be more susceptible to GSNO and hydrogen peroxide but not more susceptible to ASN than wild-type SE2472. The susceptibility of the arcA mutant to GSNO and H(2)O(2) was complemented by a plasmid harboring arcA. The coding sequence of the arcA gene in SE2472 and the coding sequence of the arcA gene in SE8743 were identical, suggesting that the difference in resistance to RNI/ROI maybe due to the activity of genes regulated by ArcA. No significant difference in virulence between the wild type and the arcA mutant of SE2472 was observed in mice. These observations show that arcA is essential for resistance of S. enterica serovar Enteritidis to nitrosative and oxidative stress. However, additional genetic loci may contribute to the resistance to RNI/ROI and unusually high virulence for mice of SE2472.

Topics: Animals; Bacterial Outer Membrane Proteins; Cloning, Molecular; Culture Media; Detergents; Disease Models, Animal; DNA, Bacterial; Drug Resistance, Bacterial; Escherichia coli Proteins; Gene Library; Genetic Testing; Heating; Hydrogen Peroxide; Hydrogen-Ion Concentration; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mutagenesis; Nitric Oxide Donors; Nitrogen; Oxidants; Plasmids; Reactive Oxygen Species; Repressor Proteins; S-Nitrosoglutathione; Salmonella enteritidis; Salmonella Infections; Sequence Analysis, DNA; Sodium Chloride; Sodium Dodecyl Sulfate; Sodium Nitrite; Virulence

Cancers and precancerous lesions of the esophagus were efficiently induced in rats by the simulation of a clinico-epidemiological setting; that is, the administration of precursors of nitrosamine. Six week old non-inbred male Wistar rats were given 2g/kg bodyweight of sarcosine ethyl ester hydrochloride (SEEH) and concurrently 0.3g/kg bodyweight of sodium nitrite (NaNO2), precursors of N-nitrososarcosine ethyl ester (NSEE), in 2% sucrose as drinking water. Group 1 received the precursors twice a week for 6 weeks followed by 8 weeks observation, and group 2, once every 3 days for 7 weeks followed by 26 weeks observation. At the end of treatment, no tumor had developed in the esophagus of rats in group 1, but the [3H]-thymidine labeling indices in both basal and superficial layer cells were higher than in the control group. On subsequent observation, papillomas appeared in group 1 (33.3%), and carcinomas in group 2 (33.3%), within 4 weeks. The tumors induced in group 1 were mostly papillomas and rarely carcinomas. When the observation was prolonged in group 2, 100% of the animals had cancer in week 20. The pathological changes of the lesions paralleled the sequential development of human squamous cell carcinoma of the esophagus. Our system has the advantages in that papillomas and cancers can be induced in rats in a short time and the agents used are less toxic than preformed nitrosamines administered previously by gastric intubation. It would serve as a useful experimental tool to study premalignant lesions and cancers of the esophagus.

Topics: Animals; Carcinogens; Carcinoma; Disease Models, Animal; Esophageal Neoplasms; Male; Nitrosamines; Precancerous Conditions; Rats; Rats, Wistar; Sodium Nitrite

Effects of simultaneous treatment with NaNO2 and butylated hydroxyanisole, catechol, or 3-methoxycatechol were examined in a rat multiorgan carcinogenesis model. Groups of 15 animals were given a single i.p. injection of 100 mg/kg of body weight diethylnitrosamine, 4 i.p. injections of 20 mg/kg of body weight N-methylnitrosourea, 4 s.c. injections of 40 mg/kg of body weight dimethylhydrazine, p.o. treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for the first 2 weeks and p.o. treatment with 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine in the drinking water for the next 2 weeks of the initial 4-week initiation period. Starting 3 days after the completion of these carcinogen treatments, animals were given diets containing 2% butylated hydroxyanisole, 0.8% catechol, 2% 3-methoxycatechol, or basal diet either alone or in combination with 0.3% sodium nitrite until week 28, when complete autopsy was performed. Histological examination showed that NaNO2 strongly enhanced development of forestomach lesions but inhibited that of glandular stomach lesions in rats simultaneously given catechol or 3-methoxycatechol with or without prior carcinogen exposure. 3-Methoxycatechol promoted esophageal carcinogenesis either with or without NaNO2, but promoting effects of catechol were evident only in the presence of NaNO2. In addition, treatment with NaNO2 after carcinogen exposure enhanced forestomach carcinogenesis. These results indicate that NaNO2 can modify phenolic antioxidant-induced cell proliferation and/or carcinogenesis, particularly in the upper digestive tract.

Topics: Animals; Antioxidants; Body Weight; Butylated Hydroxyanisole; Carcinoma in Situ; Carcinoma, Squamous Cell; Catechols; Cocarcinogenesis; Dimethylhydrazines; Disease Models, Animal; Drug Interactions; Eating; Epithelium; Hyperplasia; Liver; Male; Methylnitrosourea; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach; Stomach Neoplasms

Topics: Aminophenols; Animals; Cyanides; Disease Models, Animal; Lethal Dose 50; Male; Methemoglobin; Methemoglobinemia; Rats; Rats, Inbred Strains; Sodium Nitrite

This investigation was undertaken to determine whether it was possible to restore endothelium-dependent relaxation (EDR) in the cholesterol-fed rabbit model of atherosclerosis following discontinuation of the cholesterol. New Zealand white rabbits, approximately 8 weeks of age, were randomized into (i) control group (9 animals fed a standard rabbit diet) and (ii) experimental group (27 animals: fed the same diet supplemented with 2.5% cholesterol). The experimental animals were restored to the standard diet after 3 weeks. EDR to acetylcholine (-9.0 to -5.0 log mol/L) was examined in the experimental animals at 3, 7, and 15 weeks after commencement of the study (n = 9 at each stage) and the nine control animals examined after 7 weeks. At the end of 7 weeks, EDR to acetylcholine (-6.0 log mol/L) was significantly (p less than 0.05) impaired in the experimental group (34.3 +/- 3.8%) compared with that in the control group (79.8 +/- 3.0%). The loss of EDR was not apparent in the experimental group at 3 weeks (relaxation: 81.7 +/- 4.7%). At the end of 15 weeks, the EDR was significantly restored in the experimental group (relaxation: 63.6 +/- 5.1%). These findings demonstrate that it is possible to reverse the loss of EDR that occurs with cholesterol feeding in the rabbit by limiting the period of exposure to a high cholesterol diet.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Azo Compounds; Cholesterol, Dietary; Coronary Artery Disease; Disease Models, Animal; Endothelium, Vascular; Lipids; Microscopy, Electron, Scanning; Muscle Relaxation; Muscle, Smooth, Vascular; Organ Size; Rabbits; Sodium Nitrite; Staining and Labeling

Sprague-Dawley rats were exposed to 0, 26, or 2600 ppm lead as lead acetate in drinking water for 76 weeks. At 28 weeks of lead exposure, a portion of each group was exposed simultaneously to 6.36 g/kg ethyl urea (EU) and 2.0 g/kg sodium nitrite (NaNO2) for a duration of 20 weeks, and then continued an additional 28 weeks on standard diet free of EU and NaNO2. The animals were observed for incidence, latency, and distribution of tumors. Rats exposed to 2600 ppm lead alone had 81% renal tumors, while rats given 2600 ppm lead in combination with EU/NaNO2 had a 50% incidence. Renal tumors did not occur in the EU/NaNO2 only or EU/NaNO2-26 ppm lead groups. The major tumor type found in EU/NaNO2-exposed rats was lymphosarcoma. Lead did not appear to be syncarcinogenic to the activity of ethylnitrosourea, the carcinogen formed by oral exposure to EU and NaNO2. The lead-induced renal neoplasms were histologically similar to those which occur spontaneously in man and, therefore, may serve as an animal model to study human disease.

Topics: Animals; Disease Models, Animal; Kidney Neoplasms; Lead; Male; Neoplasms, Experimental; Nitrites; Organometallic Compounds; Rats; Rats, Inbred Strains; Sodium Nitrite; Time Factors; Urea

The antihypoxic effects of gutimine, piracetam, sodium hydroxybutyrate and lithium hydroxybityrate were studied on different models of brain hypoxia. All the drugs under study produced a remarkable antihypoxic effect in experimental asphyxic hypoxia, increasing brain resistance to oxygen deficiency and rapidly restituting brain function. Drug pretreatment of the animals with carotid artery occlusion raised the number of animals which survived 24 h after the operation. GABA salts appeared the most effective. Sodium hydroxybutyrate increased the lifespan of rats under histotoxic hypoxia.

Topics: Animals; Asphyxia; Brain Ischemia; Disease Models, Animal; Drug Evaluation, Preclinical; Electrocardiography; Electroencephalography; Guanylthiourea; Hydroxybutyrates; Hypoxia, Brain; Lithium; Male; Organometallic Compounds; Piracetam; Rats; Sodium Nitrite; Sodium Oxybate