sodium-nitrite and Body-Weight

Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18-19%), and its precursor, glutamine (17-22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavi

Topics: Animals; Anxiety; Arachidonic Acid; Association Learning; Behavior, Animal; Body Size; Body Weight; Brain; Dopamine; Epinephrine; Executive Function; Female; gamma-Aminobutyric Acid; Glutamine; Linoleic Acid; Male; Metabolome; Nitrates; Norepinephrine; Reflex, Startle; Reinforcement, Psychology; Sodium Nitrite; Zebrafish

Sodium nitrite is used to inhibit the growth of microorganisms and is responsible for the desirable red color of meat; however, it can be toxic in high quantities for humans and other animals. Moreover, glycogen, a branched polysaccharide, efficiently stores and releases glucose monosaccharides to be accessible for metabolic and synthetic requirements of the cell. Therefore, we examined the impact of dietary sodium nitrite and cod liver oil on liver glycogen.. Thirty-two Sprague-Dawley rats were treated daily with sodium nitrite (80 mg/kg) in the presence/absence of cod liver oil (5 ml/kg). Liver sections were stained with Periodic acid-Schiff. Hepatic homogenates were used for measurements of glycogen, cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), glycogen synthase, glycogen synthase kinase, pyruvate carboxylase, fructose 1,6-diphosphatase, glucose 6-phosphatase, phosphodiesterase and glycogen phosphorylase. Glucose, pyruvate tolerances and HOMA insulin resistance were also determined.. Sodium nitrite significantly increased plasma glucose and insulin resistance. Moreover, sodium nitrite significantly reduced hepatic glycogen content as well as activities of glycogen synthase, glycogen synthase kinase-3, and phosphodiesterase. Sodium nitrite elevated hepatic cAMP, PKA, pyruvate carboxylase, fructose 1,6-diphosphatase, glucose 6-phosphatase and phosphorylase. Cod liver oil significantly blocked all of these except pyruvate carboxylase, fructose 1,6-diphosphatase and glucose 6-phosphatase.. Sodium nitrite inhibited liver glycogenesis and enhanced liver glycogenolysis and gluconeogenesis, which is accompanied by hyperglycemia and insulin resistance through the activation of cAMP/PKA and the inhibition of phosphodiesterase. Cod liver oil blocked the sodium nitrite effects on glycogenesis and glycogenolysis without affecting gluconeogenesis.

Topics: Animals; Body Weight; Cod Liver Oil; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Fructose-Bisphosphatase; Gluconeogenesis; Glycogen Synthase; Insulin; Insulin Resistance; Liver; Liver Glycogen; Phosphoric Diester Hydrolases; Pyruvate Carboxylase; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Sodium Nitrite

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

Endothelial nitric-oxide synthase (eNOS) acts as a common pathogenic pathway in diabetic nephropathy (DN). However, its functional consequences are still not fully understood. Caveolin, a membrane protein, inhibits the eNOS by making caveolin-eNOS complex, and its expression is upregulated during diabetes mellitus (DM). This study was designed to determine the role of caveolin in eNOS-mediated NO synthesis and release in DN. DM in rat was induced by feeding of high-fat diet (HFD) for 2 weeks, followed by single dose of streptozotocin (STZ) (35 mg/kg, ip) further followed by HFD for further 8 weeks. Serum nitrite/nitrate ratio was measured to determine the plasma level of NO. Diabetic rat, after 6 weeks of STZ, developed elevated level of BUN, protein in urine, urinary output, serum creatinine, serum cholesterol, kidney weight, kidney weight/body weight, and renal cortical collagen content, while serum nitrite/nitrate concentration was significantly decreased as compared to normal control group. Treatment with sodium nitrite (NO donor), L: -arginine (NO precursor), daidzein (caveolin inhibitor), and combination of L: -arginine and daidzein for 2 weeks markedly attenuated these changes and increased serum nitrite/nitrate ratio. However, treatment with L-NAME, a eNOS inhibitor, significantly attenuated the L: -arginine-, daidzein-, or combination of L: -arginine and daidzein-induced ameliorative effects in DN. The finding of this study suggests that caveolin plays a vital role in the eNOS-mediated decrease in renal level of NO, which may be responsible for the development of DN in rats.

Topics: Animals; Arginine; Blood Glucose; Blood Urea Nitrogen; Body Weight; Caveolin 1; Cholesterol; Collagen; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dietary Fats; Endothelium, Vascular; Isoflavones; Kidney; Male; Nitric Oxide Synthase Type III; Nitrites; Organ Size; Proteinuria; Rats; Rats, Wistar; Sodium Nitrite; Urine

The content of nitrite and nitrate in cured meat products has been monitored in Denmark seven times between 1995 and 2006. The maximum permitted added amounts of sodium nitrite in Denmark (60 mg kg(-1) for most products up to 150 mg kg(-1) for special products) have not been exceeded, except for a few samples back in 2002. The intake, mean and intake distribution of sodium nitrite have been calculated from 1998 to 2006 with data from the Danish dietary survey conducted in 2000-02 on Danes from four to 75 years of age. The amounts used by industry have been relatively stable through the whole period with levels varying between 6 and 20 mg sodium nitrite kg(-1) with sausages, meat for open sandwiches and salami-type sausages being the greatest contributors. The mean intake of sodium nitrate was around 1 mg day(-1), which is very low compared with the total intake of 61 mg day(-1). The mean intake of sodium nitrite was 0.017 and 0.014, 0.009 and 0.008, and 0.007 and 0.003 mg kg(-1) body weight day(-1) for men and women in the age groups 4-5, 6-14 and 15-75 years, respectively, which was much lower than the acceptable daily intake (ADI) of 0.09 mg kg(-1) body weight day(-1). The 99th percentile for the group of 4-year-olds was 0.107 and 0.123 mg kg(-1) body weight day(-1) for boys and girls, respectively, and the 95th percentile was 0.057 and 0.073 mg kg(-1) body weight day(-1) for boys and girls, respectively, highest for the girls. With fewer than 100 boys and girls in the 4-5-year age group, only very few persons were responsible for the high intake. The conversion of nitrate to nitrite in the saliva and the degradation of nitrite during production and storage must also be considered when evaluating the intake of nitrite.

Topics: Adolescent; Adult; Age Factors; Aged; Animals; Body Weight; Child; Child, Preschool; Denmark; Diet; Diet Surveys; Female; Food Additives; Humans; Male; Meat Products; Middle Aged; Nitrates; Sodium Nitrite

Previous studies have shown that the minor tobacco alkaloid myosmine (5) reacts with NaNO2 in the presence of acid to yield 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, 8) via 4-(3-pyridyl)-4-oxobutanediazohydroxide (7). Intermediate 7 is also formed in the metabolism of the tobacco-specific nitrosamines N'-nitrosonornicotine (NNN, 1) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 2), resulting in pyridyloxobutylation of DNA and Hb. These pyridyloxobutyl adducts can be quantified by analyzing HPB released upon acid treatment of DNA or base treatment of Hb. Quantitation of HPB-releasing DNA and Hb adducts has been used to assess the metabolic activation of NNN and NNK in smokers and smokeless tobacco users. Because myosmine is found in the diet as well as in tobacco products, it has been suggested that nitrosation of myosmine could lead to the formation of HPB-releasing adducts in people not exposed to tobacco products. We investigated the nitrosation of myosmine in vitro and in vivo in rats. The reaction of myosmine with NaNO2 under acidic conditions produced HPB, as previously reported. A new product was identified as 3'-oximinomyosmine (11) based on its spectral properties. NNN was not detected. Groups of rats were treated with NNN, NNK, myosmine, NaNO2, or combinations of myosmine and NaNO2. HPB-releasing Hb and DNA adducts were clearly detected in the rats treated with NNN or NNK, but we found no evidence for production of these adducts from the combination of myosmine plus NaNO2. The results of this study do not support the hypothesis that exposure to dietary myosmine could lead to HPB-releasing DNA or Hb adducts in humans.

Topics: Alkaloids; Animals; Body Weight; DNA; Eating; Hemoglobins; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred F344; Sodium Nitrite; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Weight Gain

A number of heterocyclic amines (HCAs) have been shown to exert enhanced carcinogenic and mutagenic potential when given simultaneously with sodium nitrite (NaNO(2)). In the present experiment, effects of combined treatment with NaNO(2) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the most prevalent carcinogenic HCAs in the human environment, were assessed with regard to mammary tumor induction in female Sprague-Dawley (SD) rats. Animals at 6 weeks of age were given intragastric doses of 100mg/kg body weight of PhIP twice a week for 4 weeks, during which period 0 or 0.2% NaNO(2) was administered in the drinking water. Control rats received 0.2% NaNO(2) alone for the 4 weeks or non-supplemented water during the entire 48 week experimental period, without carcinogen treatment. The first tumor in the PhIP+NaNO(2) group appeared significantly later than with PhIP alone, and during the experimental period, the incidence, multiplicity and volume of mammary tumors in this group tended towards decreased, although values did not significantly differ at the terminal sacrifice. These results indicate that NaNO(2) does not enhance PhIP-induced rat mammary carcinogenesis, rather possessing some potential for inhibition.

Topics: Animals; Body Weight; Carcinogens; Cell Death; Cell Proliferation; Drug Synergism; Female; Imidazoles; Incidence; Indicators and Reagents; Mammary Neoplasms, Animal; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Tumor Cells, Cultured

The effect of antioxidant, 0.25% 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) or 0.25% ascorbic acid (AsA), on carcinogenesis induced by administration of 0.05% aminopyrine (AP) and 0.05% sodium nitrite (NaNO2), was examined using a rat multi-organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with an initiation regimen of N-diethylnitrosamine, N-methyl-N-nitrosourea, N-butyl-N-(4-hydroxybutyl)nitrosamine, N,N'-dimethylhydrazine and 2,2'-dihydroxy-di-n-propylnitrosamine during the first 4 weeks, followed by AP+NaNO2, AP+NaNO2+HTHQ, AP+NaNO2+AsA, NaNO2+HTHQ, NaNO2+AsA, each of the individual chemicals alone or basal diet and tap water as a control. All surviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic lesions. In the AP+NaNO2 group, the incidences of hepatocellular adenomas and hemangiosarcomas were 95% and 35%, respectively. When HTHQ or AsA was simultaneously administered, the incidences decreased to 58% and 11%, or to 80% and 15%, respectively. On the other hand, in the AP+NaNO2 group and the NaNO2-alone group, when HTHQ, but not AsA, was simultaneously administered, the incidence of carcinomas in the forestomach significantly increased. The results suggest that HTHQ can prevent tumor production induced by AP and NaNO2 more effectively than AsA. On the other hand, an enhancing or possible carcinogenic effect of simultaneous administration of HTHQ and NaNO2 only on the forestomach is suggested, while simultaneous treatment with the same dose of AsA and NaNO2 may not be carcinogenic to the forestomach or other organs.

Topics: Aminopyrine; Animals; Antioxidants; Ascorbic Acid; Body Weight; Glutathione Transferase; Hydroquinones; Male; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred F344; Sodium Nitrite

The effects of sodium nitrite (NaNO2), in combination with one of three antioxidants, tert-butylhydroquinone (TBHQ), alpha-tocopherol (alpha-Toc) and propyl gallate (PG), on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. Groups of 15 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 week later, were treated with 0.5% TBHQ, 1% alpha-Toc, 1% PG or basal diet with or without 0.2% NaNO2 in their drinking water until they were killed at the end of week 36. Macroscopically, in MNNG-treated animals, combined administration of alpha-Toc or PG with NaNO2 significantly increased the areas and numbers of forestomach nodules as compared with the respective antioxidant alone values. Microscopically, in MNNG-treated animals, treatment with TBHQ significantly increased the incidence and multiplicity of forestomach papillomas as compared with basal diet alone value. Combined administration of alpha-Toc with NaNO2 significantly raised the multiplicity of forestomach papillomas, with a tendency to elevation in the incidence as compared with the group given alpha-Toc alone. Incidences of forestomach moderate and/or severe hyperplasias were significantly higher in the TBHQ or PG plus NaNO2 groups than in the single compound groups. In rats without MNNG treatment, combined treatment of antioxidants with NaNO2 significantly increased the incidences of mild or moderate hyperplasia. In the glandular stomach, although the incidence of atypical hyperplasia showed a non-significant tendency for decrease with TBHQ treatment, additional administration of NaNO2 caused significant increase. These results indicate that co-administration of NaNO2 with alpha-Toc, TBHQ or PG and particularly the first, promotes forestomach carcinogenesis. Concurrent alpha-Toc, TBHQ or PG treatment with NaNO2 is likely to induce forestomach tumors in the long term.

Topics: alpha-Tocopherol; Animals; Antioxidants; Body Weight; Carcinoma, Squamous Cell; Drug Combinations; Drug Interactions; Food Preservatives; Hydroquinones; Hyperplasia; Male; Methylnitronitrosoguanidine; Papilloma; Propyl Gallate; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

Sodium nitrite is used as a color fixative and preservative in meats and fish. It is also used in manufacturing diazo dyes, nitroso compounds, and other organic compounds; in dyeing and printing textile fabrics and bleaching fibers; in photography; as a laboratory reagent and a corrosion inhibitor; in metal coatings for phosphatizing and detinning; and in the manufacture of rubber chemicals. Sodium nitrite also has been used in human and veterinary medicine as a vasodilator, a bronchial dilator, an intestinal relaxant, and an antidote for cyanide poisoning. Sodium nitrite was nominated by the FDA for toxicity and carcinogenesis studies based on its widespread use in foods. Male and female F344/N rats and B6C3F1 mice were exposed to sodium nitrite (99% pure) in drinking water for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 375, 750, 1500, 3,000, or 5000 ppm sodium nitrite (equivalent to average daily doses of approximately 30, 55, 115, 200, or 310 mg sodium nitrite/kg body weight to males and 40, 80, 130, 225, or 345 mg/kg to females) in drinking water for 14 weeks. Clinical pathology study groups of 15 male and 15 female rats were exposed to the same concentrations for 70 or 71 days. One female exposed to 3000 ppm died before the end of the study. Body weights of males exposed to 3000 or 5000 ppm and females exposed to 5000 ppm were significantly less than those of the controls. Water consumption by 5000 ppm males and 3000 and 5000 ppm females was less than that by the controls at weeks 2 and 14. Clinical findings related to sodium nitrite exposure included brown discoloration in the eyes and cyanosis of the mouth, tongue, ears, and feet of males exposed to 3000 or 5000 ppm and of females exposed to 1500 ppm or greater. Reticulocyte counts were increased in males and females exposed to 3000 or 5000 ppm. The erythron was decreased on day 19 but increased by week 14 in males and females exposed to 5000 ppm. Methemoglobin concentrations were elevated in almost all exposed groups throughout the 14 week study; a no-observed-adverse-effect level was not achieved. The relative kidney and spleen weights of males and females exposed to 3000 or 5000 ppm were significantly greater than those of the controls. Sperm motility in 1500 and 5000 ppm males was significantly decreased. Increased e. Sodium nitrite was mutagenic in Salmonella typhimurium strain TA100, with and without Aroclor 1254-induced hamster and rat liver S9 enzymes; no mutagenicity was observed in strain TA98. Results of acute bone marrow micronucleus tests with sodium nitrite in male rats and mice by intraperitoneal injection were negative. In addition, a peripheral blood micronucleus assay conducted with mice from the 14-week study gave negative results.. Under the conditions of this 2-year drinking water study, there was no evidence of carcinogenic activity of sodium nitrite in male or female F344/N rats exposed to 750, 1500, or 3000 ppm. There was no evidence of carcinogenic activity of sodium nitrite in male B6C3F1 mice exposed to 750, 1500, or 3000 ppm. There was equivocal evidence of carcinogenic activity of sodium nitrite in female B6C3F1 mice based on the positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach. Exposure to sodium nitrite in drinking water resulted in increased incidences of epithelial hyperplasia in the forestomach of male and female rats and in the glandular stomach of male mice. Decreased incidences of mononuclear cell leukemia occurred in male and female rats.

Topics: Analysis of Variance; Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Cricetinae; Female; Male; Methemoglobin; Mice; Mice, Inbred Strains; Mutagenicity Tests; Mutagens; Neoplasms; Pregnancy; Quality Control; Rats; Rats, Inbred F344; Sodium Nitrite; Survival Analysis; Time Factors; Tissue Distribution; Water Pollutants, Chemical; Water Supply

The modifying effects of concurrent administration of fish meal and sodium nitrite on the development of renal tumors after initiation with N-ethyl-N-hydroxyethylnitrosamine (EHEN) were investigated. A total of 120 male 6-week-old Wistar rats were divided into six groups. Groups 1-3 (30 animals each) were given 1000 ppm EHEN in their drinking water for 3 weeks as an initiation treatment for renal cancer induction and thereafter fed respective diets containing 64, 32, and 8% (original concentration in the basal diet) fish meal, and simultaneously given 0.12% sodium nitrite in the drinking water for 33 weeks. Groups 4-6 (ten animals each) were similarly treated without the prior application of EHEN. At the end of the 37th experimental week, all surviving animals were autopsied and examined histopathologically for the existence of renal proliferative lesions. The incidences of dysplastic lesions, adenomas or adenocarcinomas of the kidney were not significantly different among groups 1-3. No renal proliferative lesions were found in groups 4-6. Chronic nephropathy was slightly but significantly enhanced in the 64 and 32% fish meal-treated groups as compared with group 3. Our results suggest that concurrent administration of fish meal and sodium nitrite does not affect the post-initiation phase of EHEN-induced renal carcinogenesis in the rat.

Topics: Adenocarcinoma; Adenoma; Adrenal Glands; Animals; Body Weight; Cocarcinogenesis; Diet; Diethylnitrosamine; Fish Products; Kidney; Kidney Neoplasms; Liver; Male; Organ Size; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Sodium Nitrite; Time Factors

We evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. To this end, we compared the vasoprotective effect of chronic treatment with zofenopril (plus SH-group) versus lisinopril (no SH-group), or N-acetylcysteine (only SH-group) in myocardial infarcted (MI) heart failure rats. After 11 weeks of treatment, aortas were obtained and studied as ring preparations for endothelium-dependent and -independent dilatation in continuous presence of indomethacin to avoid interference of vasoactive prostanoids, and the selective presence of the NOS-inhibitor L-NMMA to determine NO-contribution. Total dilatation after receptor-dependent stimulation with acetylcholine (ACh) was attenuated (-49%, P<0.05) in untreated MI (n=11), compared to control rats with no-MI (n=8). This was in part due to impaired NO-contribution in MI (-50%, P<0.05 versus no-MI). At the same time the capacity for generation of biologically active NO after receptor-independent stimulation with A23187 remained intact. Chronic treatment with n-acetylcysteine (n=8) selectively restored NO-contribution in total dilatation to ACh. In contrast, both ACE-inhibitors fully normalized total dilatation to ACh, including the part mediated by NO (no significant differences between zofenopril (n=10) and lisinopril (n=8)). Zofenopril, but not lisinopril, additionally potentiated the effect of endogenous NO after A23187-induced release from the endothelium (+100%) as well as that of exogenous NO provided by nitroglycerin (+22%) and sodium nitrite (+36%) (for all P<0.05 versus no-MI). We conclude that ACE-inhibition with a SH-group has a potential advantage in improvement of endothelial dysfunction through increased activity of NO after release from the endothelium into the vessel wall. Furthermore, this is the first study demonstrating the selective normalizing effect of N-actylcysteine on NO-contribution to ACh-induced dilatation in experimental heart failure.

Topics: Acetylcholine; Acetylcysteine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Calcimycin; Captopril; Endothelium, Vascular; Heart Diseases; In Vitro Techniques; Lisinopril; Male; Myocardial Infarction; Nitrates; Nitrites; Nitroglycerin; omega-N-Methylarginine; Rats; Rats, Wistar; Sodium Nitrite; Sulfhydryl Compounds; Vasodilation; Vasodilator Agents

The aim of the present study was to examine the chemopreventive efficacy of S-methylcysteine (SMC) on rat hepatocarcinogenesis induced by concurrent administration of sodium nitrite (NaNO(2)) and morpholine (Mor) using a medium-term rat liver carcinogenesis bioassay (Ito test). Administration of SMC caused significant reduction in the areas of glutathione S-transferase placental form positive foci along with a significant decrease of hepatocyte 5-bromo-2'-deoxyuridine (BrdU) labeling indices. These results demonstrated potent chemopreventive effects of SMC against hepatocarcinogenesis due to concurrent administration of Mor and NaNO(2). SMC could thus be an effective chemopreventive agent for decreasing the risk of carcinogenicity from environmental precursors of N-nitroso compounds.

Topics: Animals; Anticarcinogenic Agents; Body Weight; Bromodeoxyuridine; Carcinogens; Cell Division; Cysteine; Drug Interactions; Food Preservatives; Gastric Mucosa; Glutathione Transferase; Liver; Liver Neoplasms, Experimental; Male; Morpholines; Nitrosamines; Precancerous Conditions; Rats; Rats, Inbred F344; Sodium Nitrite

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drinking; Female; Food Preservatives; Male; Mice; Pregnancy; Reproduction; Sodium Nitrite

Topics: Animals; Body Weight; Carps; Fisheries; Food Contamination; Lethal Dose 50; Sodium Nitrite; Temperature; Water Pollutants, Chemical

In experiment I, short-term effects of combined treatment with anti-oxidants, sodium ascorbate (NaAsA) and sodium nitrite (NaNO2) on forestomach cell proliferation were examined in F344 male rats. Groups of 5 animals aged 6 weeks were treated for 4 weeks with 0.8% catechol, 0.8% hydroquinone, 1% tert-butyl-hydroquinone (TBHQ), 2% gallic acid or 2% pyrogallor alone or in combination with 0.3% NaNO2 in the drinking water and/or 1% NaAsA in the diet. The thicknesses of forestomach mucosa in rats treated with anti-oxidants and NaNO2 in combination were greater than those with antioxidant alone and additional NaAsA treatment further enhanced the thickening of mucosa. It was noteworthy that values for mucosae of animals treated with NaNO2 and NaAsA without anti-oxidant were similar to those for anti-oxidants. In experiment 2, effects of combined treatment with NaAsA or ascorbic acid (AsA) and NaNO2 on carcinogenesis were examined in F344 male rats with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) pre-treatment. Groups of 20 or 15 rats, respectively, aged 6 weeks, were given a single intra-gastric administration of 150 mg/kg body weight of MNNG in DMSO:water = 1:1 or the vehicle alone by stomach tube. Starting 1 week later, they received supplements of 1% NaAsA or 1% AsA in the diet and 0.3% NaNO2 in drinking water in combination, each of the individual chemicals alone, or basal diet until the end of week 52. In MNNG-treated animals, incidences of forestomach papillomas and carcinomas were significantly enhanced in the NaNO2 alone group (84 and 47%, respectively) as compared with the basal diet group (30 and 10%), with further significant increase in carcinomas occurring with additional NaAsA (79%, p < 0.05) or AsA (85%, p < 0.05) treatment. In animals without MNNG, all animals in the NaNO2 group demonstrated mild hyperplasia, additional administration of NaAsA or AsA remarkably enhancing the grade of hyperplasia, and resulting in 53% and 20% incidences, respectively, of papillomas. Thus NaNO2 was demonstrated to exert promoter action for forestomach carcinogenesis, with NaAsA and AsA acting as co-promoters. The results strongly indicate that combined treatment with NaAsA or AsA and NaNO2 may induce forestomach carcinomas in the long term.

Topics: Animals; Ascorbic Acid; Body Weight; Carcinoma, Squamous Cell; Drug Interactions; Kidney; Liver; Male; Methylnitronitrosoguanidine; Organ Size; Papilloma; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach Neoplasms

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

The effects of sodium nitrite (NaNO2) and catechol or 3-methoxycatechol in combination were examined in male F344 rats. Animals were treated with 0.3% NaNO2 in the drinking water and 0.8% catechol or 2% 3-methoxycatechol in powdered diet for 24 weeks. While catechol or 3-methoxycatechol alone induced low incidences of mild or moderate hyperplasia, simultaneous administration of NaNO2 markedly enhanced the degree of hyperplasia and papilloma formation. In contrast, induction of submucosal hyperplasia and adenomas in the glandular epithelium was reduced. Thus, the results indicate that NaNO2 can modulate the metabolism of antioxidants, so that, possibly via production of new active moieties, targeting of forestomach epithelium is enhanced.

Topics: Adenoma; Animals; Antioxidants; Body Weight; Catechols; Drug Synergism; Epithelium; Feeding Behavior; Hyperplasia; Male; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach; Stomach Diseases; Stomach Neoplasms

Combined administration of 0.1% nitrite and 0.1% aminopyrine in the drinking water for eight to ten weeks resulted in subsequent development of both hepatocellular nodules and cholangiofibrotic lesions/cholangiocellular carcinomas in Syrian golden hamsters. Additional prior dosing with Opisthorchis viverrini metacercariae (100/animal) induced inflammatory and proliferative changes in the livers of infected hamsters and was associated with a significant increase in yields of hepatocellular and cholangiocellular preneoplastic and neoplastic lesions. Thus, environmental factors thought to be casually related to the high levels of human liver cancer observed in the Northeastern provinces of Thailand were sufficient to bring about development of equivalent tumors in experimental animals. The results indicate that parasite associated liver injury and non-specific compensatory regeneration may play an important role in generation of both hepatocellular and cholangiocellular carcinomas in man.

Topics: Adenoma, Bile Duct; Aminopyrine; Animals; Body Weight; Cricetinae; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Mesocricetus; Nitrites; Opisthorchiasis; Organ Size; Sodium Nitrite

Sodium nitrite administered in the drinking water to Long-Evans rats during pregnancy and lactation severely affected erythropoietic development, growth, and mortality in their offspring. Pregnant rats were maintained throughout gestation on 0.5, 1, 2, or 3 g NaNO2/liter. There were no significant differences between treated and control litters at birth. Thereafter, pups of treated dams on 2 and 3 g NaNO2/liter gained less weight, progressively became severely anemic, and began to die by the third week postpartum. By the second week postpartum, hemoglobin levels, RBC counts, and mean corpuscular volumes of these pups were all drastically reduced compared to controls. Blood smears showed marked anisocytosis and hypochromasia. Gross chylous serum lipemia and fatty liver degeneration were noted. Histopathology demonstrated cytoplasmic vacuolization of centrilobular hepatocytes and decreased hematopoiesis in bone marrow and spleen. Administration of 1 g NaNO2/liter resulted in hematological effects but did not affect growth or mortality. NaNO2 (0.5 g/liter) was at or near the no observed effect level. Cross-fostering indicated that treatment during the lactational period was more instrumental in producing lesions than treatment during the gestational period. The data presented are consistent with the lactational induction of severe iron deficiency in the neonate.

Topics: Animals; Animals, Newborn; Blood Chemical Analysis; Body Weight; Drinking; Erythrocyte Count; Female; Hemoglobins; Male; Maternal Behavior; Nitrites; Pregnancy; Rats; Sodium Nitrite

Cimetidine (CM), a drug widely prescribed for ulcers, readily undergoes nitrosation to form nitrosocimetidine (NCM), a genotoxic agent. In a test of the chronic effects of NCM in mice, (C57BL/6 X BALB/c)F1 mice were exposed chronically to NCM (113 or 1130 ppm) in the drinking water from preconception through prenatal and neonatal development and adult life. Each group consisted of 40 to 80 mice of each sex, and median survival time was 27 months. Other groups were given CM alone or in combination with NaNO2 (184 or 1840 ppm), or NaNO2 alone. None of the chemical treatments had large effects on reproductive parameters, survival, or incidence of nonneoplastic lesions. CM treatment was associated with a small but significant increase in incidence of lymphomas in females, 41 of 59 (69%), compared with 31 of 66 controls (47%, P = 0.01). No females receiving either dose of NCM developed mammary carcinomas (0 of 91), compared with an incidence of four of 66 controls (6%, P = 0.03). Males given the high-dose combination of CM and NaNO2 showed a higher incidence of lung tumor bearers than controls (71 of 79 versus 30 of 52, P less than 0.01) and also experienced a significant, dose-dependent increase in numbers of large lung tumors (greater than 1 cm in diameter), lung carcinoma, and metastatic lung tumors. Females given the higher dose of NCM had significantly greater incidence of mice with large lung tumors than controls (nine of 41 versus three of 66, P = 0.009). The possibility of carcinogenicity of cimetidine, nitrosocimetidine, and cimetidine plus nitrite is discussed.

Topics: Animals; Body Weight; Cimetidine; Dose-Response Relationship, Drug; Female; Fetus; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Maternal-Fetal Exchange; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms, Experimental; Nitrites; Pregnancy; Reproduction; Sex Factors; Sodium Nitrite

Sodium nitrite (NaNO2) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through day 90, at levels of 0, 0.0125, 0.025 or 0.05% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg ip of the anti-mitotic/embryotoxic drug 5-azacytidine on day 16 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. NaNO2 produced no significant reductions in parental body weight or food consumption, though it significantly increased offspring mortality and decreased weight gain at the two highest doses during the preweaning period. Functionally, NaNO2 delayed swimming development and decreased open-field activity. The open-field effect was not linearly dose dependent. In rats killed on day 90 after birth, NaNO2 produced no effects on brain or body weights. 5-Azacytidine produced evidence of substantially greater developmental toxicity than did NaNO2. NaNO2 produced a moderate degree of developmental toxicity, but no evidence was found to suggest that the central nervous system was the target organ for the toxic effects. The inclusion of tests of functional development added useful confirmatory evidence to the overall picture of NaNO2 toxicity.

Topics: Aging; Animals; Behavior, Animal; Body Weight; Female; Growth; Male; Nitrites; Rats; Rats, Inbred Strains; Reflex; Sodium Nitrite

For the purpose of ascertaining the vitamin A requirement seven experiments with 303 pigs in the live weight range between 6.5 and 114 kg were made. In three experiments under in practice conditions we checked the standard vitamin A supplement to the mixed feed with 1,732 pigs (live weight range between 8.5 and 110 kg). The supplement to vitamin-A-free rations and to those poor in or free of carotene amounted to between 0 and 8,000 IU/kg feed. Above that, between 0 and 16 mg beta-carotene and 1,000 mg nitrite/kg feed were supplemented. As long as the vitamin A store in the liver during weaning amounted to greater than 50 IU and greater than 100 IU/g at the beginning of fattening, feed intake, live weight growth and feed expenditure were not influenced by the supplement of vitamin and provitamin resp. The supplement of 250 IU resulted in the same weight growth from weaning to the end of fattening as that of 4,000 IU. Nitrite supplement had a negative effect at 250 IU, at 500 IU vitamin A consumption and weight growth tended to be only insignificantly lower. The methaemoglobin content decreasing in the course of the experiment reflects the adaptation of the pigs to the nitrite load. The consumption and growth depression caused by vitamin A deficiency could be observed from the 7th week of the experiment when casein-swelling starch rations were fed, but from the 13th week of the experiment only when cereal-soybean oilmeal rations were fed. The weight of liver, spleen, kidneys, heart and brain was not influenced by vitamin A supply. The same applies to the body composition and retention with the exception of two deficiency piglets, which contained less fat in the empty body than the control animals.

Topics: Animals; beta Carotene; Body Weight; Carotenoids; Dietary Proteins; Female; Male; Methemoglobinemia; Nutritional Requirements; Sodium Nitrite; Swine; Vitamin A

It is known that sodium nitrite and dimethylamine are toxic compounds, which may react to form dimethylnitrosamine in the gastro-intestinal tract, a much more toxic compound and a powerful cancerogen. The aim of the present work is the investigation of toxicity in young rats, caused by daily intake of sodium nitrite, administered together with dimethylamine during 30 days. The indicators examined were: histopathological analysis of the liver and kidney, transaminase in blood serum, variations in body weight and relation of weight liver/body weight. The method of analysis used to determine transaminase was that reported by Reintman and Frankel in 1957. The statistical method employed was the test of multiple comparisons based on the total ranges of Cruskal-Wallis. The results show that either significant differences were found (alpha = 0,05) among the groups (including the control), nor was necrosis observed or forming of tumors in the organs under investigation. Therefore, the doses administered does not seem to be toxic under the conditions of the experiment. Some signs of toxicity found in the group which was severely treated (10 mg of sodium nitrite and 20 mg of dimethylamine) appeared only in a few animals and it is necessary to verify the same in experiments with more animals and over a longer period of treatment.

Topics: Alanine Transaminase; Animals; Body Weight; Dimethylamines; Dose-Response Relationship, Drug; Kidney; Liver; Male; Nitrites; Organ Size; Rats; Rats, Inbred Strains; Sodium Nitrite

A nutritional and toxicological study has been made of rats, using the pair-feeding technique. The animals were fed a diet containing 5% of NO-3 ion or 0.5% of NO-2 ion (in the form of sodium salts). Under these conditions, a decrease was noted in the consumption of solid food which caused a net loss of weight. Besides, nitrates notably increase liquid intake and diuresis while nitrites induce a significant decrease in the protein retention coefficient.

Topics: Animals; Body Weight; Diuresis; Drinking; Eating; Male; Nitrates; Nitrites; Proteins; Rats; Rats, Inbred Strains; Sodium Nitrite

Topics: Animals; Body Weight; Carbaryl; Male; Nitrates; Nitrites; Organ Size; Rats; Rats, Inbred Strains; Sodium Nitrite; Time Factors

The effects of biotin deprivation on various plasma constituents were studied in male Sprague-Dawley rats, some of which were also treated with sodium nitrate (NaNO2), extra niacin or linoleate. A basal diet containing 15% pork fat (lard), 30% egg white and sucrose, was fed for 7 weeks, with or without a weekly supplement of 150 microgram biotin and the other substances mentioned. Biotin-deprived rats ate significantly less food, gained less weight and had lower food efficiency ratios than biotin-supplemented rats. Rats given NaNO2 in the drinking water had significantly higher levels of methemoglobin than those without it; values were highest when extra niacin or linoleate was added to the diet. Lactate was highest in deprived rats and was lowest in rats supplemented with biotin alone. Blood lipids were higher with than without biotin, regardless of NaNO2. Levels of phospholipids and triglycerides were highest when extra niacin was added to the diet. Further studies are needed to define the role of biotin in oxidation-reduction reactions and in regulation of lipid metabolism.

Topics: Animals; Biotin; Body Weight; Diet; Lactates; Linoleic Acids; Lipids; Male; Methemoglobinemia; Mice; Mice, Inbred Strains; Nicotinic Acids; Nitrites; Rats; Sodium Nitrite; Specific Pathogen-Free Organisms