Effect of food sources of nitrate, polyphenols, L-arginine and L-citrulline on endurance exercise performance: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Increasing nitric oxide bioavailability may induce physiological effects that enhance endurance exercise performance. This review sought to evaluate the performance effects of consuming foods containing compounds that may promote nitric oxide bioavailability. METHODS: Scopus, Web of Science, Ovid Medline, EMBASE and SportDiscus were searched, with included studies assessing endurance performance following consumption of foods containing nitrate, L-arginine, L-citrulline or polyphenols. Random effects meta-analysis was conducted, with subgroup analyses performed based on food sources, sex, fitness, performance test type and supplementation protocol (e.g. duration). RESULTS: One hundred and eighteen studies were included in the meta-analysis, which encompassed 59 polyphenol studies, 56 nitrate studies and three L-citrulline studies. No effect on exercise performance following consumption of foods rich in L-citrulline was identified (SMD=-0.03, p=0.24). Trivial but significant benefits were demonstrated for consumption of nitrate and polyphenol-rich foods (SMD=0.15 and 0.17, respectively, p<0.001), including performance in time-trial, time-to-exhaustion and intermittent-type tests, and following both acute and multiple-day supplementation, but no effect of nitrate or polyphenol consumption was found in females. Among nitrate-rich foods, beneficial effects were seen for beetroot, but not red spinach or Swiss chard and rhubarb. For polyphenol-rich foods, benefits were found for grape, (nitrate-depleted) beetroot, French maritime pine, Montmorency cherry and pomegranate, while no significant effects were evident for New Zealand blackcurrant, cocoa, ginseng, green tea or raisins. Considerable heterogeneity between polyphenol studies may reflect food-specific effects or differences in study designs and subject characteristics. Well-trained males (V̇O2max ≥65 ml.kg.min-1) exhibited small, significant benefits following polyphenol, but not nitrate consumption. CONCLUSION: Foods rich in polyphenols and nitrate provide trivial benefits for endurance exercise performance, although these effects may be food dependent. Highly trained endurance athletes do not appear to benefit from consuming nitrate-rich foods but may benefit from polyphenol consumption. Further research into food sources, dosage and supplementation duration to optimise the ergogenic response to polyphenol consumption is warranted. Further studies should evaluate whether differential sex-based responses to nitrate and polyphenol consumption are attributable to physiological differences or sample size limitations. OTHER: The review protocol was registered on the Open Science Framework ( https://osf.io/u7nsj ) and no funding was provided.

A Clearance Period after Soluble Lead Nanoparticle Inhalation Did Not Ameliorate the Negative Effects on Target Tissues Due to Decreased Immune Response.

The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO3)2 NPs], which represent a highly soluble form of lead, by inhalation. We aimed to uncover the effects of their exposure on individual target organs and to reveal potential variability in the lead clearance. We examined (i) lead biodistribution in target organs using laser ablation and inductively coupled plasma mass spectrometry (LA-ICP-MS) and atomic absorption spectrometry (AAS), (ii) lead effect on histopathological changes and immune cells response in secondary target organs and (iii) the clearance ability of target organs. In the lungs and liver, Pb(NO3)2 NP inhalation induced serious structural changes and their damage was present even after a 5-week clearance period despite the lead having been almost completely eliminated from the tissues. The numbers of macrophages significantly decreased after 11-week Pb(NO3)2 NP inhalation; conversely, abundance of alpha-smooth muscle actin (α-SMA)-positive cells, which are responsible for augmented collagen production, increased in both tissues. Moreover, the expression of nuclear factor κB (NF-κB) and selected cytokines, such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFß1), interleukin 6(IL-6), IL-1α and IL-1ß , displayed a tissue-specific response to lead exposure. In summary, diminished inflammatory response in tissues after Pb(NO3)2 NPs inhalation was associated with prolonged negative effect of lead on tissues, as demonstrated by sustained pathological changes in target organs, even after long clearance period.

MWDS-2016: THE SLOW DISSOLUTION RATE FOR PLUTONIUM NITRATE INTAKES AT THE MAYAK FACILITY.

The slow dissolution rate of material deposited in the lung plays a key role in determining the eventual radiation dose received by the lung. It is therefore of great importance to establish a reliable value for this parameter, to incorporate into the latest Mayak Worker Dosimetry System (MWDS-2016). Disparate values have been obtained for the slow dissolution rate of plutonium nitrate. A volunteer study performed by Public Health England (PHE) and an analysis of United States Transuranium and Uranium Registries (USTUR) case 0269 have yielded slow dissolution rates in the region of 10-40 × 10-4 d-1. However, autopsies performed on 20 Mayak workers, exposed predominantly to nitrates, have resulted in estimates of slow dissolution rates of around 2.4 × 10-4 d-1. Three hypotheses have been proposed to explain this discrepancy: (1) a slower dissolution rate in the interstitium, (2) a third exponential component in the dissolution function and (3) a small component of oxide in the aerosol to which Mayak 'nitrate' workers were exposed. This paper describes tests of these competing hypotheses. Bayesian methods have been applied to the following datasets: PHE volunteer data; Beagle dog data; USTUR cases and Mayak worker data. It is concluded that a mixture of oxide and nitrate material, with the oxide forming ~14% of the intake, best describes the Mayak dissolution rate, without introducing values for other parameters which conflict with other studies.

A randomised controlled trial exploring the effects of different beverages consumed alongside a nitrate-rich meal on systemic blood pressure.

BACKGROUND:: Ingestion of nitrate (NO3-)-containing vegetables, alcohol and polyphenols, separately, can reduce blood pressure (BP). However, the pharmacokinetic response to the combined ingestion of NO3- and polyphenol-rich or low polyphenol alcoholic beverages is unknown. AIM:: The aim of this study was to investigate how the consumption of low and high polyphenolic alcoholic beverages combined with a NO3--rich meal can influence NO3- metabolism and systemic BP. METHODS:: In a randomised, crossover trial, 12 normotensive males (age 25 ± 5 years) ingested an acute dose of NO3- (∼6.05 mmol) in the form of a green leafy salad, in combination with either a polyphenol-rich red wine (NIT-RW), a low polyphenol alcoholic beverage (vodka; NIT-A) or water (NIT-CON). Participants also consumed a low NO3- salad and water as a control (CON; ∼0.69 mmol NO3-). BP and plasma, salivary and urinary [NO3-] and nitrite ([NO2-]) were determined before and up to 5 h post ingestion. RESULTS:: Each NO3--rich condition elevated nitric oxide (NO) biomarkers when compared with CON ( P < 0.05). The peak rise in plasma [NO2-] occurred 1 h after NIT-RW (292 ± 210 nM) and 2 h after NIT-A (318 ± 186 nM) and NIT-CON (367 ± 179 nM). Systolic BP was reduced 2 h post consumption of NIT-RW (-4 mmHg), NIT-A (-3 mmHg) and NIT-CON (-2 mmHg) compared with CON ( P < 0.05). Diastolic BP and mean arterial pressure were also lower in NIT-RW and NIT-A compared with NIT-CON ( P < 0.05). CONCLUSIONS:: A NO3--rich meal, consumed with or without an alcoholic beverage, increases plasma [NO2-] and lowers systemic BP for 2-3 h post ingestion.

Effect of diet and gut environment on the gastrointestinal formation of N-nitroso compounds: A review.

Diet is associated with the development of cancer in the gastrointestinal (GI) tract, because dietary nitrate and nitrite are the main nitrosating agents that are responsible for the formation of carcinogenic N-nitroso compounds (NOCs) when nitrosatable substrates, such as amine and amide, are present in the GI tract. However, whether the nitroso compounds become beneficial S-nitroso compounds or carcinogenic NOCs might depend on dietary and environmental factors including food stuffs, gastric acidity, microbial flora, and the mean transit time of digesta. This review focused on GI NOC formation and environmental risk factors affecting its formation to provide appropriate nutritional strategies to prevent the development of GI cancer.

Influence of dietary nitrate food forms on nitrate metabolism and blood pressure in healthy normotensive adults.

Inorganic nitrate (NO3-) supplementation has been shown to improve cardiovascular health indices in healthy adults. The purpose of this study was to investigate how the vehicle of NO3- administration can influence NO3- metabolism and the subsequent blood pressure response. Ten healthy males consumed an acute equimolar dose of NO3- (∼5.76 mmol) in the form of a concentrated beetroot juice drink (BR; 55 mL), a non-concentrated beetroot juice drink (BL; 456 mL) and a solid beetroot flapjack (BF; 60 g). A drink containing soluble beetroot crystals (BC; ∼1.40 mmol NO3-) and a control drink (CON; 70 mL deionised water) were also ingested. BP and plasma, salivary and urinary [NO3-] and [NO2-] were determined before and up to 24 h after ingestion. All NO3--rich vehicles elevated plasma, salivary and urinary nitric oxide metabolites compared with baseline and CON (P<0.05). The peak increases in plasma [NO2-] were greater in BF (371 ± 136 nM) and BR (369 ± 167 nM) compared to BL (283 ± 93 nM; all P<0.05) and BC (232 ± 51 nM). BR, but not BF, BL and BC, reduced systolic (∼5 mmHg) and mean arterial pressure (∼3-4 mmHg; P<0.05), whereas BF reduced diastolic BP (∼4 mmHg; P < 0.05). Although plasma [NO2-] was elevated in all conditions, the consumption of a small, concentrated NO3--rich fluid (BR) was the most effective means of reducing BP. These findings have implications for the use of dietary NO3-supplements when the main objective is to maintain or improve indices of cardiovascular health.

Beetroot juice versus chard gel: A pharmacokinetic and pharmacodynamic comparison of nitrate bioavailability.

Dietary supplementation with inorganic nitrate (NO3-) has been shown to induce a multitude of advantageous cardiovascular and metabolic responses during rest and exercise. While there is some suggestion that pharmacokinetics may differ depending on the NO3- source ingested, to the best of our knowledge this has yet to be determined experimentally. Here, we compare the plasma pharmacokinetics of NO3-, nitrite (NO2-), and total nitroso species (RXNO) following oral ingestion of either NO3- rich beetroot juice (BR) or chard gels (GEL) with the associated changes in blood pressure (BP). Repeated samples of venous blood and measurements of BP were collected from nine healthy human volunteers before and after ingestion of the supplements using a cross-over design. Plasma concentrations of RXNO and NO2- were quantified using reductive gas-phase chemiluminescence and NO3- using high pressure liquid ion chromatography. We report that, [NO3-] and [NO2-] were increased and systolic BP reduced to a similar extent in each experimental arm, with considerable inter-individual variation. Intriguingly, there was a greater increase in [RXNO] following ingestion of BR in comparison to GEL, which may be a consequence of its higher polyphenol content. In conclusion, our data suggests that while differences in circulating NO2- and NO3- concentrations after oral administration of distinct NO3--rich supplementation sources are moderate, concentrations of metabolic by-products may show greater-than-expected variability; the significance of the latter observation for the biological effects under study remains to be investigated.

The plasma bioavailability of nitrate and betanin from Beta vulgaris rubra in humans.

PURPOSE: To evaluate the plasma bioavailability of betanin and nitric oxide (NOx) after consuming beetroot juice (BTJ) and whole beetroot (BF). BTJ and BF were also analysed for antioxidant capacity, polyphenol content (TPC) and betalain content. METHODS: Ten healthy males consumed either 250 ml of BTJ, 300 g of BF or a placebo drink, in a randomised, crossover design. Venous plasma samples were collected pre (baseline), 1, 2, 3, 5 and 8 h post-ingestion. Betanin content in BTJ, BF and plasma was analysed with reverse-phase high-performance liquid chromatography (HPLC) and mass spectrometry detection (LCMS). Antioxidant capacity was estimated using the Trolox equivalent antioxidant capacity (TEAC) and polyphenol content using Folin-Ciocalteu colorimetric methods [gallic acid equivalents (GAE)] and betalain content spectrophotometrically. RESULTS: TEAC was 11.4 ± 0.2 mmol/L for BTJ and 3.4 ± 0.4 µmol/g for BF. Both BTJ and BF contained a number of polyphenols (1606.9 ± 151 mg/GAE/L and 1.67 ± 0.1 mg/GAE/g, respectively), betacyanins (68.2 ± 0.4 mg/betanin equivalents/L and 19.6 ± 0.6 mg/betanin equivalents/100 g, respectively) and betaxanthins (41.7 ± 0.7 mg/indicaxanthin equivalents/L and 7.5 ± 0.2 mg/indicaxanthin equivalents/100 g, respectively). Despite high betanin contents in both BTJ (~194 mg) and BF (~66 mg), betanin could not be detected in the plasma at any time point post-ingestion. Plasma NOx was elevated above baseline for 8 h after consuming BTJ and 5 h after BF (P < 0.05). CONCLUSIONS: These data reveal that BTJ and BF are rich in phytonutrients and may provide a useful means of increasing plasma NOx bioavailability. However, betanin, the major betalain in beetroot, showed poor bioavailability in plasma.

A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 2 and 4 Weeks of Twice-Daily Ocular Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma.

PURPOSE: To evaluate the safety and ocular hypotensive efficacy of 4 trabodenoson doses administered twice daily over 14 or 28 days in subjects with ocular hypertension or primary open-angle glaucoma (POAG). METHODS: In this multicenter, randomized, double-masked, placebo-controlled, dose-escalation Phase 2 study, patients received unilateral topical twice-daily trabodenoson (50, 100, or 200 mcg) or placebo for 14 days, or 500 mcg trabodenoson or placebo for 28 days. Ocular and systemic safety and tolerability were assessed by examinations, clinical and laboratory studies. Intraocular pressure (IOP) was assessed using Goldmann tonometry. RESULTS: Trabodenoson was well tolerated; no clinically meaningful ocular or systemic side effects were identified. Trabodenoson produced a dose-dependent IOP reduction. IOP reductions in the 500 mcg group were significantly greater than placebo at all time points at Day 28. Mean IOP reductions from diurnal baseline ranged from -3.5 to -5.0 mmHg with a mean change of -4.1 mmHg in the 500 mcg group compared -1.0 to -2.5 mmHg with a mean change of -1.6 mmHg for the placebo group, and the Day 28 drop was significantly greater than at Day 14 (P = 0.0163) indicating improvement in IOP lowering with longer treatment time. IOP remained significantly reduced 24 h after the final 500 mcg dose (P = 0.048). CONCLUSION: Twice-daily ocular doses of trabodenoson, from 50 to 500 mcg, were well tolerated and showed a dose-related decrease in IOP that was statistically significant and clinically relevant at 500 mcg in patients with ocular hypertension or POAG.

Dietary inorganic nitrate: From villain to hero in metabolic disease?

Historically, inorganic nitrate was believed to be an inert by-product of nitric oxide (NO) metabolism that was readily excreted by the body. Studies utilising doses of nitrate far in excess of dietary and physiological sources reported potentially toxic and carcinogenic effects of the anion. However, nitrate is a significant component of our diets, with the majority of the anion coming from green leafy vegetables, which have been consistently shown to offer protection against obesity, type 2 diabetes and metabolic diseases. The discovery of a metabolic pathway in mammals, in which nitrate is reduced to NO, via nitrite, has warranted a re-examination of the physiological role of this small molecule. Obesity, type 2 diabetes and the metabolic syndrome are associated with a decrease in NO bioavailability. Recent research suggests that the nitrate-nitrite-NO pathway may be harnessed as a therapeutic to supplement circulating NO concentrations, with both anti-obesity and anti-diabetic effects, as well as improving vascular function. In this review, we examine the key studies that have led to the re-evaluation of the physiological function of inorganic nitrate, from toxic and carcinogenic metabolite, to a potentially important and beneficial agent in the treatment of metabolic disease.

Green Alternatives to Nitrates and Nitrites in Meat-based Products-A Review.

Several food additives are added in food for their preservation to maintain the freshness of food (antioxidants) or to slow down or stop the growth of microorganisms (preservative agents). Nitrites and nitrates are used as preservative agents in meat. Nitrites give a smoked taste, a pinkish color in the meat and protect the consumers against the risk of bacterial deterioration. Their addition is however very limited as, in high dose, it can have risks on human health and the environment. Nitrites may also combine with secondary or tertiary amines to form N-nitroso derivatives. Certain N-nitroso compounds have been shown to produce cancers in a wide range of laboratory animals. Thus, alternatives of nitrates and nitrites are the object of numerous research studies. Alternatives, such as the addition of vitamins, fruits, chemicals products, natural products containing nitrite or spices, which have similar properties of nitrites, are in evaluation. In fact, spices are considered to have several organoleptic and anti-microbial properties which would be interesting to study. Several spices and combinations of spices are being progressively evaluated. This review discusses the sources of nitrites and nitrates, their use as additives in food products, their physicochemical properties, their negatives effects and the use of alternatives of nitrites and nitrates in preserving meat products.

Plutonium-DTPA Model Application with USTUR Case 0269.

A plutonium-DTPA (Pu-DTPA) biokinetic model was introduced that had originated from the study of a plutonium-contaminated wound. This work evaluated the extension of the Pu-DTPA model to United States Transuranium and Uranium Registry (USTUR) Case 0269 involving an acute inhalation of a plutonium nitrate aerosol. Chelation was administered intermittently for the first 7 mo as Ca-EDTA, mostly through intravenous injection, with Ca-DTPA treatments administered approximately 2.5 y post intake. Urine and fecal bioassays were collected following intake for several years. Tissues were collected and analyzed for plutonium content approximately 38 y post intake. This work employed the Pu-DTPA model for predicting the urine and fecal bioassay and final tissue quantity at autopsy. The Pu-DTPA model was integrated with two separate plutonium systemic models (i.e., ICRP Publication 67 and its proposed modification). This work illustrated that the Pu-DTPA model was useful for predicting urine and fecal bioassay, including final tissue quantity, 38 y post intake.

Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.

Human tumors exhibit increased glucose uptake and metabolism as a result of high demand for ATP and anabolic substrates and this metabolotype is a negative prognostic indicator for survival. Recent studies have demonstrated that cancer cells from several tissue origins and genetic backgrounds require the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4), a regulatory enzyme that synthesizes an allosteric activator of glycolysis, fructose-2,6-bisphosphate. We report the discovery of a first-in-class PFKFB4 inhibitor, 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate (5MPN), using structure-based virtual computational screening. We find that 5MPN is a selective inhibitor of PFKFB4 that suppresses the glycolysis and proliferation of multiple human cancer cell lines but not non-transformed epithelial cells in vitro. Importantly, 5MPN has high oral bioavailability and per os administration of a non-toxic dose of 5MPN suppresses the glucose metabolism and growth of tumors in mice.

Gastric-sparing nitric oxide-releasable 'true' prodrugs of aspirin and naproxen.

Nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are gaining attention as potentially gastric-sparing NSAIDs. Herein, we report a novel class of '1-(nitrooxy)ethyl ester' group-containing NSAIDS as efficient NO releasing 'true' prodrugs of aspirin and naproxen. While an aspirin prodrug exhibited comparable oral bioavailability and antiplatelet activity (i.e., TXB2 inhibition) to those of aspirin, a naproxen prodrug exhibited better bioavailability than naproxen. These promising NO-NSAIDs protected experimental rats from gastric damage. We therefore believe that these promising NO-NSAIDs could represent a new class of potentially 'Safe NSAIDs' for the treatment of arthritic pain, inflammation and cardiovascular disorders in the case of NO-aspirin.

Increased retention of americium in kidneys as compared with plutonium in an actinide wound contamination model in the rat.

PURPOSE: Americium-241 ((241)Am) presents a potential risk for nuclear industry workers associated with reactor decommissioning and aging combustible materials. The purpose of this study was to investigate Am renal retention after actinide contamination by wounding in the rat. MATERIALS AND METHODS: Anesthetized rats were contaminated with Mixed Oxide (MOX) (7.1% Plutonium [Pu] by mass and containing 27% Am as % total alpha activity), Pu or Am nitrate following an incision wound of the hind leg. Times of euthanasia ranged from 2 hours to 5 months after contamination. Pu and Am levels were quantified following radiochemistry and alpha-spectrophotometry. RESULTS: Initial data show that over the experimental period the proportion of Am in kidneys as a fraction of total kidney alpha activity was elevated as compared to MOX powder indicating a specific retention in this organ. The percentage of Pu was similar to the powder. After MOX contamination, kidney to liver ratios appeared to increase more markedly for Am (from 0.2 at 7 days to 0.6 at 90 days) as compared with Pu (0.1 at 7 days to 0.2 at 90 days). In accordance with tissue actinide retention the dose from Am to the kidney increases with time. For comparison, the ratio of estimated equivalent doses due to Am to kidney is 1.5-fold greater than for Pu (around 90 versus 60 mSv). CONCLUSION: After actinide contamination of wounds, Am is concentrated in the kidneys as compared to Pu leading to potential exposure of renal tissue to both alpha particles and gamma radiation.

The detoxication of nitrate by two antioxidants or a probiotic, and the effects on blood and seminal plasma profiles and reproductive function of New Zealand White rabbit bucks.

Forty-two New Zealand White male rabbits were housed individually in wire cages and randomly distributed among six experimental groups of seven rabbits each, during 16 to 61 weeks of age. There were three main nitrate groups: 0 (tap water), 350 and 700 ppm. Within the 700 ppm of nitrate, there were four subgroups, in which one group was used as control group and the other three groups were supplemented with either 200 ppm of ascorbic acid (vitamin (Vit) C), 200 ppm of Vit E with 0.2 ppm of selenium (Se) and 1000 ppm of probiotic. The nitrate was supplemented as a sodium nitrate. The aim is to test the ability of Vit C and Vit E, Se and probiotic on the deleterious effects (blood and seminal plasma biochemical constituents, semen quality and productive performance) of nitrate in drinking water. Rabbits given nitrate at 700 ppm had significantly lower plasma globulin, red blood cells (RBCs), hemoglobin (Hgb), packed cell volume % (PCV%) and total antioxidant capacity (TAC) than those given the other concentrations of nitrate. Vit C, Vit E with Se and probiotic resulted in significantly (P < 0.05) greater Hgb, RBCs, PCV% and TAC than those of bucks given water supplemented with only 700 ppm nitrate, but the aspartate aminotransferase and alanine aminotransferase concentrations in seminal plasma were lower. Testosterone in the blood plasma and the seminal plasma was significantly (P < 0.05) lower in rabbits given 700 ppm nitrate than in those given other concentrations of nitrate. Vit C, Vit E with Se and the probiotic significantly increased testosterone, fertility, number of offspring and total offspring weight of rabbits sired by bucks supplemented with 700 ppm of nitrate.

Microdistribution and long-term retention of 239Pu (NO3)4 in the respiratory tracts of an acutely exposed plutonium worker and experimental beagle dogs.

The long-term retention of inhaled soluble forms of plutonium raises concerns as to the potential health effects in persons working in nuclear energy or the nuclear weapons program. The distributions of long-term retained inhaled plutonium-nitrate [(239)Pu (NO(3))(4)] deposited in the lungs of an accidentally exposed nuclear worker (Human Case 0269) and in the lungs of experimentally exposed beagle dogs with varying initial lung depositions were determined via autoradiographs of selected histologic lung, lymph node, trachea, and nasal turbinate tissue sections. These studies showed that both the human and dogs had a nonuniform distribution of plutonium throughout the lung tissue. Fibrotic scar tissue effectively encapsulated a portion of the plutonium and prevented its clearance from the body or translocation to other tissues and diminished dose to organ parenchyma. Alpha radiation activity from deposited plutonium in Human Case 0269 was observed primarily along the subpleural regions while no alpha activity was seen in the tracheobronchial lymph nodes of this individual. However, relatively high activity levels in the tracheobronchial lymph nodes of the beagles indicated the lymphatic system was effective in clearing deposited plutonium from the lung tissues. In both the human case and beagle dogs, the appearance of retained plutonium within the respiratory tract was inconsistent with current biokinetic models of clearance for soluble forms of plutonium. Bound plutonium can have a marked effect on the dose to the lungs and subsequent radiation exposure has the potential to increase cancer risk.

A comparison of organic and inorganic nitrates/nitrites.

Although both organic and inorganic nitrates/nitrites mediate their principal effects via nitric oxide, there are many important differences. Inorganic nitrate and nitrite have simple ionic structures and are produced endogenously and are present in the diet, whereas their organic counterparts are far more complex, and, with the exception of ethyl nitrite, are all medicinally synthesised products. These chemical differences underlie the differences in pharmacokinetic properties allowing for different modalities of administration, particularly of organic nitrates, due to the differences in their bioavailability and metabolic profiles. Whilst the enterosalivary circulation is a key pathway for orally ingested inorganic nitrate, preventing an abrupt effect or toxic levels of nitrite and prolonging the effects, this is not used by organic nitrates. The pharmacodynamic differences are even greater; while organic nitrates have potent acute effects causing vasodilation, inorganic nitrite's effects are more subtle and dependent on certain conditions. However, in chronic use, organic nitrates are considerably limited by the development of tolerance and endothelial dysfunction, whereas inorganic nitrate/nitrite may compensate for diminished endothelial function, and tolerance has not been reported. Also, while inorganic nitrate/nitrite has important cytoprotective effects against ischaemia-reperfusion injury, continuous use of organic nitrates may increase injury. While there are concerns that inorganic nitrate/nitrite may induce carcinogenesis, direct evidence of this in humans is lacking. While organic nitrates may continue to dominate the therapeutic arena, this may well change with the increasing recognition of their limitations, and ongoing discovery of beneficial effects and specific advantages of inorganic nitrate/nitrite.

Role of parietal and principal gastric mucosa cells in the phenomenon of concentration of aluminum and indium.

The subcellular behavior of aluminum and indium, used in medical and industrial fields, was studied in the gastric mucosa and the liver after their intragastric administration to rats, using, two of the most sensitive methods of observation and microanalysis, the transmission electron microscopy, and the secondary ion mass spectrometry. The ultrastructural study showed the presence of electron dense deposits, in the lysosomes of parietal and principal gastric mucosa cells but no loaded lysosomes were observed in the different studied hepatic territories. The microanalytical study allowed the identification of the chemical species present in those deposits as aluminum or indium isotopes and the cartography of their distribution. No modification was observed in control rats tissues. In comparison to previous studies describing the mechanism of aluminum concentration in the gastric mucosa and showing that this element was concentrated in the lysosomes of fundic and antral human gastric mucosa, our study provided additional informations about the types of cells involved in the phenomenon of concentration of aluminum and indium, which are the parietal and the principal cells of the gastric mucosa. Our study demonstrated that these cells have the ability to concentrate selectively aluminum and indium in their lysosomes, as a defensive reaction against intoxication by foreign elements.

Cyanosis by methemoglobinemia in tadpoles of Cochranella granulosa (Anura: Centrolenidae)

Tadpoles inhabit generally well oxygenated rivers and streams, nevertheless they were found in areas with limited oxygen availability inside the rivers. To assess this feature, I examined factors that influence centrolenid tadpole behaviour using Cochranella granulosa. The tadpoles were reared in well-oxygenated and hypoxic environments and their development, survivorship and growth were compared. The tadpoles in oxygenated water acquired a pale color, while tadpoles in hypoxic water grew faster and were bright red and more active. In the oxygenated water, the ammonium, which had its origin in the tadpoles’ urine and feces, was oxidized to nitrate. In contrast, in the hypoxic treatment, the nitrogen compounds remained mainly as ammonium. Presumably, the nitrate in oxygenated water was secondarily reduced to nitrite inside the long intestine coils, because all symptoms in the tadpoles point to methemoglobinemia, which can occur when the nitrite passes through the intestine wall into the bloodstream, transforming the hemoglobin into methemoglobin. This could be checked by a blood test where the percentage of methemoglobin was 2.3% in the blood of tadpoles reared in hypoxic condition, while there was a 19.3% level of methemoglobin in the blood of tadpoles reared in oxygenated water. Together with the elevated content of methemoglobin, the growth of the tadpoles was delayed in oxygenated water, which had high nitrate content. The study about quantitative food-uptake showed that the tadpoles benefit more from the food in hypoxic water, although they spent there more energy moving around than the tadpoles living in oxygenated but nitrate-charged water. Rev. Biol. Trop. 58 (4): 1467-1478. Epub 2010 December 01.

Los renacuajos por lo general viven en ríos y arroyos bien oxigenados, sin embargo, como han sido encontrados en áreas con disponibilidad de oxígeno limitada en los ríos, se estudió como influye este factor en su comportamiento. Renacuajos de Cochranella granulosa fueron criados en ambientes bien oxigenados y de hipoxia para comparar su desarrollo, supervivencia y crecimiento. En el agua que no fue cambiada durante al menos un mes, los renacuajos mostraron diferencias en su desarrollo cuando vivían en agua hipóxica u oxigenada. Los renacuajos en el agua aireada tenían un color pálido, mientras que en la hipóxica fueron más activos y de un color rojo brillante. En el agua hipóxica, el nitrógeno que se originó de la orina y las heces de los renacuajos se mantuvo principalmente en forma de amonio; en cambio, el amonio fue oxidado a nitrato en el agua aireada. Presumiblemente, el nitrato en el agua oxigenada se redujo secundariamente a nitrito dentro del intestino, ya que todos los síntomas en los renacuajos que vivían en esta agua apuntaron a una metahemoglobinemia, que se produce cuando el nitrito pasa a través de la pared del intestino a la corriente sanguínea transformando la hemoglobina en metahemoglobina. Esto pudo comprobarse mediante un análisis sanguíneo en donde el porcentaje de metahemoglobina fue del 2.3% en la sangre de los renacuajos criados en condición hipóxica y de un 19.3% de metahemoglobina en aquellos criados en agua aireada. En la misma forma en que la metahemoglobina aumenta en la sangre de los renacuajos que viven en agua oxigenada, su crecimiento disminuye en agua con alto contenido de nitrato. El estudio cuantitativo de la ingestión de nutrientes mostró que el crecimiento de los renacuajos se beneficia más de los alimentos en agua hipóxica, a pesar de que los renacuajos son más activos en sus movimientos que los que viven en agua oxigenada pero cargada de nitratos.