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Jon O Lundberg - One of the best experts on this subject based on the ideXlab platform.
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nadph oxidase in the renal microvasculature is a primary target for blood pressure lowering effects by inorganic nitrate and Nitrite
Hypertension, 2015Co-Authors: Ting Yang, Jon O Lundberg, Eddie Weitzberg, Maria Peleli, Christa Zollbrecht, Erik A G Persson, Mattias CarlstromAbstract:Renal oxidative stress and nitric oxide (NO) deficiency are key events in hypertension. Stimulation of a nitrate–Nitrite–NO pathway with dietary nitrate reduces blood pressure, but the mechanisms or target organ are not clear. We investigated the hypothesis that inorganic nitrate and Nitrite attenuate reactivity of renal microcirculation and blood pressure responses to angiotensin II (ANG II) by modulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NO bioavailability. Nitrite in the physiological range (10 −7 –10 −5 mol/L) dilated isolated perfused renal afferent arterioles, which were associated with increased NO. Contractions to ANG II (34%) and simultaneous NO synthase inhibition (56%) were attenuated by Nitrite (18% and 26%). In a model of oxidative stress (superoxide dismutase-1 knockouts), abnormal ANG II–mediated arteriolar contractions (90%) were normalized by Nitrite (44%). Mechanistically, effects of Nitrite were abolished by NO scavenger and xanthine oxidase inhibitor, but only partially attenuated by inhibiting soluble guanylyl cyclase. Inhibition of NADPH oxidase with apocynin attenuated ANG II–induced contractility (35%) similar to that of Nitrite. In the presence of Nitrite, no further effect of apocynin was observed, suggesting NADPH oxidase as a possible target. In preglomerular vascular smooth muscle cells and kidney cortex, Nitrite reduced both basal and ANG II–induced NADPH oxidase activity. These effects of Nitrite were also abolished by xanthine oxidase inhibition. Moreover, supplementation with dietary nitrate (10 −2 mol/L) reduced renal NADPH oxidase activity and attenuated ANG II–mediated arteriolar contractions and hypertension (99±2–146±2 mm Hg) compared with placebo (100±3–168±3 mm Hg). In conclusion, these novel findings position NADPH oxidase in the renal microvasculature as a prime target for blood pressure–lowering effects of inorganic nitrate and Nitrite.
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physiological role for nitrate reducing oral bacteria in blood pressure control
Free Radical Biology and Medicine, 2013Co-Authors: Vikas Kapil, Jon O Lundberg, Eddie Weitzberg, Vanessa Pearl, Syed M A Haydar, Amrita AhluwaliaAbstract:Circulating nitrate (NO3−), derived from dietary sources or endogenous nitric oxide production, is extracted from blood by the salivary glands, accumulates in saliva, and is then reduced to Nitrite (NO2−) by the oral microflora. This process has historically been viewed as harmful, because Nitrite can promote formation of potentially carcinogenic N-nitrosamines. More recent research, however, suggests that Nitrite can also serve as a precursor for systemic generation of vasodilatory nitric oxide, and exogenous administration of nitrate reduces blood pressure in humans. However, whether oral nitrate-reducing bacteria participate in “setting” blood pressure is unknown. We investigated whether suppression of the oral microflora affects systemic Nitrite levels and hence blood pressure in healthy individuals. We measured blood pressure (clinic, home, and 24-h ambulatory) in 19 healthy volunteers during an initial 7-day control period followed by a 7-day treatment period with a chlorhexidine-based antiseptic mouthwash. Oral nitrate-reducing capacity and Nitrite levels were measured after each study period. Antiseptic mouthwash treatment reduced oral Nitrite production by 90% (p < 0.001) and plasma Nitrite levels by 25% (p = 0.001) compared to the control period. Systolic and diastolic blood pressure increased by 2–3 .5 mm Hg, increases correlated to a decrease in circulating Nitrite concentrations (r2 = 0.56, p = 0.002). The blood pressure effect appeared within 1 day of disruption of the oral microflora and was sustained during the 7-day mouthwash intervention. These results suggest that the recycling of endogenous nitrate by oral bacteria plays an important role in determination of plasma Nitrite levels and thereby in the physiological control of blood pressure.
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Nitrate and Nitrite in biology, nutrition and therapeutics
Nature Chemical Biology, 2009Co-Authors: Jon O Lundberg, Nathan S Bryan, Mark T Gladwin, Nigel Benjamin, Amrita Ahluwalia, Anthony Butler, Pedro Cabrales, Angela Fago, Martin Feelisch, Peter C FordAbstract:Inorganic nitrate and Nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides. The nitrate-Nitrite-NO pathway is emerging as an important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia. The latest advances in our understanding of the biochemistry, physiology and therapeutics of nitrate, Nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.
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the increase in plasma Nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash
Nitric Oxide, 2008Co-Authors: Mirco Govoni, Emmelie A Jansson, Eddie Weitzberg, Jon O LundbergAbstract:Recent studies surprisingly show that dietary inorganic nitrate, abundant in vegetables, can be metabolized in vivo to form Nitrite and then bioactive nitric oxide. A reduction in blood pressure was recently noted in healthy volunteers after dietary supplementation with nitrate; an effect consistent with formation of vasodilatory nitric oxide. Oral bacteria have been suggested to play a role in bioactivation of nitrate by first reducing it to the more reactive anion Nitrite. In a cross-over designed study in seven healthy volunteers we examined the effects of a commercially available chlorhexidine-containing antibacterial mouthwash on salivary and plasma levels of Nitrite measured after an oral intake of sodium nitrate (10 mg/kg dissolved in water). In the control situation the salivary and plasma levels of nitrate and Nitrite increased greatly after the nitrate load. Rinsing the mouth with the antibacterial mouthwash prior to the nitrate load had no effect on nitrate accumulation in saliva or plasma but abolished its conversion to Nitrite in saliva and markedly attenuated the rise in plasma Nitrite. We conclude that the acute increase in plasma Nitrite seen after a nitrate load is critically dependent on nitrate reduction in the oral cavity by commensal bacteria. The removal of these bacteria with an antibacterial mouthwash will very likely attenuate the NO-dependent biological effects of dietary nitrate.
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the nitrate Nitrite nitric oxide pathway in physiology and therapeutics
Nature Reviews Drug Discovery, 2008Co-Authors: Jon O Lundberg, Eddie Weitzberg, Mark T GladwinAbstract:The supposedly inert end products of endogenous nitric oxide (NO) metabolism — nitrate and Nitrite — have recently been shown to be an important alternative source of NO, complementing the classical NO-synthase pathway. Lundberg and colleagues discuss the emerging role of the nitrate–Nitrite–NO pathway, highlighting the therapeutic potential of nitrate and Nitrite in various disorders, including myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration. The inorganic anions nitrate (NO3−) and Nitrite (NO2−) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism. However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical l-arginine–NO-synthase pathway, in particular in hypoxic states. This Review discusses the emerging important biological functions of the nitrate–Nitrite–NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and Nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration.
Zoltan Mester - One of the best experts on this subject based on the ideXlab platform.
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high precision quadruple isotope dilution method for simultaneous determination of Nitrite and nitrate in seawater by gcms after derivatization with triethyloxonium tetrafluoroborate
Analytica Chimica Acta, 2014Co-Authors: Enea Pagliano, Juris Meija, Zoltan MesterAbstract:Abstract Quadruple isotope dilution mass spectrometry (ID 4 MS) has been applied for simultaneous determination of Nitrite and nitrate in seawater. ID 4 MS allows high-precision measurements and entails the use of isotopic internal standards ( 18 O-Nitrite and 15 N-nitrate). We include a tutorial on ID 4 MS outlining optimal experimental design which generates results with low uncertainties and obviates the need for direct (separate) evaluation of the procedural blank. Nitrite and nitrate detection was achieved using a headspace GCMS procedure based on single-step aqueous derivatization with triethyloxonium tetrafluoroborate at room temperature. In this paper the sample preparation was revised and fundamental aspects of this chemistry are presented. The proposed method has detection limits in the low parts-per-billion for both analytes, is reliable, precise, and has been validated using a seawater certified reference material (MOOS-2). Simplicity of the experimental design, low detection limits, and the use of quadruple isotope dilution makes the present method superior to the state-of-the-art for determination of Nitrite and nitrate, and an ideal candidate for reference measurements of these analytes in seawater.
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quantification of Nitrite and nitrate in seawater by triethyloxonium tetrafluoroborate derivatization headspace spme gc ms
Talanta, 2011Co-Authors: Enea Pagliano, Emanuela Pitzalis, Massimo Onor, Ralph E. Sturgeon, Zoltan Mester, Alessandro DulivoAbstract:Abstract Triethyloxonium tetrafluoroborate derivatization combined with direct headspace (HS) or SPME-gas chromatography–mass spectrometry (GC–MS) is proposed here for the simultaneous determination of Nitrite and nitrate in seawater at micromolar level after conversion to their corresponding volatile ethyl-esters (EtO-NO and EtO-NO2). Isotopically enriched Nitrite [15N] and nitrate [15N] are employed as internal standards and for quantification purposes. HS-GC–MS provided instrumental detection limits of 0.07 μM NO2− and 2 μM NO3−. Validation of the methodology was achieved by determination of Nitrite and nitrate in MOOS-1 (Seawater Certified Reference Material for Nutrients, NRC Canada), yielding results in excellent agreement with certified values. All critical aspects connected with the potential inter-conversion between Nitrite and nitrate (less than 10%) were evaluated and corrected for by the use of the isotopically enriched internal standard.
Jose E Tanussantos - One of the best experts on this subject based on the ideXlab platform.
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gastric s nitrosothiol formation drives the antihypertensive effects of oral sodium Nitrite and nitrate in a rat model of renovascular hypertension
Free Radical Biology and Medicine, 2015Co-Authors: Lucas C Pinheiro, Jefferson H Amaral, Graziele C Ferreira, Rafael L Portella, Carla S Ceron, Marcelo F Montenegro, Jose Carlos Toledo, Jose E TanussantosAbstract: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.
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tempol enhances the antihypertensive effects of sodium Nitrite by mechanisms facilitating Nitrite derived gastric nitric oxide formation
Free Radical Biology and Medicine, 2013Co-Authors: Jefferson H Amaral, Lucas C Pinheiro, Graziele C Ferreira, Marcelo F Montenegro, Rafael P Barroso, Antonio J Costafilho, Jose E TanussantosAbstract:Abstract Orally administered Nitrite exerts antihypertensive effects associated with increased gastric nitric oxide (NO) formation. While reducing agents facilitate NO formation from Nitrite, no previous study has examined whether antioxidants with reducing properties improve the antihypertensive responses to orally administered Nitrite. We hypothesized that TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) could enhance the hypotensive effects of Nitrite in hypertensive rats by exerting antioxidant effects (and enhancing NO bioavailability) and by promoting gastric Nitrite-derived NO generation. The hypotensive effects of intravenous and oral sodium Nitrite were assessed in unanesthetized freely moving rats with L-NAME (Nω-nitro- L- arginine methyl ester; 100 mg/kg; po)-induced hypertension treated with TEMPOL (18 mg/kg; po) or vehicle. While TEMPOL exerted antioxidant effects in hypertensive rats, as revealed by lower plasma 8-isoprostane and vascular reactive oxygen species levels, this antioxidant did not affect the hypotensive responses to intravenous Nitrite. Conversely, TEMPOL enhanced the dose-dependent hypotensive responses to orally administered Nitrite, and this effect was associated with higher increases in plasma Nitrite and lower increases in plasma nitrate concentrations. In vitro experiments using electrochemical and chemiluminescence NO detection under variable pH conditions showed that TEMPOL enhanced Nitrite-derived NO formation, especially at low pH (2.0 to 4.0). TEMPOL signal evaluated by electron paramagnetic resonance decreased when Nitrite was reduced to NO under acidic conditions. Consistent with these findings, increasing gastric pH with omeprazole (30 mg/kg; po) attenuated the hypotensive responses to Nitrite and blunted the enhancement in plasma Nitrite concentrations and hypotensive effects induced by TEMPOL. Nitrite-derived NO formation in vivo was confirmed by using the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (C-PTIO), which blunted the responses to oral Nitrite. Our results showed that TEMPOL promotes Nitrite reduction to NO in the stomach and enhanced plasma Nitrite concentrations and the hypotensive effects of oral sodium Nitrite through mechanisms critically dependent on gastric pH. Interestingly, the effects of TEMPOL on Nitrite-mediated hypotension cannot be explained by increased NO formation in the stomach alone, but rather appear more directly related to increased plasma Nitrite levels and reduced nitrate levels during TEMPOL treatment. This may relate to enhanced Nitrite uptake or reduced nitrate formation from NO or Nitrite.
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increase in gastric ph reduces hypotensive effect of oral sodium Nitrite in rats
Free Radical Biology and Medicine, 2012Co-Authors: Lucas C Pinheiro, Jefferson H Amaral, Graziele C Ferreira, Marcelo F Montenegro, A Oliveira, Jose E TanussantosAbstract:Abstract The new pathway nitrate–Nitrite–nitric oxide (NO) has emerged as a physiological alternative to the classical enzymatic pathway for NO formation from l -arginine. Nitrate is converted to Nitrite by commensal bacteria in the oral cavity and the Nitrite formed is then swallowed and reduced to NO under the acidic conditions of the stomach. In this study, we tested the hypothesis that increases in gastric pH caused by omeprazole could decrease the hypotensive effect of oral sodium Nitrite. We assessed the effects of omeprazole treatment on the acute hypotensive effects produced by sodium Nitrite in normotensive and L-NAME-hypertensive free-moving rats. In addition, we assessed the changes in gastric pH and plasma levels of Nitrite, NO x (nitrate+Nitrite), and S -nitrosothiols caused by treatments. We found that the increases in gastric pH induced by omeprazole significantly reduced the hypotensive effects of sodium Nitrite in both normotensive and L-NAME-hypertensive rats. This effect of omeprazole was associated with no significant differences in plasma Nitrite, NO x , or S -nitrosothiol levels. Our results suggest that part of the hypotensive effects of oral sodium Nitrite may be due to its conversion to NO in the acidified environment of the stomach. The increase in gastric pH induced by treatment with omeprazole blunts part of the beneficial cardiovascular effects of dietary nitrate and Nitrite.
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sodium Nitrite downregulates vascular nadph oxidase and exerts antihypertensive effects in hypertension
Free Radical Biology and Medicine, 2011Co-Authors: Marcelo F Montenegro, Lucas C Pinheiro, Jefferson H Amaral, Graziele C Ferreira, Eliana K Sakamoto, Rosana I Reis, Diogo M O Marcal, Romaiana Picada Pereira, Jose E TanussantosAbstract:Dietary Nitrite and nitrate are important sources of nitric oxide (NO). However, the use of Nitrite as an antihypertensive drug may be limited by increased oxidative stress associated with hypertension. We evaluated the antihypertensive effects of sodium Nitrite given in drinking water for 4 weeks in two-kidney one-clip (2K1C) hypertensive rats and the effects induced by Nitrite on NO bioavailability and oxidative stress. We found that, even under the increased oxidative stress conditions present in 2K1C hypertension, Nitrite reduced systolic blood pressure in a dose-dependent manner. Whereas treatment with Nitrite did not significantly change plasma Nitrite concentrations in 2K1C rats, it increased plasma nitrate levels significantly. Surprisingly, Nitrite treatment exerted antioxidant effects in both hypertensive and sham-normotensive control rats. A series of in vitro experiments was carried out to show that the antioxidant effects induced by Nitrite do not involve direct antioxidant effects or xanthine oxidase activity inhibition. Conversely, Nitrite decreased vascular NADPH oxidase activity. Taken together, our results show for the first time that Nitrite has antihypertensive effects in 2K1C hypertensive rats, which may be due to its antioxidant properties resulting from vascular NADPH oxidase activity inhibition.
Enea Pagliano - One of the best experts on this subject based on the ideXlab platform.
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high precision quadruple isotope dilution method for simultaneous determination of Nitrite and nitrate in seawater by gcms after derivatization with triethyloxonium tetrafluoroborate
Analytica Chimica Acta, 2014Co-Authors: Enea Pagliano, Juris Meija, Zoltan MesterAbstract:Abstract Quadruple isotope dilution mass spectrometry (ID 4 MS) has been applied for simultaneous determination of Nitrite and nitrate in seawater. ID 4 MS allows high-precision measurements and entails the use of isotopic internal standards ( 18 O-Nitrite and 15 N-nitrate). We include a tutorial on ID 4 MS outlining optimal experimental design which generates results with low uncertainties and obviates the need for direct (separate) evaluation of the procedural blank. Nitrite and nitrate detection was achieved using a headspace GCMS procedure based on single-step aqueous derivatization with triethyloxonium tetrafluoroborate at room temperature. In this paper the sample preparation was revised and fundamental aspects of this chemistry are presented. The proposed method has detection limits in the low parts-per-billion for both analytes, is reliable, precise, and has been validated using a seawater certified reference material (MOOS-2). Simplicity of the experimental design, low detection limits, and the use of quadruple isotope dilution makes the present method superior to the state-of-the-art for determination of Nitrite and nitrate, and an ideal candidate for reference measurements of these analytes in seawater.
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quantification of Nitrite and nitrate in seawater by triethyloxonium tetrafluoroborate derivatization headspace spme gc ms
Talanta, 2011Co-Authors: Enea Pagliano, Emanuela Pitzalis, Massimo Onor, Ralph E. Sturgeon, Zoltan Mester, Alessandro DulivoAbstract:Abstract Triethyloxonium tetrafluoroborate derivatization combined with direct headspace (HS) or SPME-gas chromatography–mass spectrometry (GC–MS) is proposed here for the simultaneous determination of Nitrite and nitrate in seawater at micromolar level after conversion to their corresponding volatile ethyl-esters (EtO-NO and EtO-NO2). Isotopically enriched Nitrite [15N] and nitrate [15N] are employed as internal standards and for quantification purposes. HS-GC–MS provided instrumental detection limits of 0.07 μM NO2− and 2 μM NO3−. Validation of the methodology was achieved by determination of Nitrite and nitrate in MOOS-1 (Seawater Certified Reference Material for Nutrients, NRC Canada), yielding results in excellent agreement with certified values. All critical aspects connected with the potential inter-conversion between Nitrite and nitrate (less than 10%) were evaluated and corrected for by the use of the isotopically enriched internal standard.
F Gotz - One of the best experts on this subject based on the ideXlab platform.
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the nitrate reductase and Nitrite reductase operons and the nart gene of staphylococcus carnosus are positively controlled by the novel two component system nrebc
Journal of Bacteriology, 2002Co-Authors: Iris Fedtke, A Kamps, B Krismer, F GotzAbstract:In Staphylococcus carnosus, the nreABC (for nitrogen regulation) genes were identified and shown to link the nitrate reductase operon (narGHJI) and the putative nitrate transporter gene narT. An nreABC deletion mutant, m1, was dramatically affected in nitrate and Nitrite reduction and growth. Transcription of narT, narGHJI, and the Nitrite reductase (nir) operon was severely reduced even when cells were cultivated anaerobically without nitrate or Nitrite. nreABC transcripts were detected when cells were grown aerobically or anaerobically with or without nitrate or Nitrite. NreA is a GAF domain-containing protein of unknown function. In vivo and in vitro studies showed that NreC is phosphorylated by NreB and that phospho-NreC specifically binds to a GC-rich palindromic sequence to enhance transcription initiation. This binding motif was found at the narGHJI, nir, and narT promoters but not at the moeB promoter. NreB is a cytosolic protein with four N-terminal cysteine residues. The second cysteine residue was shown to be important for NreB function. In vitro autophosphorylation of NreB was not affected by nitrate, Nitrite, or molybdate. The nir promoter activity was iron dependent. The data provide evidence for a global regulatory system important for aerobic and anaerobic metabolism, with NreB and NreC forming a classical two-component system and NreB acting as a sensor protein with oxygen as the effector molecule.
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physiology and interaction of nitrate and Nitrite reduction in staphylococcus carnosus
Journal of Bacteriology, 1996Co-Authors: H Neubauer, F GotzAbstract:Staphylococcus carnosus reduces nitrate to ammonia in two steps. (i) Nitrate was taken up and reduced to Nitrite, and Nitrite was subsequently excreted. (ii) After depletion of nitrate, the accumulated Nitrite was imported and reduced to ammonia, which again accumulated in the medium. The localization, energy gain, and induction of the nitrate and Nitrite reductases in S. carnosus were characterized. Nitrate reductase seems to be a membrane-bound enzyme involved in respiratory energy conservation, whereas Nitrite reductase seems to be a cytosolic enzyme involved in NADH reoxidation. Syntheses of both enzymes are inhibited by oxygen and induced to greater or lesser degrees by nitrate or Nitrite, respectively. In whole cells, Nitrite reduction is inhibited by nitrate and also by high concentrations of Nitrite (> or = 10 mM). Nitrite did not influence nitrate reduction. Two possible mechanisms for the inhibition of Nitrite reduction by nitrate that are not mutually exclusive are discussed. (i) Competition for NADH nitrate reductase is expected to oxidize the bulk of the NADH because of its higher specific activity. (ii) The high rate of nitrate reduction could lead to an internal accumulation of Nitrite, possibly the result of a less efficient Nitrite reduction or export. So far, we have no evidence for the presence of other dissimilatory or assimilatory nitrate or Nitrite reductases in S. carnosus.
