Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis

Carlström, Mattias; Liu, Ming; Yang, Ting; Zollbrecht, Christa; Huang, Liyue; Peleli, Maria; Borniquel, Sara; Kishikawa, Hiroaki; Hezel, Michael; Persson, Anna; Weitzberg, Eddie; Lundberg, Jon O.

doi:10.1089/ars.2013.5481

Cited by 107 publications

(104 citation statements)

References 47 publications

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“…Three weeks of dietary nitrate supplementation in water at 0.1 mmol nitrate/kg bw/day or 1.0 mmol nitrate/kg bw/day to rats increased blood levels of nitrate in a dose‐dependent fashion and to concentrations comparable to those in humans consuming high‐nitrate fruit and vegetables (e.g., 0.1 mmol/kg/d equates to ∼372 mg and 1.0 mmol/kg/d to 3.72 grams, respectively) 9. Dietary nitrate concentrations of ∼0.1 mmol/kg/d in rats have been demonstrated to lower blood pressure 16, and intakes of ∼372 mg total nitrate per day reverse vascular dysfunction in older adult humans 42. Three weeks of dietary nitrate supplementation, a period adequate to observe rapid OVX‐associated bone loss and treatment‐associated effects 43, had no effect on tibial cancellous or cortical bone mass and architecture or histomorphometric indices of bone formation or resorption in OVX rats.…”

Section: Discussionmentioning

confidence: 99%

“…There are two major sources of endogenous NO in the body: the nitric oxide synthase (NOS) system that uses L‐arginine as a substrate and the mammalian nitrate‐nitrite‐NO pathway that uses dietary nitrate and nitrate derived from oxidation of NOS‐derived NO. Under normal conditions, these contribute about equally to NO homeostasis 16. The mammalian nitrate‐nitrite‐NO pathway is involved in the regulation of blood flow and blood pressure, cell signaling, and tissue responses to hypoxia 17.…”

Section: Introductionmentioning

confidence: 99%

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Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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ScopeStudies suggest diets rich in fruit and vegetables reduce bone loss, although the specific compounds responsible are unknown. Substrates for endogenous nitric oxide (NO) production, including organic nitrates and dietary nitrate, may support NO production in age‐related conditions, including osteoporosis. We investigated the capability of dietary nitrate to improve NO bioavailability, reduce bone turnover and loss.Methods and resultsSix‐month‐old Sprague Dawley rats [30 ovariectomized (OVX) and 10 sham‐operated (sham)] were randomized into three groups: (i) vehicle (water) control, (ii) low‐dose nitrate (LDN, 0.1 mmol nitrate/kg bw/day), or (iii) high‐dose nitrate (HDN, 1.0 mmol nitrate/kg bw/day) for three weeks. The sham received vehicle. Serum bone turnover markers; bone mass, mineral density, and quality; histomorphometric parameters; and fecal microbiome were examined. Three weeks of LDN or HDN improved NO bioavailability in a dose‐dependent manner. OVX resulted in cancellous bone loss, increased bone turnover, and fecal microbiome changes. OVX increased relative abundances of Firmicutes and decreased Bacteroideceae and Alcaligenaceae. Nitrate did not affect the skeleton or fecal microbiome.ConclusionThese data indicate that OVX affects the fecal microbiome and that the gut microbiome is associated with bone mass. Three weeks of nitrate supplementation does not slow bone loss or alter the fecal microbiome in OVX.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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“…↓, − indicates inhibition; ↑, +, stimulation; α,β, subunits of sGC; 20-HETE, 20-hydroxyeicosatetraenoic acid; AGE, advanced glycation end-products; AT II, angiotensin II; COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; H 2 S, hydrogen sulfide; LDL, low-density lipoproteins; MLCK, myosin light-chain kinase; NOX, nicotinamide adenine dinucleotide phosphate oxidase; SNO, S-nitrosylation; and XO, xanthine oxidase. by guest on May 10, 2018 http://circres.ahajournals.org/ Downloaded from on eNOS activity are prolonged exposure of the endothelial cells to increased levels of circulating aldosterone (leading to intracellular sodium accumulation thereby interrupting endothelial calcium-dependent signaling), cortisol (downregulating estrogen production), glucose (diverting glucose metabolism to the hexosamine pathway and thus increasing endothelial levels of N-acetylglucosamine which glycosylates eNOS), abnormal HDL (in patients with coronary artery disease), [128][129][130] carbamylated-HDL 125,131 (elevated in patients with end-stage renal disease and characterized by a reduced activity of the HDL-associated antioxidant enzyme paraoxonase I, and downregulating endothelial PI3K expression), high concentrations of dietary nitrate 132 (increasing eNOS phosphorylation at Thr495 and reducing that at Ser1177), the proinflammatory adipokine lipocalin-2 (in patients with obesity), the inflammatory mediator pentraxin 3 133 (activating the NFκB pathway), or progesterone (preventing the beneficial effect of estrogens). 15 Likewise, eNOS dysfunction can be favored by the relative absence of facilitating mediators such as adiponectin, angiotensin [1][2][3][4][5][6][7] (to judge from angiotensin-converting enzyme 2 deletion experiments), or apelin.…”

Section: Reduced Protein Dimerizationmentioning

confidence: 99%

Thirty Years of Saying NO

Vanhoutte

Zhao

et al. 2016

Circulation Research

319

156

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T he historical demonstration by Furchgott and Zawadzki 1 that removal of the endothelium abrogates the in vitro vasodilator effect of acetylcholine has led to the identification 30 years ago of nitric oxide (NO) as a major endogenous local regulator of vascular tone. [2][3][4][5][6][7][8][9][10] When the ability of endothelial cells to produce NO is blunted, the ensuing vascular dysfunction sets the stage for the occurrence of cardiovascular disease in general, and atherosclerosis in particular. [11][12][13][14][15] This review focuses, stepby-step, on the bioavailability (production, action, and disposition) of endothelium-derived NO as local regulator of vascular tone in health and disease. Obviously, there is much more than NO in the control of the degree of contraction of underlying vascular smooth muscle cells exerted by the endothelial cells. Indeed, they generate also prostacyclin and hyperpolarizing signals (initiating endothelium-dependent hyperpolarization [EDH] and thus relaxation) and produce vasoconstrictor mediators (endothelium-derived contracting factors and the peptide endothelin-1); those have been discussed elsewhere in detail. 15-22 Endothelial Sources of NO NO SynthaseThree NO synthase (NOS) isozymes, which are encoded by different genes, catalyze the production of NO from l-arginine: neuronal NOS (or NOS-1), cytokine-inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3).6,23-25 Although iNOS can be induced (by lipopolysaccharides and inflammatory cytokines) and neuronal NOS can be present in the blood vessel

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“…Resting tension of the arteries was set as described previously. 42,43 After stabilization and washout protocols, 1 µmol/L norepinephrine was used to preconstrict mesenteric resistance vessels to obtain a basal tone of ≈50% of its maximal diameter. When the constriction reached a steady-state plateau, sodium nitrite (10 …”

Section: Surgical Procedures and Assessment Of Cardiovascular Responsmentioning

confidence: 99%

Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

et al. 2017

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A n association between chronic use of proton pump inhibitors (PPIs) and increased risk of cardiovascular disease has been implicated. [1][2][3][4][5] For example, it seems that PPIs reduce the efficacy of antiplatelet drugs such as clopidogrel by competing with the hepatic isoenzyme CYP2C19, thereby interfering with its capacity to inhibit platelet aggregation. 6 Other studies have associated chronic use of PPI with increased cardiovascular risk, independently of treatment with clopidogrel 4 or CYP2C19 metabolism. 7,8 In addition, a recent study in diabetic patients indicates that PPIs increase blood pressure. 9 The mechanisms behind these effects are still unclear, but a reduced vascular bioavailability of NO has been suggested. 1 Moreover, it has been speculated that bioactivation of some antiplatelet drugs requires gastric nitrosation under acidic conditions. 10,11 We and others have been studying an alternative NO synthase-independent pathway for NO generation in which inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides in blood and tissues to affect cardiovascular function, including blood pressure.12 Dietary nitrate is absorbed rapidly and is extracted from blood by the salivary glands and greatly concentrated in saliva. In the mouth, commensal bacteria reduce nitrate to the more reactive nitrite anion. Nitrite is then swallowed and enters the acidic stomach where it is nonenzymatically metabolized further to form several potentially bioactive nitrogen oxides, including NO. Orally ingested nitrate clearly has robust NO-like effects systemically, including a decrease in blood pressure, [13][14][15] Abstract-Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg −1), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg −1 min −1 ) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascula...

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Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis

Abstract: These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis.

Cited by 107 publications

References 47 publications

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Thirty Years of Saying NO

Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

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